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Philosophies | Free Full-Text | The Alphabet Effect Re-Visited, McLuhan Reversals and Complexity Theory
The alphabet effect that showed that codified law, alphabetic writing, monotheism, abstract science and deductive logic are interlinked, first proposed by McLuhan and Logan (1977), is revisited. Marshall and Eric McLuhan’s (1988) insight that alphabetic writing led to the separation of figure and ground and their interplay, as well as the emergence of visual space, are reviewed and shown to be two additional effects of the alphabet. We then identify more additional new components of the alphabet effect by demonstrating that alphabetic writing also gave rise to (1) Duality, and (2) reductionism or the linear sequential relationship of causes followed by effects. We then review McLuhan’s (1962) claim that electrically configured information reversed the dominance of visual space over acoustic space and led to the reversals of (1) cause and effect, and (2) figure and ground. We then demonstrate that General System Theory first formulated by Ludwig von Bertalanffy (1968), which also includes chaos theory, complexity theory and emergence (aka emergent dynamics) and Jakob von Uexküll’s (1926) notion of umwelt also entail the reversal of many aspects of the alphabet effect such as the reversals of (1) cause and effect, and (2) figure and ground.
The Alphabet Effect Re-Visited, McLuhan Reversals and Complexity Theory
by Robert K. Logan
Department of Physics, University of Toronto, 60 St. George, Toronto, ON M5S 1A7, Canada
Philosophies 2017 , 2 (1), 2; https://doi.org/10.3390/philosophies2010002
Received: 2 November 2016 / Revised: 14 December 2016 / Accepted: 22 December 2016 / Published: 3 January 2017
(This article belongs to the Special Issue The Philosophy of and the Philosophical Roots of Marshall McLuhan and the Media Ecology School )
Abstract
:
The alphabet effect that showed that codified law, alphabetic writing, monotheism, abstract science and deductive logic are interlinked, first proposed by McLuhan and Logan (1977), is revisited. Marshall and Eric McLuhan’s (1988) insight that alphabetic writing led to the separation of figure and ground and their interplay, as well as the emergence of visual space, are reviewed and shown to be two additional effects of the alphabet. We then identify more additional new components of the alphabet effect by demonstrating that alphabetic writing also gave rise to (1) Duality, and (2) reductionism or the linear sequential relationship of causes followed by effects. We then review McLuhan’s (1962) claim that electrically configured information reversed the dominance of visual space over acoustic space and led to the reversals of (1) cause and effect, and (2) figure and ground. We then demonstrate that General System Theory first formulated by Ludwig von Bertalanffy (1968), which also includes chaos theory, complexity theory and emergence (aka emergent dynamics) and Jakob von Uexküll’s (1926) notion of umwelt also entail the reversal of many aspects of the alphabet effect such as the reversals of (1) cause and effect, and (2) figure and ground.
Keywords:
alphabet effect
;
figure
;
ground
;
alphabet
;
science
;
logic
;
1. Origin of the Alphabet Effect
McLuhan and Logan (1977) [
1
] in a paper entitled Alphabet, Mother of Invention suggested that the alphabet explains why Western thought patterns are highly abstract, compared with Eastern thought. They pointed out that there developed in the very narrow geographic zone between the Tigris-Euphrates river system and the Aegean Sea, and within the very narrow time frame between 2000 B.C. and 500 B.C. a group of innovations that constitute the basis of Western thought. These innovations included the phonetic alphabet first invented by the Seirties or Kennites living in the South Sinai desert, codified law developed by the Babylonians, monotheism inaugurated by the Hebrews, abstract theoretical science and deductive logic first introduced by the ancient Greeks. McLuhan and Logan did not suggest a direct causal connection between these innovations. Instead they suggested that that these innovations created an environment that supported their mutual development, given that these cultures, which gave rise to these developments, were in direct communication and traded with each other.
2. The Emergence of Visual Space and the Detachment of Figure and Ground and Their Interplay
Eric and Marshall McLuhan (1988) [ 2 ] (pp. 18–19) identified another effect of the alphabet namely the emergence of visual space and the subsequent detachment of figure and ground in which the figure comes into greater prominence and the ground receded to the point that it becomes subliminal (Lior Lerman private communication) [ 3 ].
The most remarkable quality of the alphabet is its abstractness of various kinds. From the patterns of separation, of ensibilities, and of figure from ground, with the subsequent suppression of ground, comes the character of stasis, one of the four features of visual space. When figure and ground are in interplay, they are in dynamic relation, continually modifying each other. Thus, stasis of the figures can only be achieved by detaching them from their ground, and is the necessary result of detachment. The sounds and sign of the phonetic alphabet are in no dynamic relation or interplay; one simply stands for the other. Both are abstracted from all meaning or relation. Oral, resonant speech is broken into irreducible (uniform) bits of meaningless sound, each connected to a sign by arbitrary association, and by uniform orthography. By means of a continuous linear sequence of signs, the bare sounds that compose speech are re-presented and re-cognized through a single sense in isolation. From this static, connected figure-detached-from-ground character, the alphabet derives its other great power of abstraction, that of translating into itself (as an abstract, unmodified/unmodifying container) the sound-systems of other languages.
] (p. 5) still claim that nevertheless figure and ground interact with each other:
All situations comprise an area of attention (figure) and a very much larger area of inattention (ground). The two continually coerce and play with each other across a common outline or boundary or interval that serves to define both simultaneously. The shape of one conforms exactly to the shape of the other. Figures rise out of, and recede back into, ground, which is con-figurational and comprises all other available figures at once…In the order of things, ground comes first and the figures emerge later. ‘Coming events cast their shadows before them’. The ground of any technology or artefact is both the situation that gives rise to it and the whole environment (medium) of services and disservices that it brings into play.
3. Figure/Ground: Cracking the McLuhan Code
The relationship of figure and ground and their interplay is a recurring and central theme of Marshall McLuhan’s understanding of media as pointed out by Logan (2011) [
4
] in an article entitled “Figure/Ground: Cracking the McLuhan Code”, where it is argued when McLuhan compares the following couplets one is the figure and the other is the ground:
In the reversal of cause and effect it is the effect that is the ground and the cause that is the figure…
In the relationship of jobs and roles it is the role that is the ground and the job that is the figure. ‘Goal seeking’ is figure and ‘role-playing’ is ground;
In the consideration of percepts and concepts it is the percept that is the ground and the concept that is the figure;
In ‘the medium is the message’ it is the medium that is the ground and the message or content that is the figure;
In ‘the user is the content’ it is the user that is the ground and the content that is the figure;
In ‘every technology has both service and disservice’ it is the disservice that is the ground and the service that is the figure;
In ‘products become services in the electric age’ it is the service that is the ground and the product that is the figure;
In ‘consumers become producers in the electric age’ it is the consumer that is the ground and the producer that is the figure;
In contrasting a point of view with pattern recognition it is the pattern recognition that is the ground and the point of view that is the figure.
In each of these figure/ground relationships the interactions between figure and ground are exactly as they were described in the previous section, namely that they “are in interplay, they are in dynamic relation, continually modifying each other [ 2 ] (p. 18)”.
4. Alphabet, Deductive Logic, Duality and Reductionism
We would like to propose another effect of the alphabet in addition to the ones identified by McLuhan, M. and Logan (1977) [
1
] and McLuhan, M. and E. (1988) [
2
]. We suggest that another effect of the alphabet was to give rise to a form of duality, that is characteristic of Western alphabetic culture, namely constitutional duality. Before establishing this connection, we need to differentiate between the different forms of duality. There is binary dualism such as distinguishing between being and non-being as in deductive logic, it is a duality which arises out of grammatical necessity. There is also a closely related duality, polarity duality, of opposites such up and down; left and right; forward and backward; hot and cold; good and evil; light and dark; and yin and yang. There is also constitutional dualism as (1) mind and body in the context of the philosophy of mind; (2) God and his creations or the physical universe; and (3) material reality and spiritual reality as described in many religions. Binary and constitutional duality are characteristic of Western alphabetic cultures. The third duality of polarity is found in all cultures. An example of polar dualities is the notion of yin and yang of Taoism found in many East Asian non-alphabetic cultures. Yin and yang are seemingly opposite but yet at the same time they are complementary, interconnected and interdependent. The very graphic design of yin and yang as represented in Taoism represents the intertwining of yin and yang as represented in this image:
In Western binary and constitutional duality, the boundaries are impermeable and the two poles of the dual relationship are quite independent of each other unlike the relationship of yin and yang.
We believe that binary and compositional forms of Western dualism are interconnected and are the effect of alphabetic writing. Binary duality is an absolute presupposition of deductive logic and deductive logic is one of the effects of alphabetic writing as noted by McLuhan and Logan (1977) [ 1 ].
The connection between the alphabet, binary duality and constitutional duality is not a direct one but one that can be established if one first accepts that there is a connection between the alphabet and deductive logic as argued by McLuhan and Logan (1977) [
1
]. Alphabetic writing encouraged the development of deductive logic because the alphabet promotes representing spoken words with a linear combination of meaningless visual signs representing phonemes assembled in the correct order. Every spoken word is first analyzed into its constituent phonemes and then those phonemes are represented by the meaningless signs of the alphabet and arranged in a logical order. This created an environment in which arguments were assembled in a similar linear sequential logical order. Rationality trumped poetics and so the arguments of the sophists were looked down on because they appealed to the emotions rather than the cold hard facts of a logical argument.
The pervasive use of uniform elements, the phonetic letters that the alphabet entailed, encouraged the additional visual matching of situational elements which formed the ground for Greek logic, geometry, and rationality. The idea of truth itself, the correspondence of thing and intellect, is based on matching…The Greek alphabet also provided both the model and the bias for classification, an essential development in Greek analytic thought during the period from 700 to 400 B.C.—especially for logic, science, and history. In addition to serving as a paradigm of abstraction and classification, the alphabet also served as a model for division and separatability. [
1
]
The Greeks applied the use of logic to create proofs of the geometric relationships that the Egyptians arrived at empirically. They were bedazzled with their new found technology of deductive logic to the point that a separation of rationality from common sense took place. It started with Parmenides who used logic to argue that nothing changes because if A were to change into B, then A would not-be and since non-being cannot be (it is a logical contradiction) nothing changes. Parmenides argument used a form of duality that entails a binary either or division but then he uses deductive logic to conclude that nothing changes and hence laid the ground work for the emergence of substance/essence dualism, a form of constitutional dualism formulated by Plato.
The idea that nothing changes was clearly in contradiction to the common sense observation of the changes in one’s everyday experiences. Plato found a way to resolve this apparent paradox and the solution was to invoke a form of substance/essence dualism and thereby created two worlds. There is the essence world of the Ideal Forms that are never changing as Parmenides required and the everyday substance world that one perceives in everyday life, which Plato likened to shadows on the wall of a cave cast by the fire burning within the cave and do change as common sense reveals and demands. Plato took his cue from Parmenides who wrote “Whence it follows that all things to which men attribute reality, generation and destruction, being and not-being, change of place, alteration of colour are no more than empty words (
http://philoctetes.free.fr/parmenides.htm
) [
5
]”.
Plato with help from Parmenides separates percepts from concepts and this dualism becomes enshrined in Western philosophical thought. Parmenides version of binary dualism and his use of deductive logic led to Plato’s constitutional dualism of the world of Ideal Forms and the everyday world of perceptions. These two domains are not opposites just as mind and body are not opposites in mind/body dualism. But what is being suggested here is that Plato’s constitutional dualism resolved the paradox that there is no change in Parmenides world whereas change is the pervasive property of the world of every day experience.
Parmenides and Plato’s dualities had the unfortunate effect of killing off the empirical spirit of the pre-Socratics like Anaxagoras, Anaximander and Heraclitus. Heraclitus proclaimed “The things of which there can be sight, hearing and learning—these are what I especially prized (the very opposite of Parmenides’ position). Men who love wisdom should acquaint themselves with a great many particulars. Seekers after gold dig up much earth and find little”. Anaxagoras having observed that meteorites that came from heaven were made of rocks concluded that heavenly bodies were also composed of rocks. Anaximander on the basis of observing the gills on a miscarried human fetus argued for evolution more than 2000 years before Darwin. The empirical spirit of the pre-Socratics was undermined by the logical arguments of Parmenides and Plato. Even Aristotle contributed to the undermining of empiricism. He argued against inertia saying that an object dropped from the mast of a ship would fall behind the mast in the opposite direction of the ship’s motion. If he only had climbed to the top of a mast and performed the experiment or asked a mariner to do it he would have discovered that his argument was wrong. These were the roots of the duality that divided the world into two spheres, the one perceived and the one conceived.
The tradition of duality even survived the scientific revolution and empirical spirit of Galileo, Borelli, Brahe, Kepler and Newton. Descartes, himself a mathematician and scientist, whose development of analytic geometry led to Newton’s calculus, divided the world into two domains the material and the spiritual. Cartesian duality paralleled Plato’s division of the two realms, the material world of every day experience and the realm of Ideal Forms. Like Parmenides who wanted to have an unchanging element in his worldview, Descartes divided the ever changing material world from the spiritual world of Mind, Soul and God and this contributed to the mind-body problem that persists to this day.
Another effect of alphabetic writing and deductive logic is the notion of the linear chain of cause and effect and hence reductionism, whereby all phenomena can be reduced to a simpler or more basic one implying that the whole is merely the sum of its parts just as the alphabet reduces all words to their basic phonemes.
5. The Reversal of the Alphabet Effects
As McLuhan (1962) [ 6 ] long ago pointed out with electrically configured information the dominance of visual space wanes giving rise to the re-emergence of acoustic space and tribal sensibilities. He suggested that with electrically configured information, the reversal of the alphabet effects of: (1) Duality; (2) Reductionism; (3) the suppression of ground; and (4) the dominance of linear cause and effect thinking, would begin to take hold.
He noted that, “The electric implosion now brings oral and tribal ear-culture to the literate West… [The] very much greater speedup, such as occurs with electricity, may serve to restore a tribal pattern of intense involvement [ 6 ] (pp. 38 & 58)”. McLuhan refers to the radio as the tribal drum with the power to “retribalize mankind, [with] its almost instant reversal of individualism into collectivism, Fascism or Marxism [ 6 ] (p. 265)”.
The separation of figure and ground that alphabetic writing gave rise to also began to reverse with electrically configured information. McLuhan for one reversed the role of figure and ground in his analysis of the effects of media and technology. He wrote:
My writings baffle most people simply because I begin with ground and they begin with figure. I begin with effects and work round to the causes , whereas the conventional pattern is to start with a somewhat arbitrary selection of ‘causes’ and then try to match these with some of the effects. It is this haphazard matching process that leads to fragmentary superficiality. As for myself, I do not have a point of view, but simply work with the total situation as obvious figures against hidden ground . [ 7 ] (p. 478)
The idea of reversal is a key to cracking the McLuhan Code, i.e. to make sense of the special way he used phrases like figure/ground and reversal. He worked backwards from effects to their causes and from the ground or environment of media to the figure of their content. He used this technique to understand the future. He once wrote, “We look at the present through a rear view mirror. We march backwards into the future”. Rather than focusing on the figure of the future through speculating he carefully studied the ground of the future, which is the present and the past. He said, “I’ve always been very careful never to predict anything that had not already happened [
8
] (p. 172)”.
McLuhan (1962) [ 6 ] wrote about the reversal of cause and effect as early as 1962 in Understanding Media. Another aspect of the alphabet effect was the consideration of the linear sequence of cause followed by effect which McLuhan observed to have been reversed.
The Nemesis of Creativity…
N. Whitehead… explained how the great discovery of the nineteenth century was the discovery of the technique of discovery. Namely, the technique of starting with the thing to be discovered and working back, step by step, as on an assembly line, to the point at which it is necessary to start in order to reach the desired object. In the arts this meant starting with the effect and then inventing a poem, painting, or building that would have just that effect and no other. [ 6 ] (p. 68)
McLuhan employed the same techniques in his analysis of the effects of technology: “The way to study the effects, for example, if you wanted to study what the motor car was, you might find out more from what it did to the environment and the community [ 8 ] (p. 90)”.
6. The Reversal of the Alphabet Effects in the Sciences
The reversals of cause and effect and figure and ground signaled by McLuhan also began to happen in the world of science with the General Systems Theory of Ludwig von Bertalanffy (1968) [ 9 ], von Uexküll’s (1926) [ 10 ] introduction of the umwelt for living organisms as well as the formulation of complexity, chaos and emergence theories. McLuhan read von Bertalanffy and von Bertalanffy read McLuhan. Each was aware of the other’s work. We are not suggesting that there was a direct causal relationship in their work. It is just that each found the other’s work reinforced their own ideas.
The next set of examples of reversals of the alphabet effect in science took place largely after McLuhan’s death in 1980, so they had no influence on him and, for the most part, the work of these scientists were not influenced by McLuhan’s work either, but as we shall demonstrate there was a certain parallel between their work and his.
Von Bertalanffy’s General Systems, complexity theory, chaos theory and emergence are closely related in that in each of these approaches there exists a supervenient system whose properties are not the product or sum of the properties of the components of that supervenient system, but are a result of the interactions of the components among themselves and with the system as a whole. We will show that the description of supervenient or emergent systems incorporates the reversal of the following: cause and effect, reductionism, the separation of figure and ground, and visual space, each a product of the alphabet effect.
An example of a supervenient or emergent system to those not familiar with the notion is a human being who is composed of billions of cells. The properties of the human being as a whole are not just the properties of his or her cells but the way those cells are organized and the way those cells interact with each other which are controlled by the needs of the human being as a whole.
The human being’s needs cause (top down) the cells to behave as they do while at the same time the cells cause (bottom up) the human being to behave as he or she does. One cannot identify the causes and the effects of the supervenient system and its components nor can one separate the causes from the effects or the effects from the causes. The supervenient system as a whole and its components relate to each other as both cause and effect and hence we have a reversal of cause and effect just as McLuhan suggested. The reason for the claim of a reversal of cause and effect within supervenient systems is that it is not possible to separate the bottom up causality of the components creating the system from the top down causality of the system acting on and controlling its components. The top down and bottom up causalities are simultaneous and cannot be separated into a linear sequential chain of one cause resulting in one effect. The space in which the supervenient or emergent system operates is metaphorically acoustic space because the effects are coming from all directions at once, both from bottom up and from top down.
One also cannot separate figure from ground. The organs, the cells, the human organism as a system cannot be divided into a figure and a ground. Is the figure the whole human and the ground the cells or the organs? Or with a focus on the organs of the human body are the organs the figure and the ground is the cells? None of these divisions make sense. The supervenient system is both figure and ground and its components are also figure and ground. The figure of the system is the ground for the components and the figure of the components are the ground for the system. The figure and ground are not only reversed they are actually obliterated. One cannot separate the top down causality of the human system on its organs and cells from the bottom up causality of the organs and cells on the whole human. The system and its components are interlinked and the components among themselves are also interlinked and the system as a whole and its components are in interplay with each other. This interplay of the system and its components is very much like the description of the interaction and interplay of figure and ground that M. and E. McLuhan (1988) [
2
] (p. 5) described and which we quoted above.
Jakob von Uexküll (1926) [
10
] introduced the notion of the umwelt of an organism, which is that part of the environment that an organism interacts with in order to survive. Here we have another example of the interplay of figure and ground characteristic of acoustic space. The umwelt is that part of the general environment or ground in which the figure of the living organism operates. There must be an umwelt for an organism to exist and there must be an organism for an umwelt to exist or for that umwelt to be defined. The umwelt creates the organism by providing the resources it needs to survive and the organism creates the umwelt in the sense without the organism there would not be an umwelt. The figure of the organism and its umwelt or ground in which it operates are in a dynamic interplay with each other.
Another approach that incorporates the reversal of cause and effect and hence the reversal of the alphabet effect is the Process Ecology approach of Robert Ulanowicz (2009) [
11
] described in his book,
A Third Window: Natural Life Beyond Newton and Darwin
. “Process ecology” is a way of explaining in a non-reductive terms the origins of life, the behavior of the ecosystems of living organisms and emergent processes in general. Process ecology is the third window for Ulanowicz superseding the first window of Newton’s physics, which is time reversal invariant and universal and the second window of Darwinian evolution, which introduces history as a factor in the evolution of the species. Darwin retains elements of Newton especially in his approach to species that he deals with as though they are static.
Ulanowicz (2009) [
11
] (pp. 74–75) specifically introduces the notion of the reversal of cause and effect in the following passage:
A configuration of processes can, as a whole, strongly affect which objects remain in the system and which pass from the scene. This observation, inverts to a degree, the conventional wisdom that it is objects that direct processes. The processes, as a union, make a palpable contribution toward the creation of their constituent elements. This reversal of causal influence lies at the crux of process ecology, and it extirpates the Newtonian stricture of closure.
Reductionists under the spell of the alphabet effect fully embrace deductive logic and this explains why they are unable to deal with process ecology and systems in which cause and effect do not follow a linear one thing at a time process as is the case with alphabetic writing. It is not the case that with the reversal of cause and effect that we are abandoning the notion that cause and effect operate, rather we embrace the obvious idea that causes and effects are non-linear. The effect of each cause has an effect back on the cause that created it. Cause A that creates an Effect B, and is then acted upon by the Effect B which changes A which changes B once again, which Changes A again and so on and so forth. This is a form of binary duality (Lior Lerman private communication) [
3
].
7. Conclusions
The alphabet effect has been revisited in light of the new patterns that emerge when the figure of the alphabet is viewed in the ground of the new digital environment. The pattern of human thought that emerges in the age of electric and digital information is quite different than the pattern of human thought when the alphabet and movable type print alone dominated the communication of information. We are not suggesting that there is a causal connection between media and the forms of human thought less we be accused of being technological determinists. We do maintain, however, that whatever the mechanism is, that the parallel of the patterns of media dynamics, on the one hand and human thought and their organization of information, on the other hand, is quite striking. Media effect the thoughts of their users and the thoughts of their users effect the media they use in a non-linear way as has been described in General Systems Theory; in chaos, complexity and emergence theory; in Ulanowicz’z process ecology; and in McLuhan’s media ecology.
Acknowledgments
I want to thank Lior Lerman for her contribution to this article which would not have been written if I had not spoken with her at the Media Ecology Association conference in Bologna. Her insights into the nature of the alphabet effect have been incorporated here and cited as private communication.
Conflicts of Interest
The authors declare no conflict of interest.
References
McLuhan, M.; Logan, R.K. Alphabet, Mother of Invention. Et Cetera 1977 , 34 , 373–383. [ Google Scholar ]
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McLuhan, M. The Gutenberg Galaxy ; University of Toronto Press: Toronto, ON, Canada, 1962. [ Google Scholar ]
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McLuhan, M.; McLuhan, S.; Staines, D. Understanding Me: Lectures and Interviews ; McClelland and Stewart: Toronto, ON, Canada, 2003. [ Google Scholar ]
Von Bertalanffy, L. General Systems Theory: Foundations, Development, Applications ; George Braziller: New York, NY, USA, 1968. [ Google Scholar ]
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AMA Style
Logan RK. The Alphabet Effect Re-Visited, McLuhan Reversals and Complexity Theory. Philosophies. 2017; 2(1):2.
https://doi.org/10.3390/philosophies2010002
Chicago/Turabian Style
Logan, Robert K. 2017. "The Alphabet Effect Re-Visited, McLuhan Reversals and Complexity Theory" Philosophies2, no. 1: 2.
https://doi.org/10.3390/philosophies2010002
| https://www.mdpi.com/2409-9287/2/1/2/html |
Issa warns taxpayers’ loss on Solyndra loan may near $850 million | The Hill
The House Oversight Committee chairman claims lost tax revenue could also drive up cost of similar loan to Fisker Automotive.
Issa warns taxpayers’ loss on Solyndra loan may near $850 million
House Oversight and Government Reform Committee Chairman Darrell Issa (R-Calif.) on Monday charged that the controversial loan to the failed solar-panel maker Solyndra could lead to hundreds of millions of dollars in lost tax revenue for the government — pushing the total cost far beyond the $535 million already incurred when the company went bankrupt.
{mosads}Issa wrote Energy Secretary Steven Chu to ask for details about the tax implications of that loan, in the wake of reports that the tax losses from Solyndra could be as high as $341 million.
He summed up the Solyndra situation by saying the combination of loan and tax losses could put the real taxpayer cost of Solyndra at $849 million.
In addition, Issa asked Chu to explain whether a $529 million loan to a California auto company poses a similar risk of tax losses.
Fisker Automotive received that loan in 2010 under the Advanced Technology Vehicles Manufacturing (ATVM) Program. Fisker has only used $193 million of its $528 million loan so far.
“As the Committee continues to conduct oversight on Fisker’s ATVM loan, DOE is withholding important documents regarding these loans,” Issa wrote in his letter. “Given DOE’s noncompliance, the Committee cannot assure taxpayers that, in the case of bankruptcy, a similar subordination of taxpayer interests will not occur.”
A DOE spokesman said Monday that DOE has been careful to manage taxpayer risk for all loan programs under its control.
“From day one, decisions made on loan applications and projects supported by loan guarantees were made on the merits after careful review by experts in the loan program,” Damien LaVera told The Hill. “Our consistent goal has been to manage these critical investments in innovative clean energy technologies in a way that manages the risk to the taxpayers.”
But Issa cited press reports in explaining that the additional $341 millionin tax losses could be the result of the way in which the Solyndra loanwas restructured. Specifically, Issa said that in 2011, the DOE convinced two private investors to put another $75 million into Solyndra. In return, the government agreed to give up priority status for being repaid in the event of a bankruptcy.
Issa said the restructuring also appeared to give the private investors the right to “maximize their share of ownership of the net operating losses,” which would help them lower their tax burden. He cited an IRS statement in U.S. Bankruptcy Court in Delaware saying the final reduced tax liability could be anywhere from $306 million to $341 million.
In light of this possibility, Issa asked whether a loan to Fisker might have been restructured in the same way. He asked Chu to provide all documents related to the tax implications of both the Solyndra and Fisker loans by Nov. 5.
A DOE official familiar with the case downplayed Issa’s fear of $300+ million in lost tax revenues, since those tax benefits could only be claimed against future Solyndra profits.
On the idea that some investors are able to claim a greater share of these losses, the official said that was an arrangement on which private investors agreed, and that the government had no say in those negotiations.
And regarding Fisker, the official said there has been on restricting of that loan at all. While DOE appears likely to take the position that Issa’s fears about both Solyndra and Fisker are not warranted, it was unclear when DOE planned to respond to Issa’s letter.
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| https://thehill.com/blogs/floor-action/house/132365-issa-warns-taxpayers-loss-on-solyndra-loan-may-near-850-million/ |
Sustainability | Free Full-Text | Can Preschool Out-of-Kindergarten Tutoring Improve Approaches to Learning for Children? Evidence from China Family Panel Studies (CFPS) 2012 to 2020
Based on data from the China Family Panel Studies in 2012, 2014, 2016, 2018, and 2020, this study used propensity-score matching to investigate whether preschool out-of-kindergarten tutoring impacts children’s approaches to learning. We discovered the following: (1) approximately one sixth of the preschool children in the sample participated in out-of-kindergarten tutoring, and the participation rate increased year on year; (2) preschool children with a higher family socioeconomic status and a higher level of urbanization in their local area participated more in out-of-kindergarten tutoring; and (3) the effect of preschool out-of-kindergarten tutoring on improving children’s approaches to learning was very limited. In particular, participation in subject-based tutoring to prepare for elementary school failed to improve children’s approaches to learning. Based on the above findings, we recommend that parents make rational choices concerning preschool out-of-kindergarten tutoring, based on a comprehensive understanding of their children. In addition, the government should increase the systematic supervision and strict regulation of institutions that provide preschool out-of-kindergarten tutoring, while actively constructing a collaborative parenting system involving home, school, and community to promote children’s healthy comprehensive development.
Can Preschool Out-of-Kindergarten Tutoring Improve Approaches to Learning for Children? Evidence from China Family Panel Studies (CFPS) 2012 to 2020
by Haiping Xue 1 , Chenchen Fang 2,* , Jin Shi 3,* , Xiaoqing Hu 1 and Fang Qian 1
1
2
National Medical Education Development Center, Peking University, Beijing 100191, China
3
College of Preschool Education, Capital Normal University, Beijing 100048, China
*
Authors to whom correspondence should be addressed.
Sustainability 2023 , 15 (2), 1246; https://doi.org/10.3390/su15021246
Received: 14 December 2022 / Revised: 25 December 2022 / Accepted: 1 January 2023 / Published: 9 January 2023
(This article belongs to the Special Issue Sustainable Early Childhood Education for the Sustainable Development of Aging China )
Abstract
:
Based on data from the China Family Panel Studies in 2012, 2014, 2016, 2018, and 2020, this study used propensity-score matching to investigate whether preschool out-of-kindergarten tutoring impacts children’s approaches to learning. We discovered the following: (1) approximately one sixth of the preschool children in the sample participated in out-of-kindergarten tutoring, and the participation rate increased year on year; (2) preschool children with a higher family socioeconomic status and a higher level of urbanization in their local area participated more in out-of-kindergarten tutoring; and (3) the effect of preschool out-of-kindergarten tutoring on improving children’s approaches to learning was very limited. In particular, participation in subject-based tutoring to prepare for elementary school failed to improve children’s approaches to learning. Based on the above findings, we recommend that parents make rational choices concerning preschool out-of-kindergarten tutoring, based on a comprehensive understanding of their children. In addition, the government should increase the systematic supervision and strict regulation of institutions that provide preschool out-of-kindergarten tutoring, while actively constructing a collaborative parenting system involving home, school, and community to promote children’s healthy comprehensive development.
Keywords:
out-of-kindergarten tutoring
;
preschool children
;
As the marketization of education continues, out-of-kindergarten tutoring for preschool children is rapidly becoming increasingly popular worldwide [ 1 , 2 ], and preschool children’s participation in out-of-kindergarten tutoring has become a common phenomenon in many countries. According to a large-scale national survey, 89.92% of preschool children in China attended out-of-kindergarten classes [ 3 ]. In the United States, 73% of parents reported having enrolled their children in out-of-kindergarten tutoring [ 4 ]. According to another survey, about 50% of preschool children in South Korea have been involved in out-of-kindergarten tutoring [ 5 ]. An Australian study showed that nearly 80% of preschool children in the survey sample were involved in out-of-kindergarten tutoring [ 6 ]. Studies in Singapore, Canada, and Hong Kong have reported similar results [ 7 , 8 , 9 ]. To provide children with an early advantage over their peers, participation in out-of-kindergarten tutoring has become a common choice among parents of preschool children around the world.
Unlike expectations for school-age children, improving cognitive skills is not the sole reason that parents choose out-of-kindergarten tutoring for preschoolers. Parents are more interested in developing good approaches to learning, such as an interest in learning, persistence, and a sense of accomplishment [ 10 ]. Approaches to learning describe the behaviors, tendencies, styles, attitudes, habits, and abilities that children exhibit during the learning process [ 11 ]. These may help preschoolers adapt to learning situations faster and better prepare them to enter elementary school [ 12 , 13 , 14 ]. They are also important predictors of children’s academic achievement; Children with better approaches to learning are more likely to achieve better academic results when they enter elementary school [ 15 , 16 , 17 ]. Approaches to learning not only play a vital role in children’s learning and development, but also represent basic skills that children need in order to adapt to their future environment and can thus affect their future lives [ 18 ]. Nevertheless, previous studies have focused almost exclusively on the effects of out-of-kindergarten tutoring on preschool children’s academic achievement [ 19 , 20 ] and have largely neglected approaches to learning as an important developmental indicator. Out-of-kindergarten tutoring, as a form of social education outside school, may impact preschool children’s approaches to learning. However, there has been a lack of research testing whether out-of-kindergarten tutoring can promote the development of preschool children’s approaches to learning, especially empirical research based on extensive data. Accordingly, this study investigates whether out-of-kindergarten tutoring affects preschool children’s approaches to learning. The findings can provide practical guidelines for the introduction of national policies related to out-of-kindergarten tutoring, empirical references to support governance of the preschool out-of-kindergarten tutoring market, and scientific guidance to allow parents to choose out-of-kindergarten tutoring rationally.
2. Literature Review
2.1. The Meaning and Composition of Approaches to Learning
Approaches to learning have recently been oriented toward “the achieving approach [ 21 , 22 ]”, which can be further divided into the “deep approach,” “surface approach,” and “strategic approach [ 23 ]”. The original concept of approaches to learning was focused more on “methods and strategies” rather than “quality” of learning. The concept of early childhood approaches to learning was first introduced by L. G. Katz, an American scholar of early childhood education, regarding the learning dispositions of young children. “Dispositions” are distinct from knowledge and skills, and comprise enduring mental habits or typical ways of responding to things or experiences in different contexts [ 24 ]. Researchers have since elaborated the term to include three specific subcategories: intentions, dispositions, and learning styles [ 25 ]. The National Education Goals Panel defines approaches to learning as the behaviors, styles, and abilities that children exhibit during the learning process, including learning styles, dispositions, attitudes, and habits in a broad sense, and in a narrower sense curiosity and exploration, creativity and initiative, concentration and persistence, and retrospection and reflection [ 11 ]. Chinese scholars have defined approaches to learning as the positive attitudes and favourable behavioral dispositions that children exhibit in the learning process [ 26 ]. The terminology does not refer to specific knowledge, abilities, skills, or emotions, but rather to how children acquire and use knowledge and skills and the role of these in motivational regulation during the learning process [ 27 ]. Specifically, the concept includes curiosity, interest in learning, initiative, persistence, concentration, imagination, creativity, problem-solving, reflection, and interpretation [ 28 , 29 ].
2.2. The Relationship between Extracurricular Tutoring and Students’ Approaches to Learning in Elementary and Secondary Schools
Numerous studies have shown that participation in extracurricular tutoring has a positive impact on elementary and secondary school students’ approaches to learning, including improvements in self-confidence, interest, responsibility, self-esteem, persistence, initiative, and autonomy. Scholars have found that it positively influences students’ attitudes toward learning, and boosts their self-confidence and interest to some extent [ 30 , 31 ]. Effective extracurricular tutoring improves students’ confidence in academic competition [ 32 , 33 ]; students show higher self-confidence up to a certain threshold, after which its positive effect diminishes [ 34 ]. Extracurricular tutoring allows students to gain broader and deeper knowledge and increases their interest in the school curriculum [ 32 ]. Additionally, it increases students’ and parents’ self-confidence, self-esteem, and other qualities [ 34 , 35 ]. Research has also shown that extracurricular tutoring helps students discover new areas of interest while developing existing ones [ 36 , 37 ]. It positively influences learners’ emotional responses and subsequently leads to increased persistence of learned behaviors and achievement [ 38 , 39 , 40 ]. Extracurricular tutoring may also improve students’ study habits and increase their initiative in the classroom [ 41 ]. In terms of specific subjects, more intense extracurricular math tutoring helps to form positive study habits [ 42 ]. Participation in extracurricular tutoring can reduce the need for parental tutoring and increase student autonomy [ 41 ]. In addition, some studies have demonstrated that non-subject-based extracurricular tutoring, especially in the arts, has significant positive effects on all dimensions of non-cognitive abilities such as self-esteem, self-control, interpersonal skills, school adaptability, leadership skills, and cooperation [ 43 , 44 ].
In contrast, other studies have found that participation in extracurricular tutoring had a negative impact on students’ approaches to learning. For example, extracurricular tutoring can reduce students’ curiosity and interest in learning [ 45 ]. Participation in extracurricular tutoring can cause students to lose their natural curiosity, creativity, communication skills, interest, passion, joy, and hope, and can reduce their intrinsic motivation to learn [ 46 , 47 , 48 , 49 ]. Excessive extracurricular tutoring increases students’ academic burden and weakens their enthusiasm for independent learning [ 50 , 51 ]. “Over-step learning” (studying content designed for older ages or grades) and intense tutoring can lead to a lack of concentration [ 49 , 52 , 53 , 54 ]. Because extracurricular tutoring focuses excessively on test-taking skills, it can have a negative impact on students’ creativity and critical thinking [ 48 , 51 , 55 ].
Our comparison of the results of these studies indicates that extracurricular tutoring has both positive and negative effects on approaches to learning. Other findings have shown that extracurricular tutoring itself neither promotes nor undermines students’ independent learning [ 56 ]. There is no evidence that extracurricular tutoring contributes to or undermines the development of motivation or learning methods [ 57 ].
2.3. The Relationship between Preschool Out-of-Kindergarten Tutoring and Children’s Approaches to Learning
“Preschool out-of-kindergarten tutoring” refers to paid educational services, such as “interest-oriented classes” and “specialty tutoring classes,” attended by children aged 3–6 outside kindergarten [ 58 ]. In recent years, studies have examined the relationship between out-of-kindergarten tutoring and approaches to learning, but the findings have been inconsistent. Covay and Carbonaro found that shadow education was significantly and positively related to children’s approaches to learning, and that approaches to learning also explained strengths in the language and math skills of children who participated in physical education and music-based shadow education, respectively [ 59 ]. Bodovski and Farkas’ analysis of data from approximately 8000 white children in an ECLS-K program found that children’s approaches to learning were positively affected by the amount of out-of-kindergarten tutoring that the children attended [ 60 ]. Chinese scholars administered a survey to preschool children in Shanxi Province to investigate the mediating effect of children’s approaches to learning in out-of-kindergarten tutoring on their learning and developmental outcomes. The results showed that varying roles for each element of the approaches to learning in out-of-kindergarten tutoring; out-of-kindergarten tutoring could positively affect children’s persistence and self-control but did not positively affect their curiosity or interest in learning [ 58 ]. Some scholars have stated that allowing children to participate in preschool out-of-kindergarten tutoring enables improved discovery and cultivation of children’s potential and talent, provided that parents respect their children’s interests and developmental patterns [ 61 , 62 ]. Kremer-Sadlik et al. concluded from interviews that parents expressed their belief that out-of-kindergarten tutoring could promote a wide range of skills including concentration [ 63 ]. Chiu and Lau studied 5–6-year-old preschoolers in Hong Kong and found that increased participation in out-of-kindergarten tutoring was associated with better teacher-reported readiness for school and lower levels of anxiety and withdrawal [ 9 ].
Inconsistent with those findings, mainland Chinese scholars conducted a survey of 984 preschool children and found that, except for significant differences in the social–emotional aspect, when children attended early childhood classes before entering kindergarten there were no significant differences in any domains, including approaches to learning [
64
]. Other studies used propensity-score matching (PSM) to explore the impact of preschool out-of-kindergarten tutoring on children’s learning and development, based on follow-up survey data from 664 and 367 children aged 3–6 years in 2017 and 2018, respectively. The results showed that participation in preschool out-of-kindergarten tutoring had no significant effect on the approaches to learning or the development of young children in various areas [
65
]. Chiu and Lau concluded that participation in out-of-kindergarten tutoring was not significantly related to children’s social competence, anger, aggression, or peer acceptance [
9
]. Moreover, the relationship between out-of-kindergarten tutoring and social–emotional outcomes is tenuous. If the quality of tutoring is not high or if students do not form meaningful connections with the activities, the outcomes are less than desirable [
66
].
The existing findings on the impact of out-of-kindergarten tutoring on children’s approaches to learning are inconsistent, and thus require further exploration and in-depth analysis. In contrast with the considerable research conducted at the stage of compulsory education, there have been few studies on the relationship between preschool out-of-kindergarten tutoring and children’s approaches to learning. This includes a lack of published research based on nationally representative survey data exploring the correlation between preschool children’s out-of-kindergarten tutoring and children’s approaches to learning. Studies that have examined the relationship between out-of-kindergarten tutoring and approaches to learning in preschool children have mainly used statistical descriptions and general regression methods, which are prone to problems of endogeneity and thus impair the reliability of findings. Based on nationally representative survey data, this study uses propensity-score matching to examine the effects of preschool out-of-kindergarten tutoring on children’s approaches to learning. This paper has the dual aims of helping parents dialectically view through empirical research the relationship between preschool out-of-kindergarten tutoring and children’s approaches to learning, to provide a reference basis for them to make rational choices, and to encourage the state to regulate preschool out-of-kindergarten tutoring.
3. Methods
3.1. Data Sources
The data for this study were obtained from the China Family Panel Studies (CFPS) of Peking University for the years 2012, 2014, 2016, 2018, and 2020. The CFPS sample covered 25 provinces in China, with a target sample size of 16,000 households, and surveyed all members of each household. Focusing on the economic and non-economic well-being of China’s residents, including many other research topics such as economic activity, educational outcomes, family relationships and dynamics, population migration, and health, CFPS is a national, large-scale, multidisciplinary social panel study. CFPS provides rare and comprehensive large-scale follow-up survey data from across China, thus constituting suitable baseline data for the current study. The subjects of this study were 8192 preschool children aged 4–6 years, and the sample sizes for each year are shown in Table 1 .
3.2. Study Variables
3.2.1. Explained Variables
The explained variables in this study were children’s approaches to learning, specifically curiosity, interest in learning, initiative, regularity, persistence, concentration, imagination, and creativity. The scale for measuring children’s approaches to learning comprised several questions assessing different aspects of approaches to learning. For example, “regularity” was measured by questions on “children’s compliance with rules,” and “persistence and concentration” by questions on “children’s attention to tasks.” The options were scored on a 5-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, and 5 = strongly agree), and the variables were identified using factor analysis. Reliability analysis of the variables was also conducted. The Kaiser–Mayer–Olkin value was 0.867 and the value of Cronbach’s alpha was 0.790, indicating good reliability and validity.
3.2.2. Core Explanatory Variable
The core explanatory variable of this study was whether preschool children participated in out-of-kindergarten tutoring, measured as a dummy variable taking a value of 1 if they participated in out-of-kindergarten tutoring and 0 otherwise. Out-of-kindergarten tutoring was then divided into subject-based and non-subject-based out-of-kindergarten tutoring. The former refers to tutoring courses with language, mathematics, or other subject knowledge as the main curriculum content, including phonics classes, Mathematical Olympiad classes, and English classes. If preschool children participated in subject-based out-of-kindergarten tutoring, they were assigned a value of 1, or 0 if otherwise. Non-subject-based tutoring refers to courses with non-knowledge-based skills, including arts and sports, as the main content of the curriculum, including dance classes, painting classes, and basketball classes. If preschool children participated in non-subject-based out-of-kindergarten tutoring, this variable was given the value 1, or 0 if otherwise.
3.2.3. Other Control Variables
Other factors associated with participation in out-of-kindergarten tutoring and children’s approaches to learning were also selected in this study as control variables, including gender, family location, per capita family income, highest level of parental occupation, highest number of years of parental education, type of kindergarten, and kindergarten location. The descriptions of specific variables are presented in
Table 2
. When examining the variable of parental occupation, this study drew on the occupational stratification study by Li, a Chinese scholar, to classify children’s parental occupations into lower, middle, or upper strata according to the socioeconomic status index, and selected the highest occupational stratum of either parent as the value to be recorded [
67
]. The lower occupational classes include commercial and service workers, unskilled workers, agricultural, forestry and fishery workers, freelancers, the unemployed, and homemakers. The mid-level careers include basic management, other professional and technical personnel, general technicians, employees of enterprises or institutions, skilled workers, military police, firefighters, and self-employed or small business owners (employing eight people or less). The upper occupational level includes heads of government bodies, enterprises, or institutions, middle management, middle and senior professional and technical personnel, general officials and civil servants, economic business personnel, and employers in private enterprises. The propensity-score matching did not include 2020 data, because when the analysis was conducted the 2020 CFPS surveyors had not yet released the variables of per capita household income, highest level of parental occupation, and time spent in parental education.
3.3. Research Methodology
The traditional ordinary least squares (OLS) method, based on the assumption of random assignment, increases the probability of sample-selection bias and counterfactual estimation bias. Therefore, as an effective method to address sample-selection bias in the process of determining the effect of out-of-kindergarten tutoring on children’s approaches to learning, this study used PSM to evaluate counterfactual treatment outcomes. Specifically, matching enables a balanced distribution of covariates between the groups that are involved or not involved in out-of-kindergarten tutoring, thus eliminating as much as possible the effect of differences in confounding variables within the sample. At the operational level, PSM identifies individuals in the treatment group that can be matched with individuals in the control group possessing similar characteristics based on the propensity scores estimated by the Logit or Probit model, and compares the differences in approaches to learning between those preschool children who participated in out-of-kindergarten tutoring and those children who did not (i.e., the average treatment effect in the treatment group). The model is expressed as follows:
ATT = E{E[Y i1 | D i = 1, p(X)]−E[Y i0 | D i = 1, p(X)]}
(1)
In the above model, Y
i1
and Y
i0
are the approaches to learning of children who participated and children who did not participate in out-of-kindergarten tutoring, respectively. D
i
is a dichotomous variable labeled D
i
= 1 if the children participated in out-of-kindergarten tutoring and D
i
= 0 if they did not. p(X) is the probability of participating in out-of-kindergarten tutoring after controlling for individual children and families. To ensure the robustness of the estimation results, this study used nearest-neighbor, radius, and kernel matching to estimate the effect of out-of-kindergarten tutoring on children’ approaches to learning.
4. Results
4.1. Participation of Preschool Children in Out-of-Kindergarten Tutoring
Figure 1 represents the participation of preschool children in out-of-kindergarten tutoring. The percentage of preschool children participating in out-of-kindergarten tutoring was 8.2% in 2012, 7.8% in 2014, 9.6% in 2016, 11.7% in 2018, and 16.9% in 2020. The proportion of preschool children participating in subject-based out-of-kindergarten tutoring increased from 2.7% in 2012 to 11.2% in 2020, indicating a growth of 8.5 percentage points. The proportion of preschool children participating in non-subject-based out-of-kindergarten tutoring increased from 4.5% in 2012 to 18.5% in 2020, reflecting a growth of 14.0 percentage points. Overall, the proportion of preschool children participating in out-of-kindergarten tutoring is on the rise.
4.2. Analysis of the Factors Influencing Preschool Children’s Participation in Out-of-Kindergarten Tutoring
Table 3
presents the results of factors influencing preschool children’s participation in out-of-kindergarten tutoring. As shown in
Table 3
, factors such as kindergarten location, per capita household income, and years of parental education significantly affected preschool children’s participation in out-of-kindergarten tutoring. Specifically, boys were significantly less likely to participate in out-of-kindergarten tutoring than girls; the higher the per capita household income, the higher was the probability of preschool children participating in out-of-kindergarten tutoring; the higher the maximum years of parental education, the higher was the probability of preschool children participating in out-of-kindergarten tutoring; and the higher the level of urbanization at the location of the kindergarten, the higher the probability of preschool children participating in out-of-kindergarten tutoring.
4.3. Balance Test
Using PSM to estimate the effect of out-of-kindergarten tutoring on preschool children’s approaches to learning, it was first necessary to conduct a balance test on the variables in the control and balance groups.
Table 4
presents the results of the balance test under the nearest-neighbor-matching method. The results of the balance test show that the standard errors of all covariates were reduced to different degrees after matching, with the highest bias reduction for gender reaching 100%, whereas the
t
-test results for each covariate in the treatment and control groups were not significant after matching. This indicates that the matching effect was relatively successful, and the matching of data eliminated differences in various aspects between preschool children who did or did not participate in out-of-kindergarten tutoring.
Figure 2 presents the common range of values for the propensity score of whether preschool children participated in out-of-kindergarten tutoring, from which it can be seen that most of the observations fell within a common range, basically satisfying the requirements for the common support assumption.
4.4. PSM model estimation results
Based on the balance test, this study used nearest-neighbor matching (1:2), radius matching (0.05), and kernel matching to estimate the effects of out-of-kindergarten tutoring on preschool children’s approaches to learning. As can be seen from Table 5 , except for 2018, when preschool children’s participation in non-subject-based out-of-kindergarten tutoring significantly improved their approaches to learning, the results of analysis for other years and for the full sample showed that preschool children’s participation in either subject-based or non-subject-based out-of-kindergarten tutoring was ineffective in improving their approaches to learning. Thus, it is evident that preschool children’s participation in out-of-kindergarten tutoring has a limited effect overall on improving children’s approaches to learning.
4.5. Robustness Test
To further verify the relationship between out-of-kindergarten tutoring and preschool children’s approaches to learning, we selected the cost of preschool children’s participation in out-of-kindergarten tutoring for robustness testing. If the cost of out-of-kindergarten tutoring for a given preschool child was greater than 0, it indicated that the preschool child participated in out-of-kindergarten tutoring, and if the cost of out-of-kindergarten tutoring was 0, it indicated that the preschool child did not participate in out-of-kindergarten tutoring. Similarly, we estimated the effect of out-of-kindergarten tutoring on preschool children’s approaches to learning, using nearest-neighbor, radius, and kernel matching applied to the full sample data. As shown in Table 6 , the effects of out-of-kindergarten tutoring on preschool children’s approaches to learning were not found to be significant, indicating that the study results are robust.
5. Disscussion
5.1. Preschoolers Are Increasingly Involved in Out-of-Kindergarten Tutoring and Non-Subject-Based Tutoring
This study found that nearly one sixth of preschool children in China participated in out-of-kindergarten tutoring in 2020, and the proportion of Chinese preschool children participating in out-of-kindergarten tutoring increased gradually between 2012 and 2020. The latter finding is consistent with those of other studies in China [
68
]. Some researchers have pointed out that China is a highly selective society that screens people at every stage of education. Being screened out means being isolated from quality educational resources [
68
], a process that has intensified in the last decade. To provide their children with an early advantage over their peers, parents are increasingly opting to “jump the gun” by using out-of-kindergarten tutoring as a way to succeed in the context of competitive education, enrolling their children in various classes at an early age [
69
]. In addition, kindergartens in China have on average 30–35 students per classroom, while class sizes for preschool out-of-kindergarten tutoring are typically much smaller [
1
]. Given that kindergarten class sizes are large, teachers tend to adopt a uniform teaching model to meet the needs of all preschoolers, which makes it difficult for them to meet individual needs. In contrast, flexible and diverse out-of-kindergarten tutoring can to a certain extent meet the individual and diverse developmental needs of children. Therefore, parents of preschoolers are choosing in increasing numbers to enroll their children in out-of-kindergarten tutoring.
As stated above, this study also found that the respective proportions of preschoolers participating in subject-based and non-subject-based out-of-kindergarten tutoring rose between 2012 and 2020. Notably, the proportion of preschoolers participating in non-subject-based out-of-kindergarten tutoring was higher in 2012, 2014, 2016, 2018, and 2020 than those receiving subject-based out-of-kindergarten tutoring, and the growth of participation in non-subject-based out-of-kindergarten tutoring was also higher, corroborating the findings of Ren et al. [
70
]. Another study in China found that the main reason that parents choose tutoring institutions for their children is in order to develop their children’s habits and interests, and exercise their abilities and thinking skills [
71
]. Preschoolers develop through play and activity, and their attention span and memory-retention time are short, so they cannot sit still in a classroom and listen so attentively as elementary and middle school students. Most subject-based out-of-kindergarten tutoring in China focuses on subject knowledge and classroom teaching, which do not suit the age characteristics of preschool children, making it difficult for such tutoring to achieve parents’ aims of cultivating their children’s interests and abilities. Thus, non-subject-based out-of-kindergarten tutoring is more popular among parents of Chinese preschoolers.
Another interesting finding resulting from the current study is that the proportion of preschool children participating in out-of-kindergarten tutoring grew at its quickest rate from 2018 to 2020, by 5.2 percentage points in just two years. In 2018, the General Office of the State Council promulgated the Opinions on Regulating the Development of private tutoring institutions, a policy that imposed stricter restrictions on extracurricular tutoring in elementary and secondary schools. Since the implementation of the policy, subject-based out-of-kindergarten tutoring during compulsory education has been subjected to numerous restrictions, and many subject-based extracurricular tutoring institutions have flocked to the preschool level in an attempt to transform their institutions by offering tutoring to preschool children. The increase in the number of preschool tutoring institutions has attracted more parents to choose out-of-kindergarten tutoring for their preschool children.
5.2. Impact of Children’s Gender, Family Socioeconomic Background, and Kindergarten Location on Preschoolers’ Participation in Out-of-Kindergarten Tutoring
This study found that gender, family socioeconomic background, and kindergarten location were important influencing factors in preschool children’s participation in out-of-kindergarten tutoring. Specifically in terms of gender, as reflected in previous studies, the participation of girls in out-of-kindergarten tutoring was significantly higher than that of boys [
20
,
72
,
73
]. According to data released by the United Nations Development Programme, Chinese women’s education levels and rates of participations in the labor force are 11.4 and 14.0 percentage points lower than those of men, respectively [
74
]. Chinese women remain at a disadvantage in terms of education and employment because of the influence of traditional cultural values. To help girls gain greater advantages in their future education and work, parents prefer to secure extracurricular tutoring as compensatory education.
Furthermore, family socioeconomic background had a significant positive effect on preschool children’s participation in out-of-kindergarten tutoring, with higher per capita household income and extended parental education associated with a higher probability of preschool children’s participation in out-of-kindergarten tutoring, consistent with the results of many previous studies [ 1 , 59 , 70 ]. In the time-based out-of-kindergarten tutoring market, per capita household income determines whether households can afford out-of-kindergarten tutoring for preschool children, with economically well-off households being more likely to pay the extra costs to invest in their children’s education [ 75 ]. Moreover, parents with more years of education themselves tend to place greater emphasis on their children’s education and are more likely to use out-of-kindergarten tutoring, as they are willing to invest more in their children to give them an advantage in educational competition [ 76 ].
Finally, this study found that the kindergarten location also had a significant effect on preschool children’s participation in out-of-kindergarten tutoring, with higher levels of urbanization in the kindergarten’s location being associated with higher probability of preschool children’s participation in out-of-kindergarten tutoring, corroborating many previous studies [
68
,
77
,
78
]. In China, most out-of-kindergarten tutoring institutions are concentrated in provincial capitals and economically developed areas. Out-of-kindergarten tutoring in areas with higher levels of urbanization is developing comparatively faster and on a larger scale, while its supply in rural areas is very limited. Furthermore, families in regions of China with higher levels of urbanization tend to have higher per capita disposable income and are more likely to invest in their children’s education. Poorer families in regions that are less economically developed, especially in rural areas, are often unable to afford out-of-kindergarten tutoring [
72
].
5.3. Preschool Out-of-Kindergarten Tutoring Has no Significant Effect on Children’s Approaches to Learning
This study found no significant effect of preschool out-of-kindergarten tutoring on children’s approaches to learning, a result which is consistent with other studies [
9
,
64
,
71
]. Preschool children are influenced by many factors, including personal factors, parenting styles, family background characteristics, educational styles, and social culture, all of which affect the development of their approaches to learning. However, it should be noted that out-of-kindergarten tutoring represents only one type of social education, and the successful development of preschool children’s approaches to learning continues to require the cooperation of families, kindergartens, and society. Another possible explanation supported by previous studies is that teacher–child interaction is an important factor in the development of children’s approaches to learning [
79
] and that out-of-kindergarten tutoring is only a supplement to schooling, with much less time spent in tutoring than in kindergarten and at home. Insufficient time and intensity of teacher–child interaction in out-of-kindergarten tutoring may explain its lack of significant effect on the development of children’s approaches to learning.
This study also found that subject-based out-of-kindergarten tutoring had no effect on preschoolers’ approaches to learning, a conclusion which is supported by the results some previous studies [
65
,
72
]. In China, preschool subject-based out-of-kindergarten tutoring often uses an elementary school curriculum to prepare students for elementary school. Preschoolers in these classes learn elementary school curriculum content in advance, such as phonics and English, which may lead to a loss of interest in learning, curb their imaginative and creative development, and be detrimental to the development of learning approaches [
80
]. Furthermore, some preschool out-of-kindergarten tutoring institutions in China have problems with inconsistent teaching quality, a lack of professionally qualified teachers, and insufficient supervision [
81
]. The low quality of some forms of out-of-kindergarten tutoring may also explain why it has no impact on children’s approaches to learning.
In general, although non-subject-based out-of-kindergarten tutoring has some impact on preschoolers’ approaches to learning, its effects are very limited and the impacts are neither obvious nor long-lasting. Non-subject-based out-of-kindergarten tutoring is not knowledge-oriented but is conducted as an activity-based experience that may have an impact on children’s interest in learning, creativity, etc. However, parents often focus on quick results when choosing non-subject-based tutoring; for instance, they want their children to master certain skills (e.g., piano or painting) quickly. To meet parents’ expectations, non-subject-based tutoring often requires a repetitive approach to education, which can damage children’s interest in learning, initiative, and other aspects of their approaches to learning.
6. Conclusions, Implication and Limitations
Based on data from 2012, 2014, 2016, 2018, and 2020, this study used PSM to explore the effects of preschool children’s participation in out-of-kindergarten tutoring on approaches to learning. The results indicated that the proportion of preschool children participating in out-of-kindergarten tutoring in China is increasing, with a higher growth rate of participation in non-subject-based out-of-kindergarten tutoring. Gender, family socioeconomic background, and kindergarten location were all influential factors in preschool children’s participation in out-of-kindergarten tutoring. Using PSM, we found that preschool children’s participation in out-of-kindergarten tutoring was hardly effective in improving their approaches to learning, especially in subject-based out-of-kindergarten tutoring.
Based on this study’s findings, we make the following recommendations. First, parents should rationally choose out-of-kindergarten tutoring based on a comprehensive understanding of their children. They should not have blind faith in out-of-kindergarten tutoring nor exaggerate its role, but should instead carefully consider the interests and developmental needs of their children. Second, the government should increase the systematic supervision of preschool out-of-kindergarten tutoring institutions to regulate them strictly and crack down on “over-step learning.” Third, we should develop a collaborative parenting system involving home, kindergarten, and community to create educational synergy and jointly promote the healthy and comprehensive development of young children.
This study has several shortcomings due to the limitations of the data. Although this study used data gathered during five periods, it did not track for analysis the dynamic effects of out-of-kindergarten tutoring on children’s approaches to learning, because panel data were not used. In addition, the data utilized in this study were not sufficiently comprehensive to measure approaches to learning and may not fully reflect the impact of out-of-kindergarten tutoring on children’s approaches to learning. Furthermore, this study did not consider the specific teaching methods and materials applied in out-of-kindergarten tutoring. In future studies, we hope to conduct follow-up surveys to measure more comprehensively children’s approaches to learning and to thoroughly explore the dynamic effects of preschool out-of-kindergarten tutoring on children’s approaches to learning.
Informed consent was obtained from all subjects involved in the study.
Conflicts of Interest
References
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Figure 1. Participation of preschoolers in out-of-kindergarten tutoring in 2012–2020.
Figure 1. Participation of preschoolers in out-of-kindergarten tutoring in 2012–2020.
Figure 2. Range of common propensity-score values.
Figure 2. Range of common propensity-score values.
Table 1. Sample sizes for 2012–2020.
Table 1. Sample sizes for 2012–2020.
Year Sample Size 2012 1610 2014 1773 2016 1560 2018 1779 2020 1470 Total 8192
Table 2. Study variables.
Table 2. Study variables.
Type Variable Description and Coding Participation in out-of-kindergarten tutoring Participation in out-of-kindergarten tutoring 0 = No, 1 = Yes Participation in subject-based out-of-kindergarten tutoring 0 = No, 1 = Yes Participation in non-subject-based out-of-kindergarten tutoring 0 = No, 1 = Yes Approaches to learning Approaches to learning score for children Obtained through the children’s approaches to learning scale; continuous variable. Control variable Gender 0 = Girl, 1 = Boy Type of the kindergarten 0 = Private kindergarten, 1 = Public kindergarten Kindergarten location 1 = Rural area (including townships), 2 = County seat, 3 = General city (including county-level cities or prefecture-level cities), 4 = Provincial capital(including municipalities) Family location 0 = Countryside, 1 = City Per capita family income 1 = Lowest 20%, 2 = Mid/Lower 20%, 3 = Middle 20%, 4 = Mid/Higher 20%, 5 = Highest 20% Highest level of parental occupation 1 = Lower, 2 = Middle, 3 = Upper Highest number of years of parental education Continuous variable
Table 3. Factors influencing children’s participation in out-of-kindergarten tutoring.
Table 3. Factors influencing children’s participation in out-of-kindergarten tutoring.
Variable Participation in Out-of-Kindergarten Tutoring Gender −0.551 ** (0.235) Family location 0.451 (0.274) Per capita family income 0.589 *** (0.112) Highest level of parental occupation 0.064 (0.192) Highest number of years of parental education 0.279 ** (0.111) Type of kindergarten 0.081 (0.252) Kindergarten location 0.599 *** (0.127) Intercept −4.666 *** (0.523)
Note: ** p < 0.01; *** p < 0.001.
Table 4. Balance-test results of nearest-neighbor matching.
Table 4. Balance-test results of nearest-neighbor matching.
Matching Treated Group Untreated Group Reduction of Standard Errors (%) Absolute Value of Reduction t Value Gender Before 0.534 0.546 −2.4 100.0 −0.29 After 0.534 0.534 0.0 0.00 Family location Before 0.730 0.331 86.9 95.4 10.32 *** After 0.730 0.712 4.0 0.37 Per capita family income Before 3.810 2.665 93.8 95.2 11.10 *** After 3.810 3.865 −4.5 −0.43 Highest level of parental occupation Before 1.982 1.622 55.9 98.3 7.02 *** After 1.982 1.976 1.0 0.08 Highest number of years of parental education Before 4.295 3.190 91.9 98.9 12.12 *** After 4.295 4.282 1.9 0.09 Type of kindergarten Before 0.494 0.402 18.5 56.1 1.71 After 0.494 0.535 −8.1 −0.57 Kindergarten location Before 2.436 1.572 90.5 98.3 9.09 *** After 2.405 2.391 1.6 0.10
Note: *** p < 0.001.
Table 5. Effect of participation in out-of-kindergarten tutoring on children’s approaches to learning.
Table 5. Effect of participation in out-of-kindergarten tutoring on children’s approaches to learning.
Year Neighbor Matching Radius Matching Kernel Matching 2012 Out-of-kindergarten tutoring −0.106 −0.173 ** −0.166 * Subject-based out-of-kindergarten tutoring −0.098 −0.186 −0.191 Non-subject-based out-of-kindergarten tutoring −0.101 −0.158 −0.141 2014 Out-of-kindergarten tutoring −0.067 −0.069 −0.075 Subject-based out-of-kindergarten tutoring 0.036 −0.085 −0.083 Non-subject-based out-of-kindergarten tutoring 0.027 −0.052 −0.049 2016 Out-of-kindergarten tutoring −0.113 −0.089 −0.086 Subject-based out-of-kindergarten tutoring −0.005 −0.118 −0.119 Non-subject-based out-of-kindergarten tutoring −0.151 −0.031 −0.033 2018 Out-of-kindergarten tutoring 0.079 0.056 0.061 Subject-based out-of-kindergarten tutoring 0.269 * 0.150 0.152 Non-subject-based out-of-kindergarten tutoring 0.171 * 0.154 * 0.156 * All samples Out-of-kindergarten tutoring −0.036 −0.064 −0.069 Subject-based out-of-kindergarten tutoring 0.027 −0.048 −0.042 Non-subject-based out-of-kindergarten tutoring 0.049 0.032 0.035
Note: * p < 0.05; ** p < 0.01.
Table 6. Robustness test for the effect of participation in out-of-kindergarten tutoring on children’s approaches to learning.
Table 6. Robustness test for the effect of participation in out-of-kindergarten tutoring on children’s approaches to learning.
All Samples Neighbor Matching Radius Matching Kernel Matching Out-of-kindergarten tutoring 0.028 0.044 0.042
Xue, H.; Fang, C.; Shi, J.; Hu, X.; Qian, F. Can Preschool Out-of-Kindergarten Tutoring Improve Approaches to Learning for Children? Evidence from China Family Panel Studies (CFPS) 2012 to 2020. Sustainability 2023, 15, 1246.
https://doi.org/10.3390/su15021246
AMA Style
Xue H, Fang C, Shi J, Hu X, Qian F. Can Preschool Out-of-Kindergarten Tutoring Improve Approaches to Learning for Children? Evidence from China Family Panel Studies (CFPS) 2012 to 2020. Sustainability. 2023; 15(2):1246.
https://doi.org/10.3390/su15021246
Chicago/Turabian Style
Xue, Haiping, Chenchen Fang, Jin Shi, Xiaoqing Hu, and Fang Qian. 2023. "Can Preschool Out-of-Kindergarten Tutoring Improve Approaches to Learning for Children? Evidence from China Family Panel Studies (CFPS) 2012 to 2020" Sustainability15, no. 2: 1246.
https://doi.org/10.3390/su15021246
| https://www.mdpi.com/2071-1050/15/2/1246/htm |
Senescence-related changes in gene expression in muscle: similarities and differences between mice and men | Physiological Genomics
A microarray study of the effect of senescence in mice on gene expression in muscle has been published recently. The present analysis was done to evaluate the extent to which the age-related differ...
Research Article
Senescence-related changes in gene expression in muscle: similarities and differences between mice and men
STEPHEN WELLE
,
ANDREW BROOKS
, and
CHARLES A. THORNTON
Published Online: 08 Mar 2001 https://doi.org/10.1152/physiolgenomics.2001.5.2.67
Abstract
A microarray study of the effect of senescence in mice on gene expression in muscle has been published recently. The present analysis was done to evaluate the extent to which the age-related differences in gene expression in murine muscle are also evident in human muscle. RNA extracted from muscle of young (21–24 yr) and old men (66–77 yr) was studied both by serial analysis of gene expression (SAGE) and by oligonucleotide microarrays. SAGE tags were detected for 61 genes homologous to genes reported to be differentially expressed in young and old murine muscle. The microarray had probe sets for 70 homologous genes. For 17 genes, there was evidence for a similar age-related change in expression in muscles of mice and men. For 32 other genes, there was evidence that the effect of age on the level of expression is not the same in mice and men. There was no evidence that older human muscle has increased expression of the stress response genes that are increased in old murine muscle.
postmaturational agingis associated with reduced muscle mass, strength, and aerobic capacity (2,6). The role of changes in gene expression in the age-related deterioration of muscle, or in adapting to the deterioration, is not clear. Recently, Lee et al. (15) used microarray technology to search for genes that are differentially expressed in gastrocnemius muscle of young adult (5 mo old) and old adult (30 mo) C57BL/6 mice. Expression of several genes involved in energy metabolism, responses to stress, and reinnervation were affected by aging. Many of the changes in gene expression associated with aging were eliminated or attenuated by caloric restriction. The relevance of these data to the aging of human muscle is not known. We recently compiled inventories of serial analysis of gene expression (SAGE) tags from old and young adult skeletal muscle (28,29), affording us the opportunity to look for similarities and differences between mice and men with respect to age-related changes in gene expression. The same RNA used to generate the SAGE tags also was analyzed with Affymetrix microarrays, the system used to examine gene expression in mice (15).
METHODS
Identification of human genes homologous to murine genes differentially expressed in young and old muscle.
Lee et al. (15) studied gene expression in murine muscle by Affymetrix oligonucleotide arrays. Gastrocnemius muscle was obtained from six male C57BL/6 mice, three of them 5 mo old and three of them 30 mo old. Relative mRNA levels in younger and older muscle were determined for 6,347 genes. The list of differentially expressed transcripts is available at http://www1.genetics.wisc.edu/prolla/prolla_tables.html. The GenBank accession numbers of the open reading frames (ORFs) of these transcripts were used to retrieve sequences with the Entrez program at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide. These sequences were used to perform BLAST searches for the most similar human mRNAs or expressed sequence tags (ESTs) ( http://www.ncbi.nlm.nih.gov/blast/blast.cgi). The GenBank accession numbers from the BLAST searches were used to find the UniGene clusters ( http://www.ncbi.nlm.nih.gov/UniGene/) for the human sequences that had the best homology with the murine ORFs.
SAGE.
The effect of age on gene expression in human muscle was determined by SAGE as previously reported (26,28,29). The RNA for these analyses was extracted from muscle of eight healthy young men (21–24 yr old, mean 23 yr) and eight healthy older men (66–77 yr old, mean 71 yr). Muscle was obtained by needle biopsy of vastus lateralis under standardized conditions, which included avoidance of any strenuous activity for 3 days before the biopsy and an overnight stay at the Clinical Research Center before the biopsy.
The SAGE method and some of the SAGE results have been published (29). With this method, inventories of short (14-base) ESTs were generated from cDNA produced from two RNA pools: one from the eight younger subjects and one from the eight older subjects. The abundance of any particular gene transcript in the sample is reflected by the number of times its corresponding SAGE tag is detected. The total number of SAGE tags cataloged was similar for the pools of RNA obtained from younger (53,875 tags) and older subjects (53,853 tags). Analysis of several transcripts in individual samples by RT-PCR indicated that the standard deviations for mRNA levels were generally similar among younger and older subjects and that most of the differences suggested by SAGE could be confirmed (29). The SAGE database also has been validated by its similarity to other databases in which the abundance of longer ESTs from muscle libraries has been cataloged (3,28). The SAGE data are available at http://www.urmc.rochester.edu/smd/crc/swindex.html.
The UniGene summary page provides a link to a program that identifies the SAGE tags associated with the sequences in the UniGene cluster. Most of the SAGE tags used in the present analysis are based on the consensus mRNA sequence, but when this information was not available, the tags predicted by a high proportion of the ESTs were used. Often, several potential SAGE tags were identified. There are several reasons for having several different SAGE tags in a UniGene cluster, including incomplete or erroneous sequences, alternative splicing, alternative polyadenylation sites, or polymorphisms. In the Supplemental appendix, we have presented the SAGE tag most likely to represent each mRNA, in some cases followed by other potential tags (to view the appendixplease refer to the Supplemental Material 1
1Supplemental material (the appendix) to this article is available online at http://physiolgenomics.physiology.org/cgi/content/full/5/2/67/DC1.
Analysis of human RNA with the Affymetrix HG-U95A microarray.
The same RNA pools that were used to generate the SAGE inventories were subjected to analysis by the Affymetrix (Santa Clara, CA) HG-U95A high-density oligonucleotide array in the University of Rochester Microarray Core Facility. This array has 12,000 probe sets corresponding to full-length human cDNAs. Each gene is represented by 16–20 pairs of 25-mer oligonucleotides that span the coding region. Sequence information for probe synthesis is derived from the UniGene database. Each probe pair consists of a perfect match sequence that is complementary to the cRNA target and a sequence that has a mismatch in a region critical for target hybridization. The mismatched oligonucleotide serves as a control for nonspecific hybridization. Biotinylated target was generated from the RNA samples as specified by Affymetrix. Quantitation of target hybridization was performed with a GeneArray Scanner (Hewlett-Packard/Affymetrix). The arrays were scanned before and after antibody amplification to address potential issues related to the dynamic range of the scanner. Average abundance of the transcripts represented on the array was scaled to the same nominal value for both samples, and the scaling factors were very close (within 3%) for the arrays used in this study. By comparison with the actual transcript concentrations as previously determined by SAGE, there was a ceiling effect for transcripts with a concentration >300 copies per myonucleus (100 SAGE tags detected) for the scan done without antibody amplification and >60 copies per myonucleus (20 SAGE tags detected) for the scan done with antibody amplification. Thus we used the low-sensitivity scan only for transcripts that produced more than 20 SAGE tags in either sample. Only two transcripts pertinent to the present analysis were too abundant for reliable analysis even with the low-sensitivity scan (i.e., >100 SAGE tags), and neither of these is represented on the HG-U95A array.
The Microarray Analysis Suite (Affymetrix) generated the comparative analysis. Distinct algorithms made an absolute call (presence/absence for each transcript), a decision about differential expression between samples [no change (NC in the Supplemental appendix), marginal increase (MI), marginal decrease (MD), increase (I), or decrease (D)], and the magnitude of the change (represented as fold change, with a value of 1 indicating no difference). The difference decision and fold change estimates are given in the appendix. The mathematical definitions for each of the algorithms are described in the Affymetrix Microarray Suite User’s Guide, Version 4.0. The algorithm for the absolute call excluded outliers (3 standard deviations or more from mean) when averaging differences between perfect match and mismatch probe pairs, but the fold change estimate is based only on probe pairs used for both samples. Occasionally, an increase or decrease in expression is indicated even when the transcript is listed as being absent in both samples, and in these cases we have simply indicated “absent both” in the appendix. In some cases a UniGene cluster is represented by more than one probe set, and these are presented separately in the Supplemental appendix.
Defining concordance or discordance between the murine and human data.
The goal of this analysis was not to make final decisions about which genes are differentially expressed in young and old muscle of both mice and men, but rather to evaluate the overall degree of consistency between the results reported for mice and the results observed in humans. Thus we did not use a stringent Pvalue to define concordance. SAGE results were considered to be consistent with the mouse data if there was a difference in tag counts in the direction predicted by the mouse study and if the probability that the difference in tag counts was due to sampling error was less than 20%. In the case of tags occurring at least five times in the inventories of both young and old muscle, the probability that a difference in SAGE tag counts of the observed magnitude and direction was caused by sampling error was computed from a standard test of the difference between two proportions (9). The Yates continuity correction was used with this test. When tags are detected less frequently, this test can be inaccurate, so the probability that the difference was the result of sampling error was computed as follows. According to the Poisson distribution, P( x) = e − y y x/ x!, where xis the number of times a particular tag was detected among the 53,850 tags cataloged for each age group in the SAGE study, and yis the actual frequency per 53,850 tags in the pool from which tags were sampled (1). The value of yis unknown, but under the null hypothesis y young= y old. The best initial estimate for yis ( x young+ x old)/2. Several values around this initial estimate (in steps of 0.2) also were used to compute P( x young) and P( x old). Decisions were made based on the value for ythat resulted in the highest probability that the difference in SAGE tag counts between young and old was caused by sampling error. The chance that xwill be nor smaller, P( x≤ n), is P( x= 0) + P( x= 1) + … + P( x= n). The chance that xwill be mor larger, P( x≥ m), is 1 − P( x= 0) − P( x= 1) − … − P( x= m− 1). Finally, P( x young≤ nand x old≥ m) = P( x≤ n) × P( x≥ m). For example, suppose that a particular gene is overexpressed in old muscle according to the data obtained in mice. We do not detect its SAGE tag in young human muscle, but we detect its SAGE tag in old muscle two times. Is this tag really more abundant in the sample from older muscle, or is there a good chance that this result would occur even if the true abundance were 1 per 53,850 tags in both samples? If y young= y old= 1, P( x young= 0) = 0.37, P( x old≥ 2) = 0.26, and P( x young= 0 and x old≥ 2) = 0.10. No other value for yresults in a larger value for P( x young= 0 and x old≥ 2). Thus, in this case, we would conclude that the SAGE data are consistent with the mouse microarray data.
SAGE results were considered to be inconsistent with the mouse data when two conditions were met. The first condition was that there was no difference (less than 1.25-fold change) in tag counts in the inventories from young and old muscle or a difference opposite in direction from what was expected from the mouse data. The other condition was that this apparent discordance was unlikely (<20% chance) to happen, when in reality there was a 1.5-fold or more difference, in the predicted direction, in the abundance of the tag in pools from young and old muscle. We used a 1.5-fold difference for this computation, even though the age-related differences in mice were ≥1.7-fold, because we were only looking for similar trends in mice and men and because most mean differences in mRNA concentrations ≥1.5-fold between young and old human muscle are statistically significant when individual RNA samples are analyzed (29). The probability of obtaining a result inconsistent with the mouse data because of sampling error was calculated as described in the preceding paragraph, except for modifications required to estimate the probability of a 1.5-fold or more difference in y(in the predicted direction). For example, suppose that a SAGE tag corresponding to a gene overexpressed in old murine muscle was detected four times in young muscle and only three times in old muscle, an apparent inconsistency with the mouse data. Are these data inconsistent with 1.5-fold or greater overexpression in older human muscle, or is there a good chance that this result would occur even if there actually is overexpression in old human muscle? We tested several sets of possible values for y, in which y old= (1.5 × y young), in increments of 0.2 for y young, to find the one value yielding the highest probability that the inconsistency between the mouse and human data were caused by sampling error. The highest probability, 0.12, was associated with y old= 4.2 and y young= 2.8. Thus we conclude that, given the observed data, it is unlikely that the gene is overexpressed by 1.5-fold or more in old human muscle.
To confirm that the microarray method and SAGE produce the same results when the same samples are analyzed, we identified 20 transcripts for which the Affymetrix algorithm indicated an increase or decrease in expression in older human muscle (limited to transcripts for which the algorithm defined the transcript as present in the sample with higher expression) and for which we could make a decision about concordance or discordance with the SAGE database using the criteria described above. In 18 of 20 cases (90%) there was concordance between methods. This outcome is consistent with our goal of making the correct decision about concordance in more than 80% of the cases. (There were 59 transcripts that were either increased or decreased in older human muscle according to the Affymetrix method, but SAGE data allowed a concordance/discordance decision in only 20 cases. It is beyond the scope of the present report to discuss differences that were not also observed in the study of mice.)
The Affymetrix algorithm for detecting differential expression considers several parameters from the raw data, and the results of these analyses are presented in the Supplemental appendix. However, this decision matrix often indicates that there is no difference between samples even when the best estimate for the magnitude of the difference is 1.5-fold or greater. As noted above, mean differences between young and old of 1.5-fold are often significantly different when individual samples are analyzed (29). Therefore, for the present analysis, we considered the human microarray data to be consistent with the murine microarray data if the difference in expression level between young and old human samples was 1.5-fold or more in the direction predicted by the murine data, even when the algorithm scored the outcome as “no change.” If the difference in humans was 1.2- to 1.4-fold in the predicted direction, then no decision was made about concordance or discordance. If the difference was 1.1-fold or less, or was in the opposite direction from that predicted by the murine data, then the results from mice and men were considered discordant.
RESULTS
Lee et al. (15) provided the GenBank accession numbers of the murine ORFs for 50 genes that were expressed at a higher level in older muscle and 52 genes that were expressed at a lower level in older muscle. The Supplemental appendixshows the ORF accession numbers and relative expression levels for these genes, along with the UniGene numbers for the corresponding human genes, expected SAGE tag sequences, SAGE tag counts in young and old human muscle, the results from the Affymetrix HG-U95A microarray analysis, and the concordance/discordance decisions based on these results.
The SAGE database had entries for 61 human genes that are homologous to murine genes differentially expressed in young and old muscle of mice. The microarray had probe sets for 70 human genes homologous to the ones differentially expressed in young and old muscle of mice. Based on one or the other method, or both, we categorized 49 results as being either concordant or discordant in mice and humans. We were not sufficiently certain of the other results to make a decision regarding concordance or discordance. The decisions were as follows: 17 results were similar in mice and men and 32 were dissimilar; 6 were classified as “overexpressed in both mice and men,” 19 as “overexpressed in mice but not in men,” 11 as “underexpressed in both mice and men,” and 13 as “underexpressed in mice but not in men.”Table 1lists the genes for which aging appeared to have a similar effect on expression in mice and men.Table 2lists those for which there was evidence that the effect of age on expression was not the same in mice and men.
<table> Table 1.Genes for which there is evidence of a similar senescence-related change in expression in muscle of C57BL/6 mice and men<tr><th rowspan=1 colspan=1> Gene</th><th rowspan=1 colspan=1> Function of Gene Product</th></tr><tbody><tr><td rowspan=1 colspan=2> Increased expression in old age</td></tr><tr><td rowspan=1 colspan=1> eIF-4A-II</td><td rowspan=1 colspan=1> Initiation of mRNA translation</td></tr><tr><td rowspan=1 colspan=1> α-Globin</td><td rowspan=1 colspan=1> Hemoglobin component</td></tr><tr><td rowspan=1 colspan=1> DHP-sensitive Ca channel</td><td rowspan=1 colspan=1> Calcium flux</td></tr><tr><td rowspan=1 colspan=1> PEA3</td><td rowspan=1 colspan=1> Myoblast differentiation</td></tr><tr><td rowspan=1 colspan=1> Rac 1</td><td rowspan=1 colspan=1> JNK activator</td></tr><tr><td rowspan=1 colspan=1> CO-029</td><td rowspan=1 colspan=1> Cell surface glycoprotein</td></tr><tr><td rowspan=1 colspan=2> Reduced expression in old age</td></tr><tr><td rowspan=1 colspan=1> Glucose-6-phosphate isomerase</td><td rowspan=1 colspan=1> Glycolysis</td></tr><tr><td rowspan=1 colspan=1> NADP transhydrogenase</td><td rowspan=1 colspan=1> Glycerophosphate shunt</td></tr><tr><td rowspan=1 colspan=1> ATP synthase 6/8</td><td rowspan=1 colspan=1> Mitochondrial ATP synthesis</td></tr><tr><td rowspan=1 colspan=1> PMP35</td><td rowspan=1 colspan=1> Peroxisome assembly</td></tr><tr><td rowspan=1 colspan=1> PmuAUF1-3</td><td rowspan=1 colspan=1> RNA metabolism</td></tr><tr><td rowspan=1 colspan=1> HSP70</td><td rowspan=1 colspan=1> Chaperone (heat shock)</td></tr><tr><td rowspan=1 colspan=1> 26S proteasome component TBP-1</td><td rowspan=1 colspan=1> Proteolysis</td></tr><tr><td rowspan=1 colspan=1> Pro-α(III) collagen</td><td rowspan=1 colspan=1> Extracellular matrix protein</td></tr><tr><td rowspan=1 colspan=1> Ox40</td><td rowspan=1 colspan=1> Signal transduction</td></tr><tr><td rowspan=1 colspan=1> Pro-α 2(I) collagen</td><td rowspan=1 colspan=1> Extracellular matrix protein</td></tr><tr><td rowspan=1 colspan=1> Perinatal myosin heavy chain</td><td rowspan=1 colspan=1> Muscle contraction (perinatal isoform may indicate presence of new fibers)</td></tr></tbody></table>
Table 1.Genes for which there is evidence of a similar senescence-related change in expression in muscle of C57BL/6 mice and men
<table> Table 2.Genes for which the effect of age on expression appears to be different in C57BL/6 mice and men<tr><th rowspan=1 colspan=1> Increased Expression in Mice but not in Men</th><th rowspan=1 colspan=1> Reduced Expression in Mice but not in Men</th></tr><tbody><tr><td rowspan=1 colspan=1> Mitochondrial sarcomeric</td><td rowspan=1 colspan=1> Glycerophosphate dehydrogenase</td></tr><tr><td rowspan=1 colspan=1> creatine kinase</td><td rowspan=1 colspan=1> Unp ubiquitin specific protease</td></tr><tr><td rowspan=1 colspan=1> 27-kDa Heat shock protein</td><td rowspan=1 colspan=1> PKCSH</td></tr><tr><td rowspan=1 colspan=1> 71-kDa Heat shock protein</td><td rowspan=1 colspan=1> Phosphoprotein phosphatase</td></tr><tr><td rowspan=1 colspan=1> Rab B</td><td rowspan=1 colspan=1> Elongation factor 1-γ</td></tr><tr><td rowspan=1 colspan=1> PKC inhibitor homolog</td><td rowspan=1 colspan=1> Wnt-4</td></tr><tr><td rowspan=1 colspan=1> Pre-B cell enhancing factor</td><td rowspan=1 colspan=1> Mitochondrial LON protease</td></tr><tr><td rowspan=1 colspan=1> precursor</td><td rowspan=1 colspan=1> GAS3</td></tr><tr><td rowspan=1 colspan=1> Adaptin complex small</td><td rowspan=1 colspan=1> Clathrin light chain B</td></tr><tr><td rowspan=1 colspan=1> chain homolog</td><td rowspan=1 colspan=1> Calpactin I light chain</td></tr><tr><td rowspan=1 colspan=1> PolyA+RNA export protein</td><td rowspan=1 colspan=1> Protein phosphatase PP2a</td></tr><tr><td rowspan=1 colspan=1> β-Centractin</td><td rowspan=1 colspan=1> Albumin gene D-box binding</td></tr><tr><td rowspan=1 colspan=1> Ypt 1</td><td rowspan=1 colspan=1> protein</td></tr><tr><td rowspan=1 colspan=1> mTGIF</td><td rowspan=1 colspan=1> Squalene synthase</td></tr><tr><td rowspan=1 colspan=1> Neurotrophin-3</td></tr><tr><td rowspan=1 colspan=1> Aldehyde dehydrogenase</td></tr><tr><td rowspan=1 colspan=1> Zinc finger protein 43</td></tr><tr><td rowspan=1 colspan=1> IGF binding protein</td></tr><tr><td rowspan=1 colspan=1> GTP binding protein</td></tr><tr><td rowspan=1 colspan=1> MAGP</td></tr><tr><td rowspan=1 colspan=1> Serum amyloid A</td></tr><tr><td rowspan=1 colspan=1> Methyl CpG binding protein</td></tr></tbody></table>
Table 2.Genes for which the effect of age on expression appears to be different in C57BL/6 mice and men
There were 13 transcripts for which a decision about concordance or discordance between mice and men could be made based on both SAGE and microarray data. In 11 cases, SAGE and the microarray analysis led to the same decision. In only two cases (calmodulin and p130 PITSL cyclin kinase) was there a conflict between the decisions based on SAGE and microarray results (and therefore no decision about concordance or discordance was made). SAGE supported the finding of reduced expression of these transcripts in older muscle, whereas the microarray method indicated that older human muscle does not have reduced expression of these genes.
The effects of age that were the largest in mice were no more likely than smaller effects to be observed in humans. The mean effect in mice was 2.4 ± 0.8-fold (mean and standard deviation) for the results concordant with the human data and 2.9 ± 0.9-fold for the results discordant with the human data.
In mice, 63% of the age-related changes in gene expression were either completely prevented or partially inhibited by caloric restriction. However, reversibility by caloric restriction was not a predictor of concordance in the effect of age in mice and men. The effect of age in mice was inhibited by caloric restriction in the case of 10 of the 17 genes (59%) listed inTable 1(concordant results) and 26 of the 32 genes (81%) listed inTable 2(discordant results).
DISCUSSION
Methods for parallel analysis of thousands of transcripts are beginning to reveal the changes in gene expression associated with senescence. Lee et al. (15) were the first to report the effect of age on the gene expression profile of a mammalian skeletal muscle. For those interested in sarcopenia in humans, it is important to know the extent to which observations in mice are relevant to the aging of human muscle. The final answer to this question will require more research, but our recent SAGE study of young and old human muscle provided an opportunity to estimate the extent to which age-related changes in murine muscle are also evident in human muscle. Because of imprecision of SAGE when tag counts are very low, and because of lack of information about how well SAGE results would support Affymetrix microarray results even when examining the same tissue in the same species, we also analyzed the human RNA with Affymetrix microarrays. Overall, based on the combination of SAGE and microarray results, we found that the effect of age on expression of specific genes in mice appeared to be similar in humans in about one-third of the cases for which a decision could be made. Thus we must be cautious about generalizing effects of age on gene expression in muscle of inbred mice to effects of age in human muscle.
Genes encoding proteins involved in glucose and energy metabolism tend to be underexpressed in older muscle in both mice and men (15,29). This finding is consistent with phenotypic, histochemical, and biochemical data indicating a reduced capacity for energy metabolism in older muscle (4,19,22). In humans, the age-related reduction in transcripts encoding glycolytic enzymes might be related to a relative reduction in the mass of type 2 fibers (29). The reduced expression in older murine muscle of several genes encoding enzymes involved in protein turnover is consistent with the slower protein synthesis in older human muscle (24,30). A few genes involved in reinnervation of muscle fibers were found to be overexpressed in older murine muscle, which is consistent with histological evidence for denervation-reinnervation cycles with aging of human muscle (17). Even though some of the gene expression data from mice are consistent with histological or biochemical human data, some of the specific genes involved in protein turnover and reinnervation that were differentially expressed in young and old murine muscle were not differentially expressed in young and old human muscle.
Lee et al. (15) listed nine stress response genes that were expressed at a higher level in old muscle than in young muscle of mice. They also noted that increased expression of another gene, sarcomeric mitochondrial creatine kinase, could reflect inactivation of its protein product by oxidative stress. We concluded that 5 of these 10 genes did not have increased expression in older human muscle. No concordance/discordance decision about the other five genes was made, but their expression was not detected in either young or old human muscle by either SAGE or by the microarray. Thus, even if there is some increase in expression of these genes in older human muscle, the absolute level of expression remains very low. Of course, this observation does not mean that accumulation of oxidative damage to macromolecules is not involved in the aging of human muscle, only that the ambient level of oxidative stress under basal conditions is not sufficient to trigger expression of these specific stress response genes.
There were 17 genes for which the effect of aging on expression appeared to be the same in mice and men (Table 1). It must be emphasized thatTable 1is a preliminary list, and that prospective studies are needed to confirm that aging alters the expression of these genes. One of the genes that appears to be more highly expressed in older muscle of both mice and humans, the transcription factor PEA3, has already been found to be expressed at a higher level in senescent muscle of rats (20). Pro-collagen I and III genes appear to be expressed at a lower level in older muscle of both mice and men, which is consistent with an age-related reduction in collagen I and III mRNA in myocardium of rats (25). Another of the genes expressed at a lower level in older muscle of both mice and humans, an ATP synthase subunit, was examined in individual human samples by quantitative RT-PCR (29). The age-related difference was highly significant according to this analysis, as were declines in senescent human muscle of several other transcripts encoding proteins involved in ATP synthesis and mitochondrial electron transport.
Many of the differences in gene expression between young and old murine muscle were not evident in human muscle. There are several possible reasons for the discrepancies other than the obvious one of species difference. These include false positives and false negatives in the databases, differences in the fiber type distributions or pattern of use in the particular muscles examined, the possibility that mice and men were examined at different relative biological ages, the effects of inbreeding on aging of the mice, more stringent selection for healthy aging in the human subjects, and limitations on physical activity imposed by caging the mice. These factors are discussed in the following paragraphs.
Some of the effects of age that were observed in mice might have been false positives that would not be confirmed with another group of mice or with an independent method. Lee et al. (15) reported differences of approximately twofold or more, based on the average of all nine individual comparisons between three mice in each age group. An independent method was not used to validate the microarray data, but in a later study (by the same group) age-related differences in gene expression in the brain were confirmed by quantitative RT-PCR for six of seven genes (16). However, the analysis of large gene array databases is a new field, and it is not clear how many of these differences would be verified in a prospective study.
There could be some “false negatives” in the human SAGE and microarray databases due to analytical imprecision. For the seven discordance decisions based only on SAGE, we were >90% confident that sampling error could not explain the discordance. For the 17 discordance decisions based only on the microarray method, the likelihood of a false negative result is low because strict criteria were used to define discordance. For the other eight discordance decisions, both SAGE and the microarray method were in agreement. Thus, for a few transcripts, we might have falsely concluded that aging did not have the same effect in mice and men. However, the number of such errors would be too small to alter the conclusion that discordant results are more frequent than concordant results when comparing the effect of age on expression of specific genes in mice and men.
The gastrocnemius muscle was studied in mice, and the vastus lateralis was studied in men. Although some of the results might have been different had the same muscle been studied in mice and men, we are most interested in effects that are evident in all muscles that suffer loss of mass and function in both humans and animal models. Nevertheless, it is worth noting some similarities and differences between these muscles both within and across species. Both human vastus lateralis and murine gastrocnemius have a mixture of different fiber types, and both are involved in the locomotion associated with routine daily activities. The aging of human gastrocnemius has been studied less extensively than the aging of vastus lateralis, but it appears to be similar with respect to selective type 2 fiber atrophy and fiber type grouping (4,14). Although one study reported reduced mitochondrial enzyme activity (including citrate synthase) in gastrocnemius of older subjects (4), similar to what has been observed in vastus lateralis (22), another study indicated that the modest decline (−21%) in citrate synthase activity in gastrocnemius of older men was not evident in vastus lateralis (−11%) (13). There is very little quantitative information on the aging of gastrocnemius muscle in mice. Some effects of aging on this muscle in mice are similar to effects that have been observed in human vastus lateralis, including fiber atrophy, lipofuscin accumulation, and mitochondrial abnormalities (18). In rats, the gastrocnemius and vastus lateralis muscles appear to undergo similar atrophic changes with senescence (8), but such a comparison has not been reported for mice. In human vastus lateralis, loss of bulk with age is related both to loss of fibers and atrophy (17). In various muscles of mice, the relative contributions of fiber loss and fiber atrophy to the age-related sarcopenia are variable (5,12,23), but gastrocnemius and vastus lateralis have not been examined.
Lee at al. (15) studied 5-mo-old and 30-mo-old mice. If the average life span of C57BL/6 mice is 30 mo (15) and that of a man living in the United States is 72 yr (11), then a 5-mo-old mouse has lived 17% of its life and a 23-yr-old man (mean age of the young men in this study) has lived 32% of his. A 30-mo-old mouse and a 71-yr-old man (mean age of older men in this study) have lived about as long as they were expected to live at the time of their birth. However, other studies have suggested that the average life span of C57BL/6 mice is closer to 25 mo (10,27). Thus the mice used in the microarray study might have been unusually old for this strain. Age as a fraction of the expected life span might not be the best indicator of the stage of biological senescence. Perhaps some of the age-related changes occur earlier or later in life (relative to mean life span) in mice than in men. Studies with a more detailed time course for postmaturational changes in gene expression, in both mice and men, would be required to address this issue.
Inbred mice might have some genetic characteristics influencing the aging process that would be rare in outbred mice or in other mammalian species. Such characteristics might influence gene expression in muscle only indirectly, for example, by altering behavior, hormone levels, or nonlethal pathologies. The overall health status of the 30-mo-old mice studied by Lee et al. (15) is unclear. The older men who donated muscle were carefully examined and found to be free of any significant acute or chronic medical problems or neuromuscular abnormalities. It must be emphasized that the selection of healthy older men does not result in a sample of subjects who have escaped the effects of aging on skeletal muscle. In our previous studies using the same selection criteria, we have documented age-related changes in muscle, including loss of mass and strength, slower protein synthesis, and an increased incidence of abnormal mitochondria (manifested as ragged red fibers) (21,30,31).
Physical activity must be considered in the interpretation gene expression in muscle. The confinement of mice in cages limits their physical activity. A lifetime of inactivity could influence the impact of aging on gene expression. It would be interesting to see if mice given access to running wheels or other devices to stimulate physical activity have the same changes in gene expression as mice maintained under standard conditions. The men who donated muscle for the SAGE study had no restrictions on their lifetime physical activity, but we excluded men with a recent history of a very high level of activity, and asked them to refrain from any strenuous activities for a few days before the biopsy. Old age often is associated with reduced physical activity (7), which might be more important than age per se in determining the expression of some genes.
Although the number of murine genes is not known, a rough estimate is that ∼10% of them were sampled by the microarray. Sampling ∼10% of the genes resulted in the discovery of ∼100 genes differentially expressed in young and old muscle. The present study suggests that fewer than half of these differences also occur in human muscle. Thus aging probably alters the expression of fewer than ∼500 genes in both species, assuming that a similar proportion of differentially expressed transcripts and a similar degree of concordance between species would be found among the unsampled genes. Identification of these genes may help to elucidate the etiology of sarcopenia and compensatory adaptations in old muscle.
We thank Dr. K. W. Kinzler for providing the SAGE protocol and software.
This research was supported by National Institutes of Health Grants AG-17891, AG-10463, AG-13070, RR-00044, and AG-18254 and by a Paul B. Beeson Physician Faculty Scholar Award to C. A. Thornton from the Alliance for Aging Research.
| https://journals.physiology.org/doi/full/10.1152/physiolgenomics.2001.5.2.67 |
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Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
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Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
Cite
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
<here is a image 0be9fc1ef745405a-7885278dd5f40684>
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Cite
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Disability design and innovation in computing research in low resource settings
<here is a image 03afd8993ddd7e2f-562efde35f46bbad>
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
These tools help visually impaired scientists read data and journals
<here is a image 0c627494b34d1749-918050291c4981b0>
Type
Book
Research Group
Disability Interactions
Disability Interactions Creating Inclusive Innovations
Catherine Holloway,Giulia Barbareschi
; 2021
Abstract
Disability Interactions Creating Inclusive Innovations
Disability interactions (DIX) is a new approach to combining cross-disciplinary methods and theories from Human Computer Interaction (HCI), disability studies, assistive technology, and social development to co-create new technologies, experiences, and ways of working with disabled people. DIX focuses on the interactions people have with their technologies and the interactions which result because of technology use. A central theme of the approach is to tackle complex issues where disability problems are part of a system that does not have a simple solution. Therefore, DIX pushes researchers and practitioners to take a challenge-based approach, which enables both applied and basic research to happen alongside one another. DIX complements other frameworks and approaches that have been developed within HCI research and beyond. Traditional accessibility approaches are likely to focus on specific aspects of technology design and use without considering how features of large-scale assistive technology systems might influence the experiences of people with disabilities. DIX aims to embrace complexity from the start, to better translate the work of accessibility and assistive technology research into the real world. DIX also has a stronger focus on user-centered and participatory approaches across the whole value chain of technology, ensuring we design with the full system of technology in mind (from conceptualization and development to large-scale distribution and access). DIX also helps to acknowledge that solutions and approaches are often non-binary and that technologies and interactions that deliver value to disabled people in one situation can become a hindrance in a different context. Therefore, it offers a more nuanced guide to designing within the disability space, which expands the more traditional problem-solving approaches to designing for accessibility. This book explores why such a novel approach is needed and gives case studies of applications highlighting how different areas of focus—from education to health to work to global development—can benefit from applying a DIX perspective. We conclude with some lessons learned and a look ahead to the next 60 years of DIX.
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Disability Interactions Creating Inclusive Innovations
<here is a image f2029e42598e251c-f9378da486987b1b>
Type
Conference Paper
Themes
Assistive & Accessible Technology
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C
The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78].
ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020
Abstract
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression.
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Value beyond function: analyzing the perception of wheelchair innovations in Kenya
| https://www.disabilityinnovation.com/publications?subject=prosthetics&type=report+book+conference-paper+phd+article |
Refworld | Bahrain: Human rights developments and Amnesty International's continuing concerns
Refworld is the leading source of information necessary for taking quality decisions on refugee status. Refworld contains a vast collection of reports relating to situations in countries of origin, policy documents and positions, and documents relating to international and national legal frameworks. The information has been carefully selected and compiled from UNHCR's global network of field offices, Governments, international, regional and non-governmental organizations, academic institutions and judicial bodies.
Bahrain: Human rights developments and Amnesty International's continuing concerns
Publisher Amnesty International
Publication Date 21 November 2000
Citation / Document Symbol MDE 11/003/2000
Cite as Amnesty International, Bahrain: Human rights developments and Amnesty International's continuing concerns , 21 November 2000, MDE 11/003/2000, available at: https://www.refworld.org/docid/3b83b6dc0.html [accessed 4 June 2023]
1. Introduction
Compared with the mid-1990s civil unrest period, the human rights situation in Bahrain in the last two years has witnessed significant improvements. There are fewer cases of arbitrary arrest or reports of torture and ill-treatment, for example. However, the mechanisms that facilitated the deterioration of the human rights situation during the unrest are still in place. These include the use of incommunicado detention which often facilitates torture or ill-treatment of prisoners, administrative detention and trials before the State Security Court whose procedures fall far short of international standards for fair trial.
The unrest started in December 1994 when thousands of people demonstrated and called for the restoration of the National Assembly which was dissolved in 1975 by order of the late Amir, Shaikh 'Issa bin Salman Al Khalifa and respect for the Constitution, sections of which have also been suspended since 1975. During the unrest gross human rights violations took place which included the arbitrary detention of thousands of people, including children and women, without charge or trial, systematic use of torture against detainees which led to at least 10 deaths in custody, the killing of civilians during demonstrations in circumstances suggesting that they may have been extrajudicially executed, grossly unfair trials before the State Security Court and the forcible exile of a number of alleged dissidents. There were many acts of violence during the unrest and Amnesty International recognized Bahrain's rights and responsibilities to maintain law and order, and urged that such measures should be consistent with human rights safeguards and not at their expense. Amnesty International documented its human rights concerns during this period in the reports entitled Bahrain: A human rights crisis(AI Index: MDE 11/16/96) and Bahrain: Women and children subject to increasing abuse(MDE 11/18/96), published in September 1995 and July 1996, respectively. However, the organization has long-standing human rights concerns in Bahrain which include administrative detention, unfair trials, forcible exile and torture and ill-treatment which continue to date, albeit on a lesser scale. Most of the victims of human rights violations are Shi'a Muslims who form the majority in Bahrain.
The Amir of Bahrain, Shaikh Hamad bin 'Issa Al Khalifa, acceded to power in March 1999 following the death of his father. Since then the Government of Bahrain has introduced a number of positive changes in the promotion and protection of human rights, including the release of hundreds of political prisoners. The Amir has publicly stated his commitment to the respect of human rights. These and other positive human rights development are highlighted in Section 1 of this report, and Amnesty International has publicly welcomed them. However, the organization remains concerned that human rights violations continue to take place and that some of the legislation, in force in the country since 1974, which in the past was a major contributing factor to the perpetration of gross human rights violations, has not been amended and continues to be used. In addition, the Bahraini Government continues to use the policy of forcible exile as a punitive measure against Bahraini dissidents and their families. These concerns are discussed in subsequent sections of this report.
At the end of June 1999 Amnesty International delegates visited Bahrain to hold introductory talks with Bahraini Government officials. This was the first visit to the country by Amnesty International in 12 years. Detailed discussions took place with the Ministers of the Interior, Justice and Islamic Affairs, Foreign Affairs, and Labour and Social Affairs, as well as with senior judges and other officials. The talks focussed on Amnesty International's human rights concerns and human rights promotion in the country. Amnesty International publicly welcomed the opening of a constructive dialogue with the authorities, but it also expressed its regret at the time that its delegates were not permitted to meet privately with other sectors of society concerned with the promotion and protection of human rights, including lawyers, journalists, medical doctors, women's groups and others. Another meeting with Bahraini officials took place at the Bahraini Embassy in the United Kingdom in July 2000 and discussions focussed on human rights developments in the country as well as Amnesty International's concerns. The organization sent a memorandum of its concerns to the Bahraini Government in November 1999 and sought the government's comments on the memorandum. Amnesty International also requested another visit to take place before the end of 2000. The organization received assurances that its delegates would be free to meet whoever they wish to meet on their next visit. At the time of writing this report no comments on the memorandum had been received. However, Amnesty International has included in this report the government's responses to a number of concerns raised in meetings in Bahrain and the United Kingdom.
Amnesty International is publishing this report, which is based on the memorandum, in the hope that it may contribute to the human rights debate now underway in the country. The organization believes that if the recommendations of this report are implemented they could help to bring Bahrain's law and practice into closer harmony with recognized international human rights standards.
2. Positive human rights developments
The Bahraini Government has taken a number of positive legislative and practical steps in the human rights field, including the release of hundreds of political prisoners, the setting up of a human rights unit within the Majlis al-Shura(Consultative Council), allowing a greater margin of freedom of expression as well as giving women the right to vote and stand as candidates in the up-coming local elections for the first time.
Since his accession to power in March 1999 the Amir, Shaikh Hamad bin 'Issa Al Khalifa, has ordered the release of more than 800 political prisoners and detainees, including prisoners of conscience.(1) The first amnesty was issued on 6 June 1999 when the Amir ordered the release of 320 people held without charge or trial in connection with anti-government protests and 41 political prisoners serving prison terms. On 17 November 1999 he ordered the release of another 200 political prisoners and detainees. On the occasion of Bahrain's national day, 16 December, 195 political detainees and prisoners were released following a pardon from the Amir. Another 37 prisoners and detainees were released during the second half of March 2000 following an amnesty by the Amir to mark the religious Islamic holiday of 'Id al-Adhha(feast of the sacrifice). To mark the Islamic new year on 5 April 2000 the Amir also ordered the release of 43 detainees held for involvement in anti-government protests. Most of those released were held without charge or trial, some for up to five years. Others had already served their sentences and were held beyond the expiry of their sentences. These releases, however, were conditional: prisoners and detainees had first to sign statements undertaking not to be involved in any anti-government activities. Following their release they were reportedly pressurized to give interviews to Bahraini newspapers in which they deplored their past actions and promised good behaviour in the future.
In October 1999 the Amir issued a decree authorizing the setting up of a Human Rights Committee within the Majlis al-Shura. Article 2 of the decree states that the Committee will be made up of six members, five of them to be elected by the Majlisat the beginning of each session of the Majlis(October) and the President of the Council appoints one of his two deputies as the sixth member and also as the Head of the Committee. According to the decree, the Human Rights Committee's tasks include studying all human rights legislation and regulations in force in Bahrain, proposing amendments in order to protect human rights, the promotion of human rights awareness and establishing and strengthening cooperation with international human rights organizations. Many Bahrainis reportedly filed complaints with the Human Rights Committee regarding such diverse issues such as dismissal from work, detention without charge or trial of a relative and ill-treatment by the police. These complaints were referred to the relevant ministries. However, the complaints have reportedly not been acted upon. To Amnesty International's knowledge the Committee has not made any proposals regarding legislative amendments. This Committee has been criticized in the Bahraini press for its apparent lack of activities.
The Amir has publicly pledged his commitment to the respect of human rights. He stated that human rights "will continue to be one of the main concerns of the state in Bahrain".(2) In an interview with Cable News Network (CNN) at the beginning of August 2000 he said that he was ready to allow free access to human rights groups, including Amnesty International.
At the end of 1999 in his speech to mark Bahrain's national day on 16 December the Amir announced that local elections would be held and that women would be able to vote and stand as candidates. As of October 2000 the date for the elections had not been set. In the same speech the Amir stated that all Bahraini citizens "are equal before the law and have equal rights and duties within the framework of our national unity and our united Bahraini family, that does not accept differentiating between one citizen and another except on the basis of good citizenship".
In May 2000 the Bahraini Government announced plans for an elected Majlis al-Shurain 2004 in which women will be allowed to vote and stand as candidates, but without specifying whether the Majliswill have legislative powers. The all-male Council, set up in 1992 following a decree from the late Amir, reviews laws drafted by the cabinet before they are sent to the Amir for final approval. In 1996, the size of the Council was increased to 40 from 30 members reportedly to widen popular representation. The Council has no legislative powers and has a four-year term which starts in October.(3) At the end of September 2000 the Amir issued Decree No. 29 appointing members of the new Council. Nineteen new members, including four women for the first time, were named and the remaining 21 were re-appointed from the outgoing Council. At the opening of the Majlis al-Shura's ninth term on 3 October 2000 the Amir announced that there will be a new constitutional and administrative set up in Bahrain before the end of this year and that this set up will be put forward to the Bahraini people, but without giving further details. There are no political parties in Bahrain and Bahraini opposition groups in exile(4), as well as a few journalists within the country expressed concern that this may mean amending the constitution without recourse to the "legitimate due process prescribed by the constitution".(5)
Since December 1999 when the Amir urged Bahraini journalists and writers to "express freely citizens' aspirations" and called on government officials to "accept constructive criticism for it serves the interests of the country" some Bahraini newspapers have carried columns dealing with issues that were taboo in the past, such as democracy, free elections, upholding the rule of law and respect for human rights. Seminars on these subjects have been organized and have been publicised in the media. In August 2000 a Journalists' Association was created to, among other things, defend journalists' rights, ensure "the necessary freedom to carry their professional duties", and to contribute to the spreading of the media awareness in the country.(6) This association is under the control of the Ministry of Cabinet Affairs and Information and, like other associations in Bahrain, therefore is not an independent trade union body.
Bahrain ratified the United Nations Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (Convention against Torture) in March 1998, initially with a reservation to Article 20.(9) However, this reservation was withdrawn as was announced by Bahraini's delegation at the Sub-Commission on Prevention of Discrimination and Protection of Minorities [now called Sub-Commission on the Promotion and Protection of Human Rights] in Geneva in August 1999. The delegation also stated that "possible accession to the Convention on the Elimination of all Forms of Discrimination against Women [CEDAW] is under consideration". Bahrain acceded to the International Convention on the Elimination of all Forms of Racial Discrimination (CERD) in March 1990, and ratified the Convention on the Rights of the Child (CRC) in 1992. Amnesty International urges the Bahraini Government to ratify other vitally important international human rights treaties, particularly the International Covenant on Civil and Political Rights (ICCPR). In June 1999 Amnesty International delegates visiting Bahrain saw very little evidence that the Government of Bahrain had conducted any public-awareness raising campaigns regarding its ratification of international human rights treaties. The organization is urging the authorities to devise sensitization programmes in relation to the rights protected by these instruments, the safeguards which are present in domestic law and ways in which individuals could access courts and other government institutions to obtain redress for violation of these rights. In addition, specific human rights training for law enforcement personnel is essential.
The Bahraini authorities have also announced that they have invited the UN Working Group on Arbitrary Detention to visit the country between 25 February and 3 March 2001. The visit was scheduled to have taken place in 1999 but was twice postponed by the government. The government has also continued to cooperate with the International Committee of the Red Cross (ICRC) allowing the latter to visit persons arrested and detained on a regular basis, in accordance with the Memorandum of Understanding signed by the two parties in October 1996.
Amnesty International has welcomed these positive steps undertaken by the Bahraini Government in the human rights field in recent years. However, the organization remains very concerned by the on-going serious violations, including the use of administrative detention, unfair trials before the State Security Court, allegations of torture and ill-treatment, forcible exile and constraints on human rights defenders. Amnesty International has been raising these concerns with the Bahraini authorities for many years and the time for action is now long overdue.
3. Administrative detention
The Decree Law on State Security Measures, in force since October 1974, empowers the Minister of the Interior to detain individuals without charge or trial for up to three years.(10) Detainees held under this provision are only permitted to submit a tadhallum(petition) to the High Court of Appeal three months after the issuing of their arrest warrant, and thereafter, six months after every decision rejecting the petition, thus denying the defendants the right to a prompt review of their detention before a court of law. Bahraini officials told Amnesty International that it has been necessary, since 1994, to use these provisions since there were insufficient court resources for the trials which would have followed upon the detainees having been indicted. The organization was also told that the reason why detainees are kept for up to three years without charge or trial was that the authorities "did not want to give them criminal records". These explanations fail to justify the grave violations of human rights which administrative detentions, especially for such long periods, entail. The absence of due process constitutes a serious violation of human rights which inflicts imprisonment without giving the detainee any opportunity to prove his or her innocence.
The wording of Article 1 of the decree allows arrest and detention of an individual in extremely wide and nebulous circumstances (see footnote 9). The law provides neither additional clarification of what may constitute "serious evidence" nor further definition of the acts described in Article 1. Officials at the Ministry of the Interior stated that these provisions were used only in cases when an individual was suspected of having used violence and that arrests did not in reality take place in circumstances as broad as were provided for. However, the cases highlighted below clearly indicate that the provisions contained in Article 1 of the Decree have been used to detain prisoners of conscience.
Administrative detainees are not made fully aware of their right to lodge a complaint or informed about how the complaint would be processed. At times lawyers have lodged complaints on behalf of detainees but these complaints were simply ignored, which discouraged some lawyers from submitting any complaints. Only on two occasions were lawyers reportedly successful in having their complaints examined by the High Court of Appeal. This was when they challenged the detention of two prominent figures, al-Shaikh 'Abd al-Amir Mansur al-Jamriand 'Abd al-Wahab Hussain(see below).
The current practice clearly violates international human rights standards. For example, Article 9 of the International Covenant on Civil and Political Rights stipulates that
"No one shall be subjected to arbitrary arrest or detention.... Anyone arrested or detained on a criminal charge shall be brought promptly before a judge or other officer authorized by law to exercise judicial power and shall be entitled to trial within a reasonable time or to release."
Article 14 of this Covenant includes the following provisions:
3. In the determination of any criminal charge against him, everyone shall be entitled to the following minimum guarantees, in full equality:
(a) To be informed promptly and in detail in a language which he understands of the nature and cause of the charge against him...
(c) To be tried without undue delay;
4. Anyone who is deprived of his liberty by arrest or detention shall be entitled to take proceedings before a court, in order that court may decide without delay on the lawfulness of his detention and order his release if the detention is not lawful.
While Bahrain is not yet a state party to this Covenant, the guarantees in these Articles embody general principles of law which are universally recognised. This was acknowledged by the Bahraini Government itself when, writing to the UN Working Group on Arbitrary Detention, it claimed that "all detentions are compatible with the provisions of the Universal Declaration of Human Rights and the International Covenant on Civil and Political Rights, although Bahrain is not a party to the latter."(11)
Principle 11(1) of the Body of Principles for the Protection of All Persons under Any Form of Detention or Imprisonment (Body of Principles) states that "A person shall not be kept in detention without being given an effective opportunity to be heard promptly by a judicial or other authority. A detained person shall have the right to defend himself or to be assisted by counsel as prescribed by law."
The UN Working Group on Arbitrary Detention has, on several occasions, pointed out this incompatibility of the 1974 law with international standards. Thus in 1998 the Working Group expressed the following opinion:
In respect of the application of the State Security Law of 1974, the Working Group refers to its previous Opinion No. 1995/35, especially paragraphs 5, 9 and 12 to 17 thereof, in which the Group concluded that the application of the Law may result in serious violations of the right to a fair trial guaranteed by articles 9 and 10 of the Universal Declaration. Its application is also contrary to principles 10 to 13, 15 to 19 and 33 of the Body of Principles for the Protection of All Persons under Any Form of Detention or Imprisonment.(12)
The Working Group urged the Bahraini Government "to take the necessary steps to remedy the situation and to bring it into conformity with the principles and standards set forth in the Universal Declaration of Human Rights."(13).
Amnesty International shares the view of the Working Group and would urge the Bahraini Government to revoke the decree and in future to arrest and detain suspects in accordance with international human rights standards.
In June 1999 Amnesty International was informed by government officials that between 400 and 500 people were still held without charge or trial. Since then scores have been released or tried and sentenced, but new arrests have taken place frequently. In November 1999 Amnesty International requested details regarding administrative detainees, including their names, places of detention, date of arrest, and the exact date of their release if there were plans to release them. The organization also requested details regarding the exact charges against detainees who were awaiting trial and sought assurances that their trials would meet internationally agreed standards for fair trials. As of October 2000 no response had been received.
However, among the people currently detained are five prisoners of conscience held since January 1996 without charge or trial. They are: al-Shaikh Hassan Sultan, al-Shaikh Hussain al-Deihi, Hassan Msheima', Sayyed Ibrahim 'Adnan al-'Alawi, 'Abd al-Wahab Hussain. The five, all prominent Shi'a Muslim leaders, were arrested on 21 and 22 January 1996. Their arrest followed mass protests against the closure by security forces of a number of mosques where prominent Shi'a Muslim leaders, including them, had been peacefully calling on the government to restore the parliament. Other prominent leaders arrested at that time included al-Shaikh 'Abd al-Amir Mansur al-Jamri, al-Shaikh 'Ali Ashurand al-Shaikh 'Ali bin Ahmad al-Jeddhafsi. Al-Shaikh al-Jamri was pardoned and released in July 1999 almost immediately after he had been sentenced to 10 years' imprisonment (see Section 4). Al-Shaikh 'Ali bin Ahmad al-Jeddhafsi was released on 26 July 1999, after three and a half years of detention without charge or trial, whereas al-Shaikh 'Ali 'Ashur was released at the beginning of September 2000 after more than four and a half years of detention without trial. All three were required to sign statements apologizing for their past political activities and committing themselves not to be involved in any political or social activities in the future.
Amnesty International has repeatedly called for the unconditional release of all prisoners of conscience held in Bahrain, including the five people mentioned above.
4. Violations of the right to fair trial
Political trials in Bahrain continue to be held before the Supreme Civil Court of Appeal, in its capacity as a State Security Court, whose procedures fall far short of internationally recognized standards for fair trial. This court is designated by Article 185 of the Penal Code to handle trials in relation to charges defined in Articles 112 to 184 of the Penal Code and relating to the internal and external security of the state. Decree No. 7 of 1976 was therefore issued setting up this special court and laying out exceptional provisions regulating its proceedings.
Hearings before this court are invariably held in cameraor with attendance restricted to only the closest relatives of the defendant, in breach of Article 10 of the UDHR which provides that everyone is entitled to a public trial. According to Article 5(5) of the 1976 Decree, defendants before this court may be convicted on the basis of "confessions" given to police or a police testimony that such "confessions" were given. Such "confessions" were in the past routinely obtained through the use of torture or other ill-treatment and the court failed to investigate claims of torture. This violates Bahrain's Constitution, Article 19(d) of which stipulates:
"No person shall be subjected to physical or mental torture, enticement or degrading treatment, and the law shall provide the penalty for these acts. Any statement or confession shall be null and void if it is proved to have been made under duress or enticement or degrading treatment or threat thereof."
The failure of this court to carry out prompt and impartial investigations of allegations of torture and other forms of ill-treatment is inconsistent with Bahrain's obligations under international human rights treaties, particularly the Convention against Torture.
This court is also not required to summon witnesses to give evidence or for cross-examination. Such evidence may be submitted in writing. There is no right of appeal against conviction and sentence. In June 1999 the Bahraini authorities told Amnesty International that the proceedings of the court provided a speedy disposal of criminal charges and that if an appeal mechanism were to be created, there may well be a reduction of the current estimated 40% acquittal rate. However, if 40% of defendants are indeed acquitted by this court, this raises serious questions regarding the legal evidential basis on which so many cases are proceeding to trial.
Detainees awaiting trial are usually held incommunicado and have no access to lawyers. Although defendants may have appointed lawyers of their own choosing, the first contact can only take place on the first day of their trial, just moments before the opening of the session.
These procedures violate internationally recognized standards for fair trial. Article 14 of the International Covenant on Civil and Political Rights includes the provision that "everyone shall be entitled to a fair... hearing by a competent, independent and impartial tribunal established by law..." as well as the rights,
"...3(b) To have adequate time and facilities for the preparation of his defence and to communicate with counsel of his own choosing...
(e) To examine, or have examined, the witnesses against him and to obtain the attendance and examination of witnesses on his behalf under the same conditions as witnesses against him...
(g) Not to be compelled to testify against himself or to confess guilt."
Article 14(5) of the Covenant provides that "Everyone convicted of a crime shall have the right to his conviction and sentence being reviewed by a higher tribunal according to law."
Similarly, these procedures violate other international standards, including Articles 10 and 11 of the Universal Declaration of Human Rights and Principles 15 and 18 of the UN Body of Principles.(14) They also violate Article 20 (c) of Bahrain's Constitution, which states that:
"An accused person shall be presumed innocent until proved guilty in a legal trial in which the necessary guarantees for the exercise of his right of defence in all the stages of investigation and trial are ensured in accordance with the law."
In a letter sent to Amnesty International in September 1998 the Bahraini Government stated that
"...Concerns that those appearing before the so-called "State Security Court" (in reality the High Court of Appeal sitting to hear state security offences as prescribed by law) may not receive a fair trial are absolutely unfounded, and based on a fundamental misconception of the law. The Court's enabling legislation (Legislative Decree No.7 of 1976) specifically states that the Court is bound as an overriding priority by the provisions of Bahrain's Code of Criminal Procedure, 1966. In summary, the Code of Criminal Procedures applies to all Criminal trials in Bahrain and fully provides for all internationally established legal, evidential and procedural principles regarding fair trials. The High Court of Appeal therefore must, and in practice does, apply all the normal rules of criminal evidence and procedure in priority to any others. In short, the Court conducts itself in accordance with internationally recognized principles and procedural safeguards for a full and fair trial. Allegations of denial of proper legal advice and representation are also purely propagandist and, of course, untrue."
This statement however fails to address the absence of vital safeguards for fair trial in proceedings before the State Security Court, such as the right to have a fair and public hearing before a competent court, the defendants' right to have adequate time and facilities to communicate with lawyers of their own choosing and prepare their defence, their right not be compelled to testify against themselves or to confess guilt, and importantly, their right to have their conviction and sentence being reviewed by a higher tribunal. Amnesty International regards the provision of an appeal mechanism in relation to all determinations of criminal responsibility as an absolute safeguard that cannot be relinquished.
Scores of people have in the last 12 months been given prison sentences after unfair trials before this court. For example, on 3 May 2000 the State Security Court pronounced judgement in the case of 10 people charged with illegal activities and plotting to destabilize the country. Three people, 'Ali Mahdi Ahmad Youssef, Sa'eed al-Shaikh, and Hesham 'Ali Hassan Ahmadwere sentenced to seven, five and two years' imprisonment, respectively and fines. A fourth, 'Aqil al-Jaziri, was sentenced in absentiato seven years' imprisonment and a fine. Six people, including a Lebanese national, were acquitted. The nine people present were arrested at the beginning of November 1998 and were reportedly tortured while held incommunicado to extract confessions from them. No investigation into their torture allegations is known to have been carried out. They were detained without trial and without access to lawyers until 17 January 2000 when they appeared briefly before the State Security Court for the first time. One more court session took place on 29 January before the verdict was announced on 3 May.
Three women, Hanan Salman Ahmad Haidar, aged 21, Salwa Hassan Ahmad Haidar, aged 35, and Leeda Ahmad 'Issa al-'Oreibi, aged 27, appeared before the State Security Court in Jaw on 14 May 2000 and were sentenced to a one-year prison term each for "distributing leaflets and undertaking activities harmful to security". The three women were among a number of people arrested in November 1998. Hanan Haidar and Salwa Haidar were arrested on 4 November 1998 in al-Daih village near Manama and were reportedly tortured in 'Issa Town police station. No investigation into their torture allegation is reported to have been conducted. Leeda Ahmad 'Issa al-'Oreibi was arrested in Sanabis on 15 November 1998. She was held in al-Khamis police station. The three were all released on bail a few weeks later. After the sentencing the women were held in a detention centre in 'Issa town. They were released on 25 September 2000 reportedly following an amnesty.
Al-Shaikh 'Abd al-Amir Mansur al-Jamriwas tried in 1999 and sentenced to 10 years' imprisonment before he was released following a pardon from the Amir. He had been held without charge or trial for over three years. On 21 February 1999 he appeared before the State Security Court in Jaw on charges including incitement to acts of violence, sabotage and spying for a foreign country, which he denied in the court. He was given access to a government-appointed lawyer only one hour before the trial session began, and his family were able to appoint, during that session, four other lawyers to take charge of his defence. His wife and children were allowed to attend the trial session, which was otherwise held in camera. In detention, al-Shaikh 'Abd al-Amir al-Jamri was said to have been pressurized by members of the security service in March and April 1998 to sign a statement that he admitted responsibility for the civil unrest in the country. However, on several occasions when he was brought before an investigating judge he refused to sign any statement and stated that he had signed the previous one under duress. Al-Shaikh al-Jamri appeared again before the court on 4 July and on 7 July 1999 he was sentenced to 10 years' imprisonment and a fine equivalent to $US 15 million.
After the court had given its verdict al-Shaikh al-Jamri was reportedly taken to the Security and Intelligence Service (SIS) building and met with a senior security official who reportedly showed him a written statement and then told him that he had two choices: either to accept the conditions laid out in the statement and he would be released immediately or refuse these conditions with the outcome that he would spend 10 years in prison. The conditions included refraining from making any political demands, refraining from undertaking any social, political or religious activities, and officially asking for a pardon from the Amir. Al-Shaikh al-Jamri was apparently told that if he signed the statement he would be released immediately. He accepted the conditions, signed the statement and was released the following day after the Amir issued the pardon. Since his release al-Shaikh al-Jamri has been living under house arrest.
"While expressing his appreciation for Mr. Al-Jamri's release, the Special Rapporteur is nevertheless concerned at the lack of independence of the tribunal which tried and convicted him."(15)
5. Forcible exile as a form of punishment
The Bahraini Government's use of forcible exile as a punitive measure against suspected non-violent opposition activists or critics of the government remains a long-standing concern for Amnesty International. While in the late 1970s the victims were mostly trade unionists and others active in left-wing organizations, since the early 1980s, the victims had mostly been Shi'a Muslims suspected of having links with Iran. Until the beginning of the 1990s former political detainees and sometimes even entire families had been rounded up, stripped of their Bahraini passports or identity documents and forced to board boats bound for Iran, although they had no knowledge of that country or any family or relatives there.
In recent years, forcible exile has been imposed exclusively upon Bahraini nationals attempting to return to their country after many years spent abroad in voluntary exile or for educational purposes. Those who have attempted to return include the wives and families of a number of former political prisoners who had originally fled the country to escape harassment. Returning Bahraini nationals are usually detained at Bahrain International Airport, sometimes for up to 10 days, and interrogated about alleged political opposition activities. They are issued with new Bahraini passports valid for one year, which indicates that there is no dispute regarding their citizenship, yet which are not valid for Bahrain, and then they are returned to their former country of residence, or elsewhere, on the first available flight. No reasons for the expulsions or details of the legal basis for such measures are given. They are denied any opportunity to appeal against the decision to expel them or to challenge its legality through the courts.
Amnesty International has expressed its concern in relation to the policy of forcible exile on many occasions in the past and has documented many such cases.(16) This policy contravenes international human rights standards, including the Universal Declaration of Human Rights, Article 13(2) of which states that "Everyone has the right to leave any country, including his own, and to return to his country.", and Article 12(4) of the International Covenant on Civil and Political Rights. It also violates Article 17(c) of the Bahraini Constitution which states that "No citizen shall be deported from Bahrain, nor shall he be denied re-entry".
Officials in the Ministry of the Interior told Amnesty International in June 1999 that some of those deported were not Bahrain nationals and others had either obtained a passport of another state (which led to their automatically forfeiting their Bahraini passport) or had irregularities (not specified) in their documentation or did not have valid passports. They also stated that the reason why those arriving at the airport were given new Bahraini passports valid for a limited period of time and not valid for entry into Bahrain was that the Government of Bahrain wanted to help them to travel, as no other country would otherwise allow them entry. Almost all those forcibly exiled still have relatives and family members living in Bahrain. A number of Bahrainis had been allowed to go back to the country since the early 1990s following amnesties. For example, two amnesties were declared in April and June 1992 by the late Amir, Shaikh 'Issa bin Salman Al Khalifa, allowing the return of a total of 121 nationals living abroad, although the identities of those concerned were not made public.
The organization welcomed the two amnesties issued by the Amir, Shaikh Hamad bin 'Issa Al Khalifa on 6 June and 3 November 1999 allowing 32 people in exile to return to the country. Those who benefited, however, were required to write to the Amir requesting a pardon and promising good behaviour in the future. Once in Bahrain many were required to give interviews to newspapers thanking the government for allowing them into the country and promising good behaviour in future. There are an estimated 700 Bahrainis, including women and children, who are still currently prevented from returning to their country. Amnesty International also knows of a number of Bahraini nationals who wrote to the authorities after Shaikh Hamad bin 'Issa Al Khalifa acceded to power, seeking permission to return to their country but are still awaiting a response.
The following cases are a sample of dozens of Bahraini nationals who have been prevented from returning to their country in the course of the last two years:
'Abd al Jalil al-Nu'aimi
, aged 53, left Bahrain in 1975, two months after the dissolution of the parliament. He first attempted to return to Bahrain in 1993. He was held at the airport, issued with a new passport valid for one year and was forcibly returned to Syria. He has been living in the United Arab Emirates (U.A.E.) for the last five years. On 16 June 2000 he flew to Bahrain. He was held at the airport and was interrogated. He was told by the airport security authorities that he would not be allowed to enter the country since he had not sent a letter to the Amir asking for a pardon. He stated that he did not commit any crime and requested a meeting with the head of the Human Rights Committee of the
Majlis al-Shura
. This request was denied and his passport was renewed for one year and he was sent back to Dubai the following day.
Khadija Ahmad Gharib al-Qassab
, aged 41, married with four children, has been prevented from entering Bahrain because of her husband's alleged activities for an unauthorized Bahraini Islamist group. She left Bahrain in 1985 to marry in Syria. She has been living with her husband in Denmark since 1989. On 9 April 2000 she and her children attempted to return to Bahrain for the first time since 1985. At the airport they were held for four days during which she was interrogated and then sent back to Denmark. She was asked questions about her husband who had been living in exile since the early 1980s. The airport security authorities wanted to know her husband's activities, the reason he was not travelling with her and whether or not he had refugee status in Denmark. When she arrived at the airport her mother, brothers and sisters, all living in Bahrain, waited for hours but were not allowed to see her and her children.
Hashim Kadhim Sa'eed
left Bahrain in 1981 and went to live in India. In 1992 following the two amnesties announced by the late Amir he, his wife and their four children attempted to go back to Bahrain. They were held at the airport for three days during which they were interrogated and his expired passport, containing the names of his wife and children, was confiscated. Hashim Kadhim Sa'eed protested to the airport authorities about his detention and the refusal to let him and his family into the country. He stated that if he was suspected of any wrongdoing then he should be brought before a court of law. His protests were disregarded and they were given one new Bahraini passport for the whole family, valid for one year, and sent to Dubai. Hashim Sa'eed attempted to go back to Bahrain in 1998 with his family but were again turned away. In August 1999 he tried again on his own. On arrival at Bahrain International Airport he was held at the airport from 14 until 17 August, issued with a new one-year passport for the whole family and sent back to Dubai.
In some countries, especially in the Gulf, Bahraini exiles have difficulties in obtaining jobs with passports that have already expired or are valid for one year only. They have difficulties in enrolling their children into state schools since parents have to show passports valid for five years. Their grown up children also have difficulties in joining universities because they cannot produce valid passports.
Those who have not attempted to return to Bahrain in recent years and whose passports have expired are able to send their passports through Bahraini embassies for renewal in Bahrain. However they have to wait for months before they receive back their passports. Mahmoud Mohammad Ja'far Shaikh Mohsen al-'Arab, aged 41 married with children, was forced to leave Bahrain in August 1980. He had been arrested five times, the last of which was in July 1980, and was reportedly subjected to torture. He left Bahrain for India with a newly issued Bahraini passport valid for five years. He stayed in India for 14 years, during which he married a Bahraini national and had four children born there. His passport had already expired and he did not try to renew it at the Bahraini Embassy in India because he feared it could be confiscated. He attempted to enter Bahrain in October 1993 with his family. When they arrived at Bahrain International Airport on 12 October they were held for 30 hours and were interrogated. His wife's and his passports were confiscated and they were given two new passports and then deported to the U.A.E.. Both new passports were valid for one year and the wife's new passport contained the names and photographs of the children. They have been living in the U.A.E. since October 1993. In 1996 Mahmoud al-'Arab attempted with his family to enter Bahrain but were prevented and were sent back to Dubai. Every year they renew their passports at the Bahraini Embassy in Abu Dhabi. They wait for four months before they obtain their one-year passports. Mahmoud al-'Arab's and his wife's families and relatives are all in Bahrain. His wife's father died in Bahrain three years ago but she was not permitted to enter the country to attend his funeral.
Amnesty International is urging the Government of Bahrain to issue a public declaration that all Bahraini nationals are entitled to return to Bahrain as the policy of forcible exile violates international human rights standards as well as provisions contained in the Bahraini Constitution.
6. Torture, ill-treatment and impunity
Bahraini legislation clearly prohibits the use of torture. Article 19(d) of the Constitution states that "No person shall be subjected to physical or mental torture, enticement or degrading treatment, and the law shall provide the penalty for these acts. Any statement or confession shall be null and void if it is proved to have been made under duress or enticement or degrading treatment or threat thereof.". Article 208 of the Penal Code states that "Imprisonment [no terms given] shall be the penalty imposed on every public official who uses torture, force or threat, either personally or through a third party, against an accused person, witness or expert to force him to confess to having committed a crime or to give statements or information in respect thereof. The penalty shall be life imprisonment should the use of torture or force lead to death." These provisions notwithstanding, the use of torture against detainees to extract confessions has been widespread, particularly during the civil unrest from 1994 until 1997. A number of detainees died in custody in circumstances suggesting that their death was caused by torture or that torture was a contributory factor. Methods of torture include severe beating with electric cables on the back and on the soles of the feet, suspension by the limbs, victims being blindfolded and forced to stand for hours with their hands tied behind their back and solitary confinement. Amnesty International has over the years raised with the Government of Bahrain its concerns about allegations of torture and ill-treatment of individuals in detention, and has published numerous reports and released urgent appeals detailing cases of torture, especially during the civil unrest.
Incidents of torture have decreased since Bahrain ratified the Convention against Torture in March 1998. Nevertheless allegations of torture and ill-treatment have occasionally been reported since then. On 19 July 1998 Nuh Khalil 'Abdallah Al Nuh, aged 22, was arrested apparently in good health at his shop in al-Nu'aim, a district of Manama. Two days later his body was handed over to his family for burial bearing physical marks, suggesting that he had been tortured. The Bahraini Government was reported to have promised an investigation into the death. On 24 August 1998 Amnesty International wrote to the Government expressing grave concern at the death of Nuh Khalil 'Abdallah Al Nuh and urging that a prompt, independent and impartial investigation be set up and that details of the methodology or process, as well as the findings of such an investigation be made public. No investigation is known to have been carried out.
Mohammad Sa'eed al-Maqabi, a 32-year-old bus driver, arrived in Bahrain from a trip to Syria on 20 August 2000. He was stopped at a checkpoint on the causeway between Saudi Arabia and Bahrain and was searched. He was released but the security forces confiscated some of the books he was carrying. The following day he was re-arrested at his home in the village of Barbar, east of Manama, on suspicion that he had maintained links with a Bahraini opposition activist living abroad and who had been in the past been tried and acquitted. Mohammad Sa'eed al-Maqabi was reportedly tortured: he was suspended for hours during which he was beaten with a cable on the soles of the feet ( falaqa). As a result he lost consciousness and was taken to hospital. He was released on 28 August.
Amnesty International is particularly concerned at the large number of juveniles who have been arrested on suspicion they had written anti-government graffiti, detained for hours or days and reportedly subjected to various forms of torture or ill-treatment, including beating, being forced to stand continuously for long periods of time, sleep deprivation and sexual harassment, and then released. For example, on 27 July 2000 a number of juveniles, including al-Sayyid Mahmoud al-Sayyid 'Alawi al-Sayyid Ibrahimand al-Sayyid Jawwad al-Sayyid Hassan, both aged 16, were arrested in Abu Saiba'. They were held without charge for several days during which they were reportedly ill-treated before they were released. During the second week of August 2000, seven boys aged between 12 and 17, including Mahmoud Hassan, Taleb 'Ali al-Asfarand Hamza 'Ali al-Asfar, aged 15, 13 and 12, respectively, were arrested in the village of al-Daih and reportedly transferred to al-Khamis police station for interrogation, where they were at risk of torture or ill-treatment since they were held incommunicado. Families of detained juveniles are reportedly not notified until a few days after arrests have taken place.
Torture and ill-treatment of juveniles violate Article 37 (a) of the Convention of the Rights of the Child which states that "No child shall be subjected to torture or other cruel, inhuman or degrading treatment or punishment...", and Article 37 (b) which stresses that "No child shall be deprived of his or her liberty unlawfully or arbitrarily" and that "the arrest, detention or imprisonment of a child shall be in conformity with the law and shall be used only as a measure of last resort and for the shortest appropriate period of time".
The UN Special Rapporteur on torture has sent numerous communications to the Bahraini Government raising cases of allegations of torture, including of juveniles. His report to the 55th Commission on Human Rights in 1999 stated that "the Special Rapporteur is sufficiently concerned about persistent allegations of torture to have requested from the Government an invitation to visit the country".(17) In his reply to this request the Permanent Representative of Bahrain in Geneva stated that "an invitation should await the planned visit of the Working Group on Arbitrary Detention and that a joint visit, as tentatively suggested by the Special Rapporteur, risked complicating decision-making regarding cooperation with the Commission's mechanisms".(18)
Allegations of torture and deaths in custody in suspicious circumstances have rarely been investigated by the Bahraini authorities. This contravenes the requirements of the Convention against Torture, Article 12 of which calls for a "prompt and impartial investigation, wherever there is reasonable ground to believe that an act of torture has been committed in any territory under its jurisdiction".
Amnesty International was told by officials from the Ministry of the Interior in June 1999 that the Public Prosecutor's Office will have the responsibility for the conduct of investigations into allegations of torture and deaths in custody. (The Public Prosecutor's Office remains under the umbrella of the Ministry of Interior). Amnesty International was also told that a general procedure for the processing of complaints against the police is set out in the Public Security Ordinanceof 1982. Amnesty International received a copy of extracts from the Ordinance, including a full chapter ( Chapter IV - Disciplinary Actions and Trials), from the Government of Bahrain in August 1999. The chapter deals with the various disciplinary measures that members of the Public Security Forces would face if they infringe the rules contained in the Ordinance, or decisions issued by the Minister of the Interior, or directives issued by the Director-General of the Public Security, or crimes prescribed in the Code of Criminal Procedure. This chapter also discusses how investigations into these infringements are conducted and by whom, but there is no reference to any procedure enabling victims of torture or other human rights violations to lodge complaints against members of the Public Security alleged to have committed those violations or how to seek redress. Nor is there a reference to the provisions of Article 208 of the Penal Code. In addition, the impartiality and independence of the investigations are not guaranteed given that the Director-General of the Public Security orders the formation of the "Investigating Committee" which consists of two or more officers. An investigation under the Ordinancetherefore fails to meet the requirements of Convention against Torture, including that which obliges the Government of Bahrain to prosecute those alleged to have committed torture.
Amnesty International has welcomed the initiative of the Ministry of the Interior in publishing a manual for prisoners (A Prisoner's Guide to Rights and Obligations 1997)but is concerned that shackles could be used as a form of punishment.(19) The use of shackles for punishment is considered to constitute cruel, inhuman or degrading treatment and is prohibited under international law. Article 31 of the Standard Minimum Rules for the Treatment of Prisoners states that "Corporal punishment, punishment by placing in a dark cell, and all cruel, inhuman or degrading punishments shall be completely prohibited as punishments for disciplinary offences", and Article 33 stipulates that "Instruments of restraints, such as handcuffs, chains, irons and straitjackets, shall never be applied as a punishment...". The Guidehowever does not provide advice to prisoners on how to lodge a complaint regarding their treatment or other issues nor does it have any entry relating to access to legal counsel whilst in detention.
Officials from the Ministry of the Interior also admitted that law enforcement officials against whom findings of torture had been made had not been prosecuted, despite the provisions of Article 208 of the Penal Code, Article 75 of the Code of Criminal Procedure and the obligations under the Convention against Torture. Amnesty International was told that one officer had been "disciplined" following a finding that he had perpetrated torture. Amnesty International stresses that provisions criminalizing torture will remain a "dead letter" until sufficient commitment is demonstrated to there being proper prosecutions. Prosecuting those responsible for acts of torture would send a clear signal to the people of Bahrain and to the international community of the government's serious commitment to eradicate torture.
Amnesty International urges the Bahraini Government to take steps to assist and compensate all victims of torture as stipulated by the Convention against Torture, Article 14 of which clearly states that:
"1. Each State Party shall ensure in its legal system that the victim of an act of torture obtains redress and has an enforceable right to fair and adequate compensation, including the means for as full rehabilitation as possible. In the event of the death of the victim as a result of an act of torture, his dependants shall be entitled to compensation."
7. The Death Penalty
Three Bahraini nationals are currently under sentence of death. 'Ali Ahmad 'Abdallah al-'Usfur, Youssef Hussain 'Abd al-Baqiand Ahmad Khalil Ibrahim al-Kattabwere sentenced to death after unfair trials before the State Security Court in July 1996. They had been convicted of carrying out a fire-bomb attack on a restaurant in Sitra which resulted in the death of seven Bangladeshi nationals. Amnesty International has on several occasions written to the Bahraini authorities urging that the three death sentences be commuted to prison terms. No response had been received from the authorities. Death sentences have to be referred to the Amir for ratification before being carried out.
The death penalty has rarely been applied in Bahrain. Only one execution has been carried out since 1977.(20) However, Bahrain's penal code provides this punishment for a number of offences. Amnesty International urges the Government of Bahrain to declare a moratorium on executions as called for by the United Nations Commission on Human Rights in April 1999.(21)
8. Restrictions on non-governmental organizations (NGOs)
During their visit to Bahrain in June 1999 Amnesty International delegates met with the Minister and officials at the Ministry of Labour and Social Affairs, which also organized a formal meeting with representatives of many charitable and professional societies. It was with great regret that the delegates learned that their request to meet representatives of some of these associations, including the Lawyers' Society and organizations concerned with the rights of women and children, was turned down by the authorities.
In the meeting with the Minister of Labour and Social Affairs and other senior officials at the Ministry the delegates were provided with the Legislative Decree No. 21 of 1989 with Respect to Promulgating the Law of Social and Cultural Societies and Clubs, Associations Carrying on Youth and Sports Activities and Private Organizations and were able to ask questions about the procedure for consideration of a request for registration of a society. Notably absent is any association working for human rights. Indeed, the delegates were informed by an official from the Ministry of Labour and Social Affairs that any application for registration on the part of a human rights association at that time would be "discouraged". The 1989 Decree implicitly excludes human rights associations from its rubric and imposes many restrictions on other associations' activities. For example, Article 33 of the Decree requires organizers of general meetings to provide the agenda and 15 days prior notification, and permits the Government to "designate the person it deems fit for attending the said meeting," and Article 38 requires that minutes and resolutions be provided to the government within 15 days of the meeting". Article 13 effectively bans independent trade unions by stipulating that all labour-related activities be undertaken by the official General Committee of Bahraini Workers and Joint Labour-Management Committees. Amnesty International delegates were told that this Legislative Decree was being reviewed. The organization has urged that such amendments be introduced to make it consistent with relevant international human rights standards.
Amnesty International considers the free functioning of a broad human rights NGO community as a pre-requisite for any civil society in which human rights protection and promotion are respected. In pursuing their activities, human rights defenders should enjoy basic human rights, such as the right to freedom of expression, opinion and assembly, as well as the right to a fair trial, freedom from arbitrary arrest, ill-treatment and torture and the right to life. All these rights are enshrined in several UN treaties and declarations, including the Universal Declaration on Human Rights, the International Covenant on Civil and Political Rights and the Convention against Torture. In addition, Amnesty International would draw the Government of Bahrain's attention to the Declaration on the Right and Responsibility of Individuals, Groups and Organs of Society to Promote and Protect Universally Recognized Human Rights and Fundamental Freedoms adopted by the UN General Assembly on 10 December 1998. Article 5 of the Declaration states that "For the purpose of promoting and protecting human rights and fundamental freedoms, everyone has the right, individually and in association with others, at the national and international levels:
a) To meet or assemble peacefully;
b) To form, join and participate in non-governmental organizations, associations or groups;
c) To communicate with non-governmental or intergovernmental organizations.
The rights to freedom of expression and association are vital for the advancement of other rights. Amnesty International urges the Government of Bahrain to consider ways in which human rights NGOs could be allowed not only to function without hindrance or restrictions, but be actively encouraged to engage in human rights promotion and protection.
Amnesty International learned that on 8 August 2000 a group of people, including lawyers, submitted to the Minister of Labour and Social Affairs a registration request for a new independent human rights association, and at the time of writing this report they had not yet received a response.
9. Conclusion and recommendations
A steady improvement in the overall human rights situation has evolved in Bahrain as a result of the end of the civil unrest and decisions taken by the government in the promotion and protection of human rights. While acknowledging these positive developments, Amnesty International is, however, concerned that human rights violations, in the form of arbitrary detention, reports of torture and ill-treatment, unfair trials and forcible exile continue to take place. The organization urges the Bahraini Government to:
Ratify the International Covenant on Civil and Political Rights (and its Optional Protocols), the International Covenant on Economic, Social and Cultural Rights, the Convention on the Elimination of all Forms of Discrimination against Women and its Optional Protocol, and to implement them in law and practice.
Release all prisoners of conscience immediately and unconditionally.
End the use of administrative detention which results in arbitrary detention in contradiction with Bahrain's international obligations and ensure that detainees in all cases are brought promptly before a judge. In addition, it should ensure that all people under any form of detention have the right to take proceedings before a court in order that the court may decide without delay on the lawfulness of the detention and order release if the detention is unlawful.
Give urgent consideration to the insertion into the Code of Criminal Procedure of a provision requiring a detainee to have access without delay to legal counsel of his/her own choice and to require arresting officers to notify detainees of that right and to register that notification.
Set up an independent body to undertake prompt, thorough and impartial investigations into all allegations of torture and ill-treatment, including cases of death in custody, and ensure that the methods and findings of such investigations are made public.
Bring to justice anyone responsible for committing acts of torture and other serious human rights violations. All investigations and trials should be held before ordinary criminal courts in accordance with international standards for fair trial.
Issue a public declaration that torture will not be tolerated under any circumstances.
Assist and compensate all victims of torture.
End the practice of forcible exile and issue a public declaration that all Bahraini nationals living abroad are entitled to return to Bahrain.
Establish an appeal procedure from decisions of the High Court of Appeal.
Establish national bodies which will review without delay the consistency of domestic laws and procedures with international law obligations.
Give serious consideration to transferring the function of the Public Prosecutor's Office from the Ministry of Interior to the Ministry of Justice.
Amend the Legislative Decree No. 21 of 1989 with Respect to Promulgating the Law of Social and Cultural Societies and Clubs, Associations Carrying on Youth and Sports Activities and Private Organizations, to ensure that non-governmental organizations, including human rights groups, can function without restrictions.
Ensure that judges are provided with relevant training in international human rights standards.
Ensure that lawyers are able to perform all of their professional functions without intimidation, hindrance, harassment or improper interference.
Introduce human rights education programs at all levels of education and initiate a comprehensive human rights awareness program making use of all media, to ensure that all people living in Bahrain are aware of their rights as guaranteed by the UDHR and international treaties ratified by Bahrain.
(1) The term "prisoners of conscience" refers to the imprisonment, detention or other physical restrictions imposed on any person by reason of his or her political, religious, or other conscientiously held beliefs, or by reason of his or her ethnic origin, sex, colour, language, national or social origin, economic status, birth, or other status, provided that he or she has not used or advocated violence.
(2) Gulf Daily News, 16/12/1999.
(3) The Amir is the legislator in Bahrain. Article 35(a) of the Constitution states that "The Amir shall have the right to initiate laws, and he alone shall ratify and promulgate the laws".
(4) The biggest opposition group, Bahrain Freedom Movement, is based in London. Other opposition groups in exile include the Islamic Front for the Liberation of Bahrain, the National Front for the Liberation of Bahrain and Bahrain Popular Front.
(5) Article 104(a) of Bahrain's Constitution stipulates that "Notwithstanding the provision of Article (35) of this Constitution, for an amendment to be made to any provision of this Constitution, it is stipulated that it shall be passed by a majority vote of two-thirds of the members constituting the [National] Assembly and ratified by the Amir".
(6) Akhbar al-Khalij, 30 August 2000.
(7) Decree Law No. 19/2000.
(8) This Article states that "A Supreme Council of the Judiciary shall be formed by a law which shall supervise the functions of the Courts and the offices relating thereto. The law shall specify the jurisdiction of the said Council over the functional affairs of both the judiciary and the public prosecution."
(9) According to this Article if the Committee against Torture receives reliable information suggesting that torture is practised systematically in the territory of a State Party, it invites that state to cooperate with it in the examination of the information. The Committee may also designate one or more of its members to make a confidential inquiry and to report to the Committee.
(10) This Article states that "If there is serious evidence that a person has perpetrated acts, made statements, carried out activities, or has been involved in contacts inside or outside the country, the nature of which is deemed to be prejudicial to the internal or external security of the state or to its basic statutes or its social or economic system, or which are deemed to be a seditious nature affecting or likely to affect existing relations between the people and the government, or between the various state institutions, or between groups of people, or between employees of institutions and companies, or the aim of which was to assist in the perpetration of acts of sabotage or the dissemination of subversive propaganda or atheistic principles. The Minister of Interior may order the arrest of that person, committing him to one of Bahrain's prisons, searching him, his residence and the place of his work, and may take any measure which he deems necessary for gathering evidence and completing investigations.
The period of detention may not exceed three years. Searches may only be made and the measures provided for in the first paragraph may only be taken upon judicial writ.
Anyone arrested under the provisions of the first paragraph may submit a complaint against the arrest order, after the expiry of three months from the date of its execution, to the Supreme Court of Appeal. The complaint is renewable at the end of every six months from the date of the decree rejecting the complaint". (Amnesty International's translation)
(11) E/CN.4/1999/63/Add.1, Opinion No. 6/1998 (Bahrain), at para. 6.
(12) E/CN.4/1999/63/Add.1, Opinion No. 6/1998 (Bahrain), para. 8.
(13) Ibid., para. 12(a).
(14) Amnesty International has issued a number of reports detailing the unfairness of trial procedures followed in political and security cases in the country, including Bahrain: Violations of Human Rights(AI Index: MDE 11/01/91), published in May 1991, and Bahrain: A Human Rights Crisis(AI Index: MDE 11/16/95), issued in September 1995.
(15) E/CN.4/2000/61, 21 February 2000, para. 49.
(16) See for example the report issued in December 1993 and entitled " Bahrain - Banned from Bahrain: forcible exile of Bahraini Nationals", AI Index: MDE 11/04/93.
(17) E/CN.4/1999/61 Report of the SR on torture, 12.01.99, para. 78
(18) Ibid, para. 7
(19) "Cuffing the hands and legs in fetters for a period of up to one month", page 36. In this section of the Guide prisoners could also be "handcuffed and leg-cuffed in iron fetters" in certain situations, including if they are on death row or if they have attempted or are planning to escape.
(20) 'Issa Ahmad Qambar, a Bahraini national, was executed by firing squad in March 1996. He was sentenced to death in July 1995 after having been found guilty of premeditated murder of a police official.
(21) In its Resolution 1999/61, adopted on 28 April the Commission called on all states which maintain the death penalty to "establish a moratorium on executions, with a view to completely abolishing the death penalty".
Copyright notice: © Copyright Amnesty International
| https://www.refworld.org/cgi-bin/texis/vtx/rwmain?docid=3b83b6dc0&page=printdoc |
Crucial, Up-to-date Data for PRUITTHEALTH - VALDOSTA, Review & Ratings
The most comprehensive and up to date information on PRUITTHEALTH - VALDOSTA. Find general information about PRUITTHEALTH - VALDOSTA along with detailed ratings, trend analysis, deficiencies, and ownership. Updated Monthly.
PRUITTHEALTH - VALDOSTA: Data Analysis and Ratings
CMS Five Star Rating(2 out of 5):
2501 NORTH ASHLEY STREET VALDOSTA, GA 31602
229-244-7368
Data date:May 01, 2019
This is not the most recent data for PRUITTHEALTH - VALDOSTA. For the most recent information,click here.
The Most Important Data about PRUITTHEALTH - VALDOSTA
We've looked at a lot of nursing homes, this is what we think you need to see first and if you don't want to spend a lot of time. (It's the tl;dr section.)
There is no indication of abuse occuring at PRUITTHEALTH - VALDOSTA. (CMS flags facilities where abuse has either happened or is very likely.)
CMS 5-Star Overall Rating:
(2 out of 5):(The national average overall star rating is 3 stars.)
Current Trend:Worsening
Total Nursing Hours Spent Per Resident Per Day: 3.58(The national average is 3.74 )
Best Nursing Homes in GA
What is this page all about?
Below is everything shred of information that we can find about PRUITTHEALTH - VALDOSTA, along with our best effort to make sense of the data. Our purpose here is to help you to make good decisions when picking a nursing home and to keep you informed once you have chosen a home. We know from personal experience that choosing a nursing home is not something you do once and then you forget about it. In fact, it gets worse. Once you select a nursing home and get through the initial steps of figuring out how to pay for it, then the real worries start. Are they taking good care of me or my loved one? This is the question that will keep you up at night: Can I really trust these people? We wish we could answer this question, we can't. What he can do is churn through the tons of data and try and help you to make sense of it. We hope it helps.
General Data Card
These are the basic data points for the facility.
Data date:May 01, 2019
Address:2501 NORTH ASHLEY STREET
VALDOSTA, GA 31602
Phone: 229-244-7368
Medicare Provider Number:115377
Participating in Medicare Since:June 15, 1989
No. of Certified Beds:98
No. of Residents:75
Occupancy:76.53 % (as of
05/28/2023 )
Amount fined in recent period:$0.00
Complaints filed:1
Ratings History for PRUITTHEALTH - VALDOSTA
Review of PRUITTHEALTH - VALDOSTA Ratings and Inspection Scores
CMS regularly inspects every skilled nursing facility. (The timing is supposed to be annually, but since the beginning of the Covid pandemic, these inspections have not occured as frequently.) The results of the multi-day inspection is reduced to a series of scores which are then translated into the star ratings. The health inspection scores are an absolute value, so you can compare one facility's score directly to another. The Overall Star rating is based on the facility's performance as compared to other facilities in the same state, so you cannot easily compare one facility's Overall star rating to a facility in another state.
Ratings
Overall Rating 2: Health Inspection Rating 2: Quality Rating 3: Staffing Rating 2:
Inspection Scores
Cycle 1 Score (as of November 16, 2018) 44 Cycle 2 Score (as of October 26, 2017) 20 Cycle 3 Score (as of September 15, 2016) 20 Weighted All Cycles Score 32
It has been 5 months since the most recent inspection.
What Goes Into the Nursing Home's 5-Star Rating
CMS has put a lot of effort into creating its very elaborate 5-Star Quality Rating System specifically to provide a quick way for residents and family members to easily understand how well a nursing home is performing and to make comparing nursing homes easier. The rating system allows people to easily compare facilities across numerous dimensions with the express purpose of identifying the best and best performing nursing homes. The rating system was initially developed in 2008 and the methodologies are regularly reviewed and updated.
The rating system has five separate ratings including:
Overall rating
Health Inspection rating
Staff rating
RN Staffing rating
Quality Measures rating
Nursing homes are rated from 1-star to 5-stars with 1-star being the best rating and 5-star being the best rating. For the Health Inspection Rating the nursing homes in each state are ranked based on their weighted three year inspection score. The top 10 percent of nursing homes (those with the lowest scores) are awarded a 5-star rating; the bottom 20 percent (those with the highest scores) are awarded a 1-star rating. In between 1-star and 5-star, the remaining homes are divided equally into three tranches which correspond with the stars 2 to 4. The staff ratings and quality measure ratings follow a similar process but the divisions are based on a national ranking. The division between star ratings is called the “cut-rate”. Cut-rates are redefined periodically and are published by CMS.See the latest cut rates on this table.
Calculating the Overall Star Rating is done differently. According to CMS, the reason for adopting a different system is to give the Health Inspection Rating higher weight in the Overall Rating. So, since there are FIVE ratings and FIVE stars for each rating, there must also be a FIVE step process to calculate the Overall Rating (so symetrical!) :
Begin with the Health Inspection Rating
Add one star to the Health Inspection Rating if the Staffing Rating is at least four-stars and is higher than the Health Inspection Rating. (We will call this the "Adjusted Rating".)
Subtract one star from the Health Inspection Rating if the Staffing Rating is one-star.
Add a star to the Adjusted Rating if the Quality Measure Rating is 5-stars.
Subtract one star from the Adjusted Rating if the Quality Measure Rating is 1-star.
Throughout the calculation of the Overall Rating, the rating cannot exceed 5-stars. The Overall Rating is capped at 2-stars if the Health Inspection rating is 1-star. No Overall Rating is awarded if the nursing home does not have a Health Inspection Rating (This effectively means that a nursing home is not rated until the home has been operating for more than two years.)
Changes in a nursing homes star rating can be due to the results of a new health inspection report, the processing of new complaints, the aging of older complaints, a new inspection control survey, a revisit, or the resolution of disputes that change the scope and or severity of deficiencies.
Most Recent Nursing Home Inspections
CMS is required to inspect each senior nursing facility at least annually. These inspections take several days. Additional follow-up inspections as conducted as needed or for certain purposes. Inspections stopped for more than seven months in 2020 due to the Covid pandemic. That stoppage has caused all inspections to be delayed as the inspectors continue to deal with a backlog. The table below shows the latest inspections for PRUITTHEALTH - VALDOSTA including health, fire, and inspection control inspections:
No Inspection Information is Available
Owner and Operator Information for PRUITTHEALTH - VALDOSTA
Our database of owners and operators shows all direct owners of the nursing nurse, any managers and directors, and the most adjacent indirect owners of the facility (that is, if the direct owner is company, then the owners of that company.) Lists of nursing home owners are available and you can search for nursing home owners and operators on our site.
Business Entity Name:
LOWNDES COUNTY HEALTH SERVICES LLC
Owners:
J PAIGE PRUITT TRUST (INDIRECT)
LISA P HAMBY TRUST (INDIRECT)
NEIL L PRUITT JR TRUST (INDIRECT)
UHS-PRUITT HOLDINGS, INC. (INDIRECT)
UNITED HEALTH SERVICES INC (INDIRECT)
UNITED HEALTH SERVICES OF GEORGIA, INC. (DIRECT- 99%)
Managers and Directors:
BARRY AUDAIN (MANAGING EMPLOYEE)
NEIL PRUITT (OPERATIONAL/MANAGERIAL CONTROL)
Analysis of Nursing Hours Spent Per Patient
CMS provides detailed information about how long nursing staff spends with residents. This data includes nursing subcategories of Registered Nurse, Licensed Practical Nurse, and non-nursing Certified Nursing Assistants. More hours spend per patient should can indicate a better facility or it could indicate more complicated situations.
The nursing staff of PRUITTHEALTH - VALDOSTA spends LESS time on average with its residents than the state average and
LESS time than the national average for total nursing homes spent per resident.
Type Facility State / National Avg
Registered Nurse (RN)
Hours 0.44 0.44 /
0.65
Case Mix 0.33 0.36 /
0.39
Adjusted 0.50 NA /
NA
Licensed Practical Nurse (LPN)
Hours 1.01 1.03 /
0.88
Case Mix 0.77 NA /
NA
Adjusted 0.99 NA /
NA
Certified Nursing Assistants (CNA)
Hours 2.13 1.93 /
2.21
Case Mix 2.26 NA /
NA
Adjusted 1.96 NA /
NA
Total Licensed Staff
Hours 1.45 1.47 /
1.53
Physical Therapist (PT)
Hours 0.04 0.05 /
0.07
Total Nursing Homes Spent per Resident on Average
Hours 3.58 3.40 /
3.74
Case Mix 3.36 3.12 /
3.16
Adjusted 3.42 NA /
NA
Quality Measures
Quality measures are based both on patient survey information and on the results of actual claims that are filed with CMS. It is not clear what period is covered in the measures.
Desc. Perc. State Avg. / Comparison
Percentage of short-stay residents who were rehospitalized after a nursing home admission (qm521) 22.6% 21.3% Worse
Percentage of short-stay residents who had an outpatient emergency department visit (qm522) 11.8% 10.8% Worse
Number of hospitalizations per 1000 long-stay resident days (qm551) 1.3% 1.9% Better
Number of outpatient emergency department visits per 1000 long-stay resident days (qm552) 0.7% 1.2% Better
Percentage of long-stay residents whose need for help with daily activities has increased (qm401) 7.8% 16.6% Better
Percentage of long-stay residents who self-report moderate to severe pain (qm402) 7.5% 7.6% Better
Percentage of long-stay residents who lose too much weight (qm404) 3.9% 6.6% Better
Percentage of low risk long-stay residents who lose control of their bowels or bladder (qm405) 33.6% 46.6% Better
Percentage of long-stay residents with a catheter inserted and left in their bladder (qm406) 4.1% 2.1% Worse
Percentage of long-stay residents with a urinary tract infection (qm407) 1.9% 3.6% Better
Percentage of long-stay residents who have depressive symptoms (qm408) 12.6% 4.6% Worse
Percentage of long-stay residents who were physically restrained (qm409) 0.0% 0.3% Better
Percentage of long-stay residents experiencing one or more falls with major injury (qm410) 2.2% 3.4% Better
Percentage of long-stay residents assessed and appropriately given the pneumococcal vaccine (qm415) 100.0% 93.1% Better
Percentage of long-stay residents who received an antipsychotic medication (qm419) 14.7% 18.2% Better
Percentage of short-stay residents who self-report moderate to severe pain (qm424) 14.4% 12.3% Worse
Percentage of short-stay residents assessed and appropriately given the pneumococcal vaccine (qm430) 90.5% 80.7% Better
Percentage of short-stay residents who newly received an antipsychotic medication (qm434) 4.4% 2.6% Worse
Percentage of long-stay residents whose ability to move independently worsened (qm451) 16.8% 19.1% Better
Percentage of long-stay residents who received an antianxiety or hypnotic medication (qm452) 36.2% 23.5% Worse
Percentage of high risk long-stay residents with pressure ulcers (qm453) 13.4% 9.1% Worse
Percentage of long-stay residents assessed and appropriately given the seasonal influenza vaccine (qm454) 100.0% 94.4% Better
Percentage of short-stay residents who made improvements in function (qm471) 60.8% 64.4% Worse
Percentage of short-stay residents who were assessed and appropriately given the seasonal influenza vaccine (qm472) 86.7% 80.9% Better
PRUITTHEALTH - VALDOSTA Violations, Complaints and Fines
These are complaints and fines that are reported by CMS. Some of the data is not very recent, but we have decided to include it here so that you have as much information as possible.
Amount fined in recent period:$0.00, Complaints filed:1
Deficiency Deficiency Date / Date Corrected
Corridors that are separated from use areas by walls constructed to limit the passage of smoke. (Fire Safety) 09-15-2016 /
10-30-2016
Walls that prevent smoke from passing through and would resist fire for at least one hour. (Fire Safety) 09-15-2016 /
10-30-2016
Record of quarterly fire drills for each shift under varying conditions. (Fire Safety) 09-15-2016 /
10-30-2016
Automatic sprinkler systems that have been maintained in working order. (Fire Safety) 09-15-2016 /
10-30-2016
Properly installed electrical wiring and equipment. (Fire Safety) 09-15-2016 /
10-30-2016
Provide housekeeping and maintenance services. (Health) 09-15-2016 /
10-30-2016
Provide care by qualified persons according to each resident's written plan of care. (Health) 09-15-2016 /
10-30-2016
Assist those residents who need help with eating/drinking, grooming and personal and oral hygiene. (Health) 09-15-2016 /
10-30-2016
Develop policies and procedures for influenza and pneumococcal immunizations. (Health) 09-15-2016 /
10-30-2016
Add doors in an exit area that do not require the use of a key from the exit side unless in case of special locking arrangements. (Fire Safety) 10-24-2017 /
12-10-2017
Install proper backup exit lighting. (Fire Safety) 10-24-2017 /
12-10-2017
Install emergency lighting that can last at least 1 1/2 hours. (Fire Safety) 10-24-2017 /
12-10-2017
Ensure that special areas are constructed so that walls can resist fire for one hour or have an approved fire extinguishing system. (Fire Safety) 10-24-2017 /
12-10-2017
Install corridor and hallway doors that block smoke. (Fire Safety) 10-24-2017 /
12-10-2017
Ensure smoke barriers are constructed to a 1 hour fire resistance rating. (Fire Safety) 10-24-2017 /
12-10-2017
Install smoke barrier doors that can resist smoke for at least 20 minutes. (Fire Safety) 10-24-2017 /
12-10-2017
Have properly installed electrical wiring and gas equipment. (Fire Safety) 10-24-2017 /
12-10-2017
Provide care for residents in a way that maintains or improves their dignity and respect in full recognition of their individuality. (Health) 10-26-2017 /
12-10-2017
Reasonably accommodate the needs and preferences of each resident. (Health) 10-26-2017 /
12-10-2017
Provide care by qualified persons according to each resident's written plan of care. (Health) 10-26-2017 /
12-10-2017
Have a program that investigates, controls and keeps infection from spreading. (Health) 10-26-2017 /
12-10-2017
Inspect, test, and maintain automatic sprinkler systems. (Fire Safety) 11-14-2018 /
12-31-2018
Ensure smoke barriers are constructed to a 1 hour fire resistance rating. (Fire Safety) 11-14-2018 /
12-31-2018
Provide and implement an infection prevention and control program. (Health) 11-16-2018 /
12-31-2018
Develop and implement a complete care plan that meets all the resident's needs, with timetables and actions that can be measured. (Health) 03-13-2019 /
04-05-2019
Ensure that a nursing home area is free from accident hazards and provides adequate supervision to prevent accidents. (Health) 03-13-2019 /
04-05-2019
Hospitals Near PRUITTHEALTH - VALDOSTA
Quite often skilled nursing facilities and hospitals work closely together to help patients recover or manage a terminal illness. Hospitals deals with acute care while nursing homes treat patients for a longer period of time. New residents at skilled nursing homes typically come from a hospital and nursing home residents may be readmitted to a hospital if their recovery does not proceed well. (Hospital readmission rates are closely monitored by CMS.) Consequently it is important that you consider which hospitals are near a nursing home which choosing one. Below is a list of hospitals near PRUITTHEALTH - VALDOSTA.
This information is based on the most recent Hospital data. Historical data is not available.
Hospital 5-Star Overall Rating
SOUTH GEORGIA MEDICAL CENTER 2501 NORTH PATTERSON STREET, PO BOX 1727 VALDOSTA, GA 31602 3
COOK MEDICAL CENTER A CAMPUS OF TIFT REG MED CTR 260 MJ TAYLOR ROAD ADEL, GA 31620 Not Available
SGMC BERRIEN CAMPUS 1221 E MCPHERSON AVENUE NASHVILLE, GA 31639 Not Available
SGMC LANIER CAMPUS 116 WEST THIGPEN AVENUE LAKELAND, GA 31635 Not Available
BROOKS COUNTY HOSPITAL 903 N COURT STREET QUITMAN, GA 31643 Not Available
GREENLEAF CENTER 2209 PINEVIEW DRIVE VALDOSTA, GA 31602 Not Available
Medical Professionals Associated with PRUITTHEALTH - VALDOSTA
These are the doctors who are affiliated with PRUITTHEALTH - VALDOSTA. The data is from the most recent period. Historical data is not available.
LYNN LEE ( INTERNAL MEDICINE - SOUTHWELL AMBULATORY INC )
JAROD BAILEY ( INTERNAL MEDICINE )
Detailed Analysis Pages:
Depending on the nursing home, this page can get really long. So, we have also broken up the data onto separate pages to allow you to find what you want more easily. We will keep adding to these pages as we continue to analyze the nursing home database.
CMS Five Star Ratings and Quality Measures for PRUITTHEALTH - VALDOSTA
Five different rating results plus detailed inspection numbers and quality measures for PRUITTHEALTH - VALDOSTA.
Covid Infections at PRUITTHEALTH - VALDOSTA
This report is updated weekly and shows new and historical infection levels.
Nursing Hours Analysis for PRUITTHEALTH - VALDOSTA
How long a nurse spends with a resident can be an important factor in their recovery. This page shows the average nursing hours spent per resident for RNs, LPNs, CNAs, PTs and all licensed staff.
Ownership Details for PRUITTHEALTH - VALDOSTA
A list of all of the registered owners for PRUITTHEALTH - VALDOSTA. This includes direct and indirect owners and managers.
Noted Deficiencies for PRUITTHEALTH - VALDOSTA
A list of all of the deficiencies for the facility. This includes a description, type of deficiency, incident date and when the facility reports that the incident was corrected.
Comparison Ranking of Nearby Skilled Nursing Facilities
How does PRUITTHEALTH - VALDOSTA compare to other skilled nursing facilities? This list shows the competitive set within a 25 mile radius.
Best Nursing Homes in VALDOSTA, GA
Homes that you should consider. A list ranking the best skilled nursing facilities in VALDOSTA based on their weighted inspection score as of May 01, 2019.
Worst Nursing Homes in VALDOSTA, GA
Homes that you avoid if possible. A list ranking the worst skilled nursing facilities in VALDOSTA based on their weighted inspection score as of May 01, 2019.
Other Data Periods:
May 2019 Jun 2019 Jul 2019
Search for Doctors
Search for Hospice
| https://www.nursinghomedatabase.com/home/GA/VALDOSTA/31602/pruitthealth-valdosta/2019-05-01 |
Here's what we really know about CBD's benefits - Futurity
Far-reaching medical claims tout the success of CBD at treating everything from acne to Parkinson's. But what's the reality? An expert weighs in.
Here’s what we really know about CBD’s benefits
(Credit:Enecta Cannabis extracts/Unsplash)
Tags
anxiety
cannabis
medications
myths
pain
University
Johns Hopkins University
Assertions about the benefits of CBD often go far beyond what science has shown, according to one expert.
Celebrated for its purportedtherapeutic effectsand legal when derived from hemp—a form of thecannabis plant—CBD is in shampoos, hand lotions, skin creams, and even dog treats. Far-reaching medical claims tout its success at treating various conditions such asanxiety, acne, insomnia, addiction, inflammation, and Parkinson’s disease.
Cannabis researcherRyan Vandrey, an associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, and other researchers are working to understand the effects of the compound and what conditions it might actually help.
Here, he talks about his research and his concerns about the growing CBD market:
Q
Does CBD get you high? What does the research say?
A
THC, another chemical component of cannabis, drives most of the effects we typically associate with the drug, such as the subjective “high.” There’s this perception that CBD is not psychoactive, but I think that’s inaccurate.
Research from our lab and others shows that CBD can produce subjective drug effects. CBD drug effects are different from THC and do not seem to produce intoxicating effects where performance or cognition is impaired. While that’s not a bad thing, impacting mood and behavior is a psychoactive drug effect. For example, caffeine is a psychoactive drug because it affects brain function and mood.
Q
Are products that contain CBD safe?
A
There’s an inadequate regulatory framework to ensure that these products are tested, appropriately labeled, and free of contamination.
There’s no way to tell how much a person should take or how to determine if it’s even helping their condition, and we still don’t know what kinds of patients are going to best benefit from CBD versus another medical intervention. Researchers are most commonly studying CBD’s application in anxiety, insomnia, post-traumatic stress disorder,painand inflammation, and autism.
Some people are taking CBD for general wellness, and we have no evidence that’s a good idea. Anytime you take a medication chronically, it’s going to impact your physiology. It could be harmful. It could interact with other medications in a substantial way.
The US Food and Drug Administration was recently given regulatory power over hemp, and has since enacted certain restrictions on CBD. It is now illegal to market CBD by adding it to food or labeling it as a dietary supplement.
Q
A JAMAstudy in which you participated shows that nearly a quarter of the CBD/hemp products sold on the internet contain THC even though THC wasn’t listed on the labels. What does that mean for the public?
A
Most people who use CBD are completely unaware of the possibility of THC exposure. With the legalization of hemp—which is simply cannabis with less than 0.3% THC—and hemp-derived products containing CBD, there’s potential for those products to have a significant impact on drug testing programs.
My lab just completed our first CBD study, which showed that a single instance of vaping cannabis that has 0.39% THC in it (similar to the legal allowance in hemp of 0.3%) can result in a positive drug test for THC. We’re interested in determining whether using CBD may affect the outcomes of workplace drug tests and roadside tests for driving while intoxicated or under the influence.
Also, depending on the amount used and route of administration, these products have the potential to produce impairing drug effects. So we need to ensure there are evaluation mechanisms that can differentiate between someone who is using a legal drug versus an illegal drug. Similarly, we need to be able to recognize the difference between a drug that can impair your ability to operate a vehicle versus one that does not.
Q
What CBD studies is your team working on?
A
We’re characterizing the drug’s effects in healthy adults who are given a dose of CBD and looking to see whether there’s a difference if the drug is inhaled or swallowed. We’re also conducting long-term observational research on people who are using cannabis, hemp, and CBD products for medicinal purposes. We want to know why people are using it and look at their health outcomes.
We’re also looking at whether CBD’s effect changes when used in conjunction with THC.
Q
Can you tell us a little about the initial findings from the long-term observational study?
A
We found that, among individuals with a variety of health problems such as epilepsy, chronic pain, autism, anxiety, and other serious health conditions, those who were using a cannabis product—people predominantly used CBD products—reported a betterquality of lifeand satisfaction with health, pain, sleep, and mood compared with those who were not using cannabis products.
When those who were not using cannabis at the time of our first survey later started using cannabis, they showed improvements in those same health measures that mirrored the differences between the cannabis users and nonusers in the beginning.
Though we can’t say definitively that CBD is effective for any of these health problems, the outcomes of this study highlight the need for additional research on hemp/CBD products in controlled clinical trials, especially for autism, anxiety, depression, multiple sclerosis, chronic pain, and epilepsy conditions other than Dravet syndrome and Lennox-Gastaut syndrome.
Q
What’s your advice for someone who wants to try CBD?
A
My advice always is, first and foremost, to talk to your physician before you try any new drug, including CBD.
Just because you can buy it at CVS and Walgreens, and because there’s generally no impairment and potential for abuse, doesn’t mean that it’s without risk and an appropriate treatment for you. That discussion should focus on what treatment options are available and what the relative potential for risk and benefit would be for each option.
I have the same recommendation about CBD products for pets. We have even less research to back up CBD as a treatment for them.
All told, I think there is a real therapeutic potential for cannabinoids, but we cannot abandon the methods used to bring all other medications to market. Data that can be used to determine efficacy, safety, dosing, and formulation is needed for each therapeutic area in which CBD is believed to be beneficial.
We also must be mindful of gimmick products for which there is no reason to believe CBD is a meaningful addition.
Source: Marc Shapiro for Johns Hopkins University
| https://www.futurity.org/cbd-facts-benefits-pain-anxiety-2247702/ |
EclipseWise - Penumbral Lunar Eclipse of 1481 May 13
This page is part of the EclipseWise.com Website. It contains predictions, diagrams and links for the Penumbral Lunar Eclipse of 1481 May 13 .
Fred Espenak
Introduction
The Penumbral Lunar Eclipse of 1481 May 13
is visible from the geographic regions shown on the map to the right.
The diagram above the map depicts the Moon's path with respect to Earth's umbral and penumbral shadows.
Click on the figure to enlarge it.
For an explanation of the features appearing in the figure,
see
Key to Lunar Eclipse Figures
.
The instant of greatest eclipse
takes place on 1481 May 13 at 14:33:55 TD (14:30:21 UT1).
This is 0.7 days after the Moon reaches perigee.
During the eclipse, the Moon is in the constellation Ophiuchus
.
The synodic month
in which the eclipse takes place has a
Brown Lunation Number
of -5462.
The eclipse belongs to Saros 93
and is number 67 of 71 eclipses in the series.
All eclipses in this series occur at the Moon’s
descending node
.
The Moon moves northward with respect to the node with each succeeding eclipse in the series and gamma
increases.
The penumbral lunar eclipse of 1481 May 13 is followed two weeks later by a annular solar eclipse on 1481 May 28
.
Another lunar eclipse occurs one synodic month
after the 1481 May 13 eclipse. It is the penumbral lunar eclipse of 1481 Jun 11
.
These eclipses all take place during a single
eclipse season
.
The eclipse predictions are given in both
Terrestrial Dynamical Time (TD)
and Universal Time (UT1)
.
The parameter ΔT
is used to convert between these two times (i.e.,
UT1 = TD - ΔT
). ΔT
has a value of
214.8
seconds for this eclipse.
The following links provide maps and data for the eclipse.
Eclipse Figure - eclipse geometry diagram and map of eclipse visibility
Saros 93 Table - data for all eclipses in the Saros series
The tables below contain detailed predictions and additional information on the
Penumbral Lunar Eclipse of 1481 May 13
.
Eclipse Data: Penumbral Lunar Eclipse of 1481 May 13
Eclipse Characteristics
Parameter Value
Penumbral Magnitude 0.63767
Umbral Magnitude -0.30842
Gamma 1.19527
Epsilon 1.2186°
Opposition Times
Event Calendar Date & Time Julian Date
Greatest Eclipse 1481 May 13 at 14:33:55.4 TD (14:30:20.5 UT1) 2262126.104404
Ecliptic Opposition 1481 May 13 at 14:22:05.1 TD (14:18:30.3 UT1) 2262126.096184
Equatorial Opposition 1481 May 13 at 13:55:30.4 TD (13:51:55.6 UT1) 2262126.077727
Geocentric Coordinates of Sun and Moon
1481 May 13 at 14:33:55.4 TD (14:30:20.5 UT1)
Coordinate Sun Moon
Right Ascension 03h56m36.7s 15h58m08.8s
Declination +20°28'38.6" -19°18'47.7"
Semi-Diameter 15'46.3" 16'40.2"
Eq. Hor. Parallax 08.7" 1°01'10.8"
Geocentric Libration of Moon
Angle Value
l 1.6°
b -1.5°
c 10.2°
Earth's Shadows
Parameter Value
Penumbral Radius 1.2951°
Umbral Radius 0.7694°
Prediction Paramaters
Paramater Value
Ephemerides JPL DE406
ΔT 214.8 s
Shadow Rule Danjon
Shadow Enlargement 1.010
Saros Series 93 (67/71)
Explanation of Lunar Eclipse Data Tables
Eclipse Contacts: Penumbral Lunar Eclipse of 1481 May 13
Lunar Eclipse Contacts
Eclipse Event Contact Time
TD
Time
UT1 Zenith Latitude Zenith Longitude Position Angle Axis Distance
Penumbral Begins P1 12:53:07.5 12:49:32.7 19°00.2'S 165°54.5'E 338.1° 1.5733°
Greatest Eclipse Greatest 14:33:55.4 14:30:20.5 19°18.8'S 141°42.9'E 17.3° 1.2186°
Penumbral Ends P4 16:14:39.9 16:11:05.1 19°37.0'S 117°32.3'E 56.5° 1.5726°
Eclipse Durations
Eclipse Phase Duration
Penumbral (P4 - P1) 03h21m32.4s
Explanation of Lunar Eclipse Contacts Table
Polynomial Besselian Elements: Penumbral Lunar Eclipse of 1481 May 13
Polynomial Besselian Elements
1481 May 13 at 15:00:00.0 TD (=t0)
n x y d f1 f2 f3
0 0.60766 1.08722 0.3575 1.29506 0.76935 0.27781
1 0.56525 -0.17577 0.0001 -0.00017 -0.00017 -0.00005
2 -0.00009 0.00011 -0.0000 -0.00000 -0.00000 -0.00000
3 -0.00001 0.00000 - - - -
At time t1 (decimal hours), each besselian element is evaluated by:
x = x0 + x1*t + x2*t 2
+ x3*t 3
(or x = Σ [xn*t n
]; n = 0 to 3)
where: t = t1 - t0 (decimal hours) and t0 = 15.000
Explanation of Besselian Elements
Links for the Penumbral Lunar Eclipse of 1481 May 13
Eclipse Figure - eclipse geometry diagram and map of eclipse visibility
Saros 93 Table - data for all eclipses in the Saros series
Penumbral Lunar Eclipse of 1481 May 13 - Google search for links to this eclipse
Links to Additional Lunar Eclipse Information
Home - home page of EclipseWise with predictions for both solar and lunar eclipses
Lunar Eclipses - primary page for lunar eclipse predictions
Lunar Eclipse Links - detailed directory of links
Six Millennium Catalog of Lunar Eclipses - covers the years -2999 to +3000 (3000 BCE to 3000 CE)
Saros Catalog of Lunar Eclipses - covers Saros series -29 through 190
Javascript Lunar Eclipse Explorer - calculate all lunar eclipses visible from a city
Thousand Year Canon of Lunar Eclipses 1501 to 2500
- link to the publication
MrEclipse.com - Eclipse resources and tips on photography
Lunar Eclipses for Beginners - a primer on solar eclipse basics
MrEclipse Photo Index - an index of lunar eclipse photographs
Calendar
The Gregorian
calendar (also called the Western calendar) is internationally the most widely used civil calendar.
It is named for Pope Gregory XIII, who introduced it in 1582.
On this website, the Gregorian
calendar is used for all calendar dates from 1582 Oct 15 onwards.
Before that date, the Julian
calendar is used.
For more information on this topic, see Calendar Dates
.
The Julian
calendar does not include the year 0.
Thus the year 1 BCE is followed by the year 1 CE (See: BCE/CE Dating Conventions
).
This is awkward for arithmetic calculations.
Years in this catalog are numbered astronomically and include the year 0.
Historians should note there is a difference of one year between astronomical dates and BCE dates.
Thus, the astronomical year 0 corresponds to 1 BCE, and astronomical year -1 corresponds to 2 BCE, etc..
Eclipse Predictions
Predictions for the
Penumbral Lunar Eclipse of 1481 May 13
were generated using the
JPL DE406
solar and lunar ephemerides.
The lunar coordinates were calculated with respect to the Moon's Center of Mass
.
The predictions are given in both
Terrestrial Dynamical Time (TD)
and Universal Time (UT1)
.
The parameter ΔT
is used to convert between these two times (i.e.,
UT1 = TD - ΔT
). ΔT
has a value of
214.8
seconds for this eclipse.
Acknowledgments
Some of the content on this web site is based on the book
Thousand Year Canon of Lunar Eclipses 1501 to 2500
.
All eclipse calculations are by Fred Espenak, and he assumes full responsibility for their accuracy.
Permission is granted to reproduce eclipse data when accompanied by a link to this page and an acknowledgment:
"Eclipse Predictions by Fred Espenak, www.EclipseWise.com"
The use of diagrams and maps is permitted provided that they are NOT
altered (except for re-sizing) and the embedded credit line is
NOT
removed or covered. | https://www.eclipsewise.com/lunar/LEprime/1401-1500/LE1481May13Nprime.html |
Alzheimer Disease | Consultant360
Clinical Updates
Ongoing updates of key clinical trial advances and new study data for common conditions.
Introduction Etiology Screening and Diagnosis Treatment and Management Conclusion References
Introduction
Alzheimer disease (AD) is the most common cause of dementia, 1 the sixth leading cause of death in the United States, and the fifth among adults aged 65 years or older. 2 It is estimated that the prevalence of AD in adults aged 65 years or older is approximately 6.5 million in 2022, corresponding to a prevalence rate of 10.7%. 3 Importantly, the prevalence in Americans aged 65 or older is expected to increase to 12.7 million by 2050. 3 Furthermore, the proportion of deaths related to AD in the United States increased 89% between 2000 and 2014, 4 and the estimated direct and indirect health-care–related costs for AD are nearly $500 billion annually. 5 AD is characterized by an irreversible and progressive decline in 2 or more cognitive domains (ie, memory, language, executive and visuospatial function, personality, and behavior) resulting in a decreased ability to perform instrumental and/or basic daily activities. 6 Therefore, it is critical to screen for, diagnose, and treat AD.
Etiology
Various etiological mechanisms have been proposed to explain the underlying AD pathology. 7,8 First, there is an abnormal production of amyloid-β that is then deposited extracellularly in diffuse neuritic plaques and can trigger synaptic damage and a neuron loss cascade. The accumulation amyloid-β leads to hyperphosphorylation of τ (p-τ), a microtube assembly protein, which then accumulates in intracellular neurofibrillary tangles. 7,8 These tangles prevent the normal functioning of other cellular proteins, and toxic τ also enhances amyloid-β production. 7 In addition, the brains of patients with AD have a cholinergic deficit, which plays a role in memory and learning and may explain some of the symptoms associated with AD. Finally, the progressive neuronal loss of AD is related to overexposure to the neurotransmitter glutamate. 7
Other important etiological mechanisms include vascular disease, diabetes and hyperinsulinemia, and neuron inflammation. 7 The risk for AD increases with age, one of the main risk factors for the disease. Another important risk factor is being a carrier for the fourth form of the apolipoprotein E gene (APOE-ε4 genotype). 9 In addition, women older than 80 years are more likely to develop AD and to have a higher τ load than men, despite a similar amyloid burden. 10
Screening and Diagnosis
The hallmark pathological criteria for diagnosing AD include increased levels of amyloid-β neuritic plaques and p-τ neurofibrillary tangles, and updated diagnostic guidelines for AD were published in 2011. 11-16 Diagnosis of AD involves a series of tests in addition to considering both medical and family histories. A neurological examination, mental cognitive status tests (Mini-Cog, Short Informant Questionnaire on Cognitive Decline in the Elderly, AD8 Dementia Screening Interview, Quick Dementia Rating System), measurement of vitamin B12 levels, and examination of AD biomarkers are recommended. 15,17
AD biomarkers include: 6,9
Imaging studies including positron emission tomography imaging with amyloid-specific tracers (florbetapir, florbetaben, and flutemetamol) and τ-specific tracers (flortaucipir, THK5317, PBB3, and [18F]MK-6240), and with fluorodeoxyglucose to detect decreased metabolic activity; and magnetic resonance imaging to detect hippocampal volume or medial temporal lobe atrophy. 18,19
Measurement of amyloid-β 42, p-τ, and total τ levels in the cerebrospinal fluid.
Various serum tests are in development. PrecivityAD™, which is not approved by the US Food and Drug Administration (FDA), was the first commercially available blood test for patients aged 60 years or older who experienced cognitive impairment. 20,21 The FDA has granted Breakthrough Device Designation for 2 serum tests: pTau-181 and AlzoSure® Predict. 22,23
Finally, there are genetic tests for risk genes, APOE-ε4, and for deterministic genes, the amyloid-β precursor protein, presenilin 1, and presenilin 2. Genetic testing for APOE-ε4 is not recommended outside of a research setting, as having the allele does not mean a person has or will develop AD. In families with a risk of early onset AD, genetic testing for deterministic genes is common. However, it is important to note that the time course for progression in patients with these genes is variable. 13,15
Treatment and Management
Currently, no medications cure AD, but some FDA-approved medications may change the progression of the disease or help manage the symptoms. 7 Aducanumab, an amyloid-β–directed antibody, is the only treatment that targets the pathophysiology of the disease. 24 FDA-approved treatments for cognitive symptoms include the NMDA-receptor blocker memantine and cholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine. 7 In addition, the combination of memantine and donepezil is also FDA approved for moderate to severe AD. 7 Suvorexant is approved for treating insomnia in adults and is effective in patients with mild to moderate AD. 25,26 In addition to these treatments, the management of cardiovascular disease risk factors, the adherence to the Mediterranean diet, and regular aerobic exercise are recommended to help reduce the risk of disease progression. 6
There are also several treatments that may be used off-label to help manage the symptoms of AD, including antidepressants (ie, citalopram, fluoxetine, paroxetine, sertraline, and trazodone), anxiolytics (ie, lorazepam and oxazepam), antipsychotic medications (ie, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone), stimulants (ie, modafinil), and mood stabilizers (ie, carbamazepine and lithium). 27,28 These also include therapies that do not directly affect the nervous system, such as calcium-channel blockers (ie, dihydropyridines and dantrolene), phosphodiesterase inhibitors (ie, sildenafil), insulin and glucagon-like peptide-1 receptor agonists (ie, insulin and liraglutide), nonsteroidal anti-inflammatory drugs (ie, diclofenac), antivirals (ie, acyclovir) antibiotics (ie, minocycline and rifamycin), and antioxidants (ie, melatonin). 28
Finally, in addition to FDA-approved treatments, patients may also be eligible for enrollment in clinical trials. Currently, ClinicalTrials.gov lists 717 studies for patients with AD that are not yet recruiting, recruiting, or enrolling by invitation. 29 Patients may qualify for participation in ongoing clinical trials depending on their demographics, disease status, and location.
Conclusion
The number of patients with AD will rapidly increase in the next few decades. While currently no treatments cure AD, some medications can be used to slow the progression of the disease and help manage the symptoms. There are also many ongoing clinical trials that may result in newer treatments in the future. Because of the expected rise in cases, it is important that health care professionals are aware of the guidelines for diagnosing and treating patients with AD.
References
1. Bondi MW, Edmonds EC, Salmon DP. Alzheimer's disease: past, present, and future. J Int Neuropsychol Soc . 2017;23(9-10):818-831. doi:10.1017/S135561771700100X
2. Matthews KA, Xu W, Gaglioti AH, et al. Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015-2060) in adults aged ≥65 years. Alzheimers Dement . 2019;15(1):17-24. doi:10.1016/j.jalz.2018.06.3063
3. 2022 Alzheimer's disease facts and figures . Alzheimers Dement . 2022;18(4):700-789. doi:10.1002/alz.12638
4. 2017 Alzheimer's disease facts and figures. Alzheimers Dement . 2017;13(4):325-373. doi: 10.1016/j.jalz.2017.02.001
5. Takizawa C, Thompson PL, van Walsem A, Faure C, Maier WC. Epidemiological and economic burden of Alzheimer's disease: a systematic literature review of data across Europe and the United States of America. J Alzheimers Dis . 2015;43(4):1271-1284. doi:10.3233/JAD-141134
6. Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment. F1000Res . 2018;7:F1000. doi:10.12688/f1000research.14506.1
7. Briggs R, Kennelly SP, O'Neill D. Drug treatments in Alzheimer's disease. Clin Med (Lond) . 2016;16(3):247-253. doi:10.7861/clinmedicine.16-3-247
8. Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther . 2017;9(1):71. doi:10.1186/s13195-017-0297-z
9. Mantzavinos V, Alexiou A. Biomarkers for Alzheimer's disease diagnosis. Curr Alzheimer Res . 2017;14(11):1149-1154. doi:10.2174/1567205014666170203125942
10. Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol . 2019;76(5):542-551. doi:10.1001/jamaneurol.2018.4693
11. Dubois B, Hampel H, Feldman HH, et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimers Dement . 2016;12(3):292-323. doi:10.1016/j.jalz.2016.02.002
12. De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer's disease. Subcell Biochem . 2012;65:329-352. doi:10.1007/978-94-007-5416-4_14
13. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement . 2011;7(3):270-279. doi:10.1016/j.jalz.2011.03.008
14. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement . 2011;7(3):257-262. doi:10.1016/j.jalz.2011.03.004
15. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement . 2011;7(3):263-269. doi:10.1016/j.jalz.2011.03.005
16. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement . 2011;7(3):280-292. doi:10.1016/j.jalz.2011.03.003
17. Alzheimer's and related dementia resources for professionals. National Institute on Aging. Reviewed November 5, 2021. Accessed April 27, 2022. https://www.nia.nih.gov/health/alzheimers-dementia-resources-for-professionals
18. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer's disease: causes and treatment. Molecules . 2020;25(24):5789. doi:10.3390/molecules25245789
19. Okamura N, Harada R, Ishiki A, Kikuchi A, Nakamura T, Kudo Y. The development and validation of tau PET tracers: current status and future directions. Clin Transl Imaging . 2018;6(4):305-316. doi:10.1007/s40336-018-0290-y
20. Alzheimer’s Breakthrough: C2N First to Offer a Widely Accessible Blood Test. News release. PrevivityAD. October 29, 2020. Accessed April 26, 2022. https://bit.ly/3OHq943
21. The First Alzheimer’s Blood Test Is Now Commercially Available. News Release. Massachussets General Hospital. December 4, 2020. Accessed April 26, 2022. https://ftdboston.org/2020/12/04/the-first-alzheimers-blood-test-is-now-commercially-available
22. Quanterix’s Alzheimer’s Blood Test Designated a Breakthrough Device. News Release. FDA News. October 15, 2021. Accessed April 26, 2022. https://www.fdanews.com/articles/204866-quanterixs-alzheimers-blood-test-designated-a-breakthrough-device
23. FDA Grants Breakthrough Device Designation to Diadem's AlzoSure® Predict Prognostic Blood Test for the Early Prediction of Alzheimer's Disease. BioSpace. News Release. January 18, 2022. Accessed April 26, 2022. https://www.biospace.com/article/releases/fda-grants-breakthrough-device-designation-to-diadem-s-alzosure-predict-prognostic-blood-test-for-the-early-prediction-of-alzheimer-s-disease/
24. FDA Grants Accelerated Approval for Alzheimer’s Drug. US Food & Drug Association. News Release. June 7, 2021. Accessed April 26, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
25. FDA Approves BELSOMRA® (suvorexant) for the Treatment of Insomnia. Merck. News Release. August 13, 2014. Accessed April 27, 2022. https://www.merck.com/news/fda-approves-belsomra-suvorexant-for-the-treatment-of-insomnia
26. Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement . 2020;16(3):541-551. doi:10.1002/alz.12035
27. Treatments for behavior. Alzheimer's Association. Accessed April 27, 2022. https://www.alz.org/alzheimers-dementia/treatments/treatments-for-behavior
28. Norins LC. Repurposing licensed drugs for use against Alzheimer's disease. J Alzheimers Dis . 2021;81(3):921-932. doi:10.3233/JAD-210080
29. Recruiting, Not yet recruiting, Enrolling by invitation Studies: Alzheimer Disease. ClinicalTrials.gov. Accessed April 27, 2022. https://bit.ly/3kiZkFz
Research Summaries
| https://www.consultant360.com/clinical-updates/alzheimer-disease?page=6%3Fpage=3%3Fpage=7%3Fpage=6%3Fpage=7 |
IN RE BFP | 974 F.2d 1144 (1992) | 2d114411939 | Leagle.com
SNEED Circuit Judge This is a consolidated appeal by BFP a California partnership from an adversary proceeding in the bankruptcy...2d114411939
IN RE BFP
Nos. 91-55632, 91-54480.
View Case
Cited Cases
Citing Case
974 F.2d 1144 (1992)
In re BFP, a Partnership, Debtor.
BFP, a Partnership, Plaintiff-Appellant,
v.
IMPERIAL SAVINGS & LOAN ASSOCIATION, Defendant, and
Paul Osborne; William Little; Dennis Roy; Arthur Ritz; Jose Cruz; Richard Marcz, Defendants-Appellees.
In re BFP, a Partnership, Debtor.
BFP, Appellant,
v.
IMPERIAL SAVINGS & LOAN ASSOCIATION, Appellee.
United States Court of Appeals, Ninth Circuit. https://leagle.com/images/logo.png
Argued and Submitted July 9, 1992.
Decided September 8, 1992.
Attorney(s) appearing for the Case
Roy B. Woolsey, Newport Beach, Cal., for plaintiff-appellant.
Michael R. Sment, Rich & Ezer, Los Angeles, Cal., Robert F. Kidd, Graham & James, San Francisco, Cal., for defendants-appellees.
Before: SNEED and D.W. NELSON, Circuit Judges, and ROLL, District Judge.
United States Court of Appeals, Ninth Circuit.
SNEED, Circuit Judge:
This is a consolidated appeal by BFP, a California partnership, from an adversary proceeding in the bankruptcy court instituted to avoid a transfer of property under the avoiding powers of 11 U.S.C. § 548(a)(2)(A). We affirm.
[974 F.2d 1145]
I.
FACTS AND PROCEEDINGS BELOW
In July of 1987, Wayne and Marlene Pedersen and Russell Barton entered into a written arrangement involving the purchase of a home in Newport Beach, California owned by Sheldon and Ann Foreman. The Pedersens were to buy the Foreman home for $356,250 plus some rare coins, whose value is not disclosed in the pleadings. The Pedersens planned to raise the $356,250 from a bank loan, itself to be secured by a first deed of trust on the property. It is reasonable to assume that the Foremans believed their home had a value in excess of $356,250. The precise extent to which the Pedersens and Barton shared that view is less certain.
The Pedersens also agreed to give Barton a 180-day option to purchase the home, after the Pedersens themselves effected its purchase from the Foremans. Barton planned to remodel. In exchange for the option to buy, Barton agreed to pay the Pedersens 25% of any profits earned on the home's resale.
In August of 1987, after the property went into escrow, a shadow passed over the transaction. Local newspapers reported that Wayne Pedersen was under investigation for fraudulent sales of rare coins. This caused the Foremans some trepidation, and all the parties agreed orally to structure a somewhat different arrangement. Instead of the Pedersens being the buyers, a partnership, BFP, was formed. Its sole partners were Wayne and Marlene Pedersen and Russell Barton. Similar to the prior agreement between the Pedersens and Barton, the partnership agreed to divide profits from the resale of the Foreman home 75% to Barton and 25% to the Pedersens. The following transactions then took place.
On August 27, 1987, the Foremans deeded the property to the Pedersens. On the same day, the Pedersens then deeded the property over to BFP, the partnership. The Pedersens borrowed $356,250 from appellee Imperial Federal Savings Association 1and BFP "borrowed" $200,000, in the form of a six-month promissory note, from the Foremans. Ostensibly, the note served as replacement value for the rare coins. Both loans were secured by deeds of trust on the home, Imperial's being a first, the Foremans' a second.
The Foremans' earlier misgivings proved well founded. Despite their initial conveyance to BFP, the Pedersens conveyed the property a second time to a concern called Off Road Vehicles — Recreation and Family Campground, Inc. BFP and the Foremans sued in state court to quiet title to the property.
While the state court suit was pending, Imperial, whose loan was not being serviced, instituted foreclosure proceedings on the property. Off Road then filed an involuntary bankruptcy petition on behalf of BFP in order to secure an automatic stay of the foreclosure. BFP moved to dismiss the involuntary petition, and Imperial moved to lift the automatic stay. The bankruptcy court granted both motions; it lifted the stay on June 12, 1989, and dismissed the involuntary case on June 14, 1989.
With the stay lifted, Imperial continued its foreclosure of the property. On July 12, 1989, Imperial conducted a foreclosure sale and sold the property to appellee Paul Osborne for $433,000. Osborne had no notice of the title dispute, and bought the property in good faith. BFP alleges that the property was actually worth over $725,000 at the time of the sale to Osborne. As a result, BFP claims that its equity in the property was lost.
On July 21, 1989, the state court in the suit to quiet title announced its intended ruling. The court decided to rescind the 1987 conveyance from the Foremans to the Pedersens and to award both the Foremans
[974 F.2d 1146]
and Barton damages against the Pedersens. The court entered final judgment on October 12, 1989.
On August 18, 1989, after the state court announced its quiet title decision, BFP filed a second state court action which sought to rescind Imperial's conveyance to Osborne. The Foremans joined this action because, while their initial conveyance had been rescinded by the quiet title action, their ownership interest in the property stood to be destroyed by Osborne's good faith purchase of the property at Imperial's foreclosure sale. The stated grounds of this second state court action were that Imperial did not comply with the foreclosure procedures set forth in California Civil Code §§ 2924 et seq.
On October 25, 1989, BFP filed for Chapter 11 bankruptcy, which caused the second state court suit to be stayed. BFP then instituted the adversary proceeding that is the subject of this appeal.
The bankruptcy court on March 6, 1990 dashed BFP's and, no doubt, the Foremans' hopes when it dismissed the adversary complaint against Osborne for failure to state a claim. The court noted that BFP did not make any allegation that Imperial's trustee sale was in violation of California law, nor did BFP assert that the sale was conducted fraudulently or collusively. The court also found that Osborne was a bona fide purchaser for value, without notice, and ruled that there was no legal authority to set aside the sale as to Osborne. The district court summarily affirmed this dismissal, and BFP appealed on May 9, 1991.
The adversary proceeding continued to the summary judgment stage against Imperial and on July 10, 1990, the bankruptcy judge granted summary judgment in favor of Imperial. It based its decision on two grounds. First, it held that there was no transfer of an interest in property by virtue of the first state court judgment, which rescinded the deed from the Foremans to the Pedersens. Wrote the court: "[T]he Pedersons [ sic] did not have an interest in property when they purported to transfer the title to the property to BFP. Therefor [ sic], BFP never received good title." Alternatively, the bankruptcy court ruled that Imperial's sale to Osborne could not be avoided under 11 U.S.C. § 548(a)(2)(A) because "a reasonably equivalent value was received in exchange for the transfer, [and] the nonjudicial foreclosure sale was noncollusive and regularly conducted."
In a published opinion, In re BFP,132 B.R. 748(Bankr.9th Cir.1991), the bankruptcy appellate panel affirmed. The court applied its previous decision, In re Madrid,21 B.R. 424(Bankr.9th Cir.1982), aff'd on other grounds,725 F.2d 1197(9th Cir.), cert. denied,469 U.S. 833, 105 S.Ct. 125, 83 L.Ed.2d 66 (1984), which held that the sale price in a noncollusive, regularly conducted foreclosure sale is, as a matter of law, reasonably equivalent value for purposes of 11 U.S.C. § 548(a)(2)(A). Judge Volinn, who had dissented in Madrid,once more dissented. See In re BFP,132 B.R. at 751-52 (Volinn, J., dissenting). This time he argued that Madridshould be overruled in light of more recent decisions from courts of appeals in other circuits, which themselves followed the suggested course of his earlier Madriddissent. BFP appeals the bankruptcy appellate panel decision. We must now decide whether the bankruptcy court, the district court, and the bankruptcy appellate panel were correct in letting Imperial's foreclosure and Osborne's purchase of the Foreman home stand.
II.
JURISDICTION AND STANDARDS OF REVIEW
We have jurisdiction pursuant to 28 U.S.C. § 158(d).
The bankruptcy appellate panel's decision in the
Imperial
case and the district court's summary affirmance in the
Osborne
case are reviewed de novo. Findings of fact in the bankruptcy court are reviewed for clear error. We may affirm on any ground finding support in the record.
[974 F.2d 1147]
See In re Siriani,967 F.2d 302, 303-04 (9th Cir.1992).
III.
FRAUDULENT TRANSFERS UNDER SECTION 548(a)(2)
Section 548(a)(2) of the Bankruptcy Code sets forth the avoiding powers of a bankruptcy trustee as they relate to fraudulent transfers of a debtor's interest in property. To avoid a transfer under this section, four elements must be satisfied:
(1) the debtor must have an interest in the property;
(2) the debtor must have been insolvent at the time of the transfer or become insolvent as a result of the transfer;
(3) the transfer must have occurred within one year of the bankruptcy filing; and
(4) the debtor must have received less than a reasonably equivalent value for the transfer.
See In re Bundles,856 F.2d 815, 816-17 (7th Cir.1988). Only the first and last elements are disputed on this appeal.
A. Did BFP have a property interest in the Foreman home?
Whether a debtor has a property interest under 11 U.S.C. § 548 is a question determined by state law. See In re Torrez,63 B.R. 751, 754 (9th Cir. BAP 1986). As noted above, the bankruptcy court found that BFP did not obtain good title to the Foreman home by virtue of the state court ruling rescinding the deed from the Foremans to the Pedersens. Imperial contends that the bankruptcy court was correct, and offers a number of arguments in support of its position. 2
Legal arguments aside, however, the judgment of the state court clearly quieted title in favor of boththe Foremans and BFP as against all other parties in the state court action. After first rescinding the original deed from the Foremans to the Pedersens, the state court ruled as follows: "It is further ordered, adjudged and decreed that plaintiffs B.F.P., Sheldon L. Foreman and Ann Fant Foreman are the sole owners of said real property in fee simple, and Sheldon L. Foreman and Ann Fant Foreman are the owners of the note secured by deed of trust ... dated September 16, 1987" (emphasis supplied). The September 16, 1987 deed of trust secures BFP's $200,000 note given to the Foremans. Thus, the state court judgment settled title in favor of the Foremans and BFP as co-owners in fee simple, and, in addition, validated the Foreman's second deed of trust against BFP's fee interest securing the $200,000 debt owed by the partnership to the Foremans.
Admittedly, the state court's reasoning is difficult to follow.
3
But the judgment is valid, and we must give it full faith and credit. It follows that BFP did indeed have
[974 F.2d 1148]
a property interest in the Foreman home at the time of Imperial's foreclosure sale to Osborne.
B. Did BFP receive "reasonably equivalent value" under 11 U.S.C. § 548(a)(2)(A)?
The bankruptcy appellate panel below applied its earlier decision in Madridand held that the price received at a noncollusive, regularly conducted foreclosure sale establishes as a matter of law reasonably equivalent value under 11 U.S.C. § 548(a)(2)(A). Although the issue is a close one, we agree that the Madridrule is the appropriate interpretation of the Bankruptcy Code. As the Sixth Circuit has stated, "[T]he better view is that reasonable equivalence for the purposes of a foreclosure sale under § 548(a)(2)(A) should be consonant with the state law of fraudulent conveyances." In re Winshall Settlor's Trust,758 F.2d 1136, 1139 (6th Cir.1985) (citing Madrid). We necessarily part from the positions taken by the Fifth Circuit in Durrett v. Washington Nat'l Ins. Co.,621 F.2d 201(5th Cir.1980) 4and the Seventh Circuit in Bundles. 5
The Bundlesanalysis (and implicitly that of the Durrettapproach) rests on a plain-language interpretation of § 548(a)(2). Granting an irrebuttablepresumption of reasonable equivalence under a noncollusive foreclosure sale, the Bundlescourt argues, effectively creates a judicial exception to the trustee's avoiding powers under § 548. Id.at 823. In turn, an irrebuttable presumption undermines the ability of the trustee or debtor to recover lost equity, which is the purpose of the § 548 avoiding powers. The position is persuasive, but we think that broader considerations require a different result.
As has been widely recognized, allowing a bankruptcy court to undo a foreclosure sale carries with it the strong potential to destabilize state mortgage transactions. Professor Ehrlich summarizes the result succinctly:
[T]he prospect that trial courts will determine reasonable equivalence on a case-by-case basis is untenable from both federal and state perspectives. From a state viewpoint, an ad hoc approach produces intolerable uncertainty regarding the finality of any purchase at a foreclosure sale even if the price paid at the sale is close to, but not equal to, the retail market value. From a federal perspective, this uncertainty undermines the price-maximizing objectives of section 548(a)(2) because potential buyers will discount their assessment of the true market value of the property to reflect this uncertainty. Scott B. Ehrlich, Avoidance of Foreclosure Sales as Fraudulent Conveyances: Accommodating State and Federal Objectives, 71 Va.L.Rev. 933, 963-64 (1985). Professor Ehrlich's observations are persuasive. It makes little sense to interpret § 548(a)(2)(A) in a way that will likely discourage healthy foreclosure bidding.
Perhaps more importantly, by following the Madridformulation we are able to give a reasonable meaning to § 548 without unduly upsetting local real estate markets or state law. Unlike the Bundlescourt, we see the issue as bothone of statutory interpretation andthe growing tension between preemption and the requirements of a vigorous federal system. The Supreme Court has recently reminded us that our interpretation of federal statutes should be tempered with due regard for traditional state areas of regulation. See Cipollone v. Liggett Group, Inc.,___ U.S. ___, ___-___, 112 S.Ct. 2608, 2617-18, 120 L.Ed.2d 407 (1992). Thus, by interpreting § 548 in accordance with the Madridformulation, we are able to balance bankruptcy policy and comity concerns. 6
We therefore hold that the price received at a noncollusive, regularly conducted foreclosure sale establishes irrebuttably reasonably equivalent value under 11 U.S.C. § 548(a)(2)(A). 7
AFFIRMED.
FootNotes
* Honorable John M. Roll, United States District Judge for the District of Arizona, sitting by designation.
1. Since the commencement of this suit, the Resolution Trust Corporation has been appointed receiver of Imperial. For convenience, we will continue to refer to the savings association by its former name.
2. For instance, Imperial posits that BFP would be unable to obtain "bona fide purchaser" status from the Pedersen-to-BFP grant because the Pedersens were general partners of BFP. BFP, asserts Imperial, is therefore imputed with knowledge of the Pedersen's fraudulent intent by virtue of California partnership law,
see
Cal. Corp.Code § 15012, and the Pedersen-to-BFP deed is consequently avoidable to the same extent as the Foreman-to-Pedersen deed,
see Perry v. O'Donnell,
749 F.2d 1346
, 1349 (9th Cir.1984).
3. The state court seems to hold that the Foreman-to-Pedersen deed became avoidable by a failure of consideration caused by the Pedersens. However, the Foremans received over $365,000 of loan proceeds upon their transfer of title to the Pedersens. There is additional language in the judgment that implies that the failure of consideration took place as a result of the Pedersen's subsequent breach of both the BFP partnership agreement and contractual duties owed to the Foremans. How this breach would cause a failure of consideration, as that concept is normally understood, or how the breach would affect the original grant, is not explained.
Imperial describes the state court judgment as one which found fraud perpetrated by the Pedersens which in turn induced the Foremans to deed over their property. This is certainly a plausible reading of the facts, but it is just not supported by the state court judgment or its official "Explanation of Decision." Indeed, the state court flatly ruled that "there was no such conspiracy to defraud" on the part of the Pedersens.
4. The "
Durrett
rule" holds that so long as the debtor received at least 70% of fair market value, the sale cannot be avoided under § 548(a)(2)(A). As has been pointed out elsewhere, the actual holding of
Durrett
does not explicitly establish a 70% floor. Rather, the court merely noted that it was unable to find a case that had approved a transfer "for less than 70 percent of the market value of the property." 621 F.2d at 203. For analytical purposes, it is nonetheless useful to treat
Durrett
as standing for the notion that some level of price inadequacy will result in a fraudulent transfer under § 548(a)(2)(A). This is the interpretation given
Durrett
by numerous bankruptcy courts, and, historical accuracy aside, is in fact the "
Durrett
rule."
See
Alan S. Gover & Glenn D. West,
The Texas Nonjudicial Foreclosure Process — A Proposal to Reconcile the Procedures Mandated by State Law with the Fraudulent Conveyance Principles of the Bankruptcy Code,
43 Sw.L.J. 1061, 1062 (1990).
5. The
Bundles
court rejected both
Durrett
and
Madrid,
opting instead for what it called a middle ground approach. Under the
Bundles
formulation, "[r]easonable equivalence should depend on all the facts of each case." 856 F.2d at 824. The court felt that the "starting point" of the inquiry should be the fair market value, but listed also as relevant the market value as affected by the "fact of foreclosure." In the "usual circumstances," the court opined, a rebuttable presumption of reasonable equivalence would be appropriate. Nonetheless, state-specific foreclosure procedures might alter the analysis if they were not designed to "return to the debtor-mortgagor his equity in the property."
Id.
Thus it is proper to examine state foreclosure procedures and inquire whether "there was a fair appraisal of the property, whether the property was advertised widely, and whether competitive bidding was encouraged."
Id.
Still, it is necessary "to accord respect to the state foreclosure sale proceedings."
Id.
at 825.
6. We should note also that the
Madrid
formulation has been adopted by the National Conference of Commissioners on Uniform State Laws,
see
Unif. Fraudulent Transfer Act § 3(b) (1984), and has been recommended by the American Bar Association,
see
1983 A.B.A. Sec. of Real Prop.Rep. 106B.
7. We also agree with the lower courts that the applicable state procedures were complied with in this case and that BFP received adequate notice of the foreclosure under California law.
| https://www.leagle.com/decision/19922118974f2d114411939 |
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Dobozy, B Dobozy, B Dobrea-Grindahl, Mary Dobszay, Á Dobszay, L Dobszay, Éászló Dobszay, L Dochartaigh, Seoirse Ó Doctor, Jennifer R. Dodd, Rose. Dodd, Julian Dodgion, Dottie Dodgson, Paul Doe, Julia Doffman, Mark Doggett, Peter Doggett, Peter. Doheny, James. Doherty, Harry. Doherty, Conor Doherty, Matt Dohnányi, E Dóka, Krisztina Dokalik, Dietmar Dokter, Julia Doky, Niels Lan Dolan, Emily I. Dolan, Therese Dolp, Laura Dombi, J Dombiné, J Domingo-Montesinos, Isabel-María Domínguez-López, Juan-José Domínguez, Freddy Cristóba Domínguez-Moreno, Áurea Domokos, M Domokos, Z Domoney, Kelly. Dömötör, Endre Dömötör, Zs Dompnier, Bernard Don Juan Archiv Wien. Donaldson, William Donau-Universität Krems. Dong, Lorraine. Dong, Arthur E. Donlon, Denise Donnelly, K. J. Donnelly, Stephen E. Donnelly, Ryann Doonan, Simon Dóra, Schneller Dóra, Pál-Kovács Dorbayani, Mosi Dore, Florence Dorf, Samuel N. Dorfman, Jay Dori, Dafna Dorottya, Németh Dorset, Erik Dougherty, William Patrick Doughty, Karolina Douglas, Tana Douse, Cliff Dovchin, Sender Dovercourt, Jonny Dow, Rosie Dowling, Martin W. Downes, Julia. Downes, Lawrence Downes, Stephen C. Downes, Andy Downing, Antonio Michael. Downing, K. K. Doyle, Alan Doyle, Tom Doyle, David M. Dózsa, K Dr. Rolf von Bockel Drabløs, Per Elias Drach, Saša Dragheim-Lauritsen, Tejs Dragonová, Martina Draheim, Joachim Drake, Nick J. Draper, Jason. Dratwicki, Alexandre. Drecki, Jacek Roman Drees, Stefan Drever, John Levack Dreyfus, Kay Driscoll, Jim Driscoll, Colin Driscoll, Christopher M. Dromey, Christopher Droumeva, Milena Drudy, Andy Drury, Sara A. Mehltre Drury, Jeffrey P. Mehltre Drury, John Drüner, Annie-Laure Drüner, Ulrich Dryden, Lynn Drysdale, John D. Du, Xinping = 杜新平 Dubber, Andrew. Dubois, Pierre DuBreuil, Alexandre Duch, Michael Francis Duchesneau, Michel Dudrah, Rajinder Kumar Dueck, Jonathan Duff, Jeff Duffett, Mark Duffy, Timothy Duffy, Michael J. Duffy, Michelle Dufour, Denis. Dufour, Valérie Dugan, Franjo Dukay, Barnabás Dukay, B Dunbar, Julie C. Duncan, Dayton Duncan, Stuart P. Duncan, Cheryll Duncan, Cheryll. Dunedin Dancers. Dungan, Myles Dunkel, Mario. Dunn, Henry Dunsby, Jonathan Durakoglu, Aysegul Duraković, Lada Durkin, Rachael Durney, Daniel Durrand, Mark Dusinberre, Edward Dümling, Albrecht Dürrfeld, Peter. Dvořák Society for Czech and Slovak Music, Dwyer, Benjamin Dyck, Kirsten Dyer, Joseph Henry Dylan, Bob Dyndahl, Petter. Eagle, Douglas Spotted Eames, Michael Earle, Ben Earles, Andrew Easlea, Daryl. Easlea, Daryl Eavis, Michael Eavis, Emily Ebenezer, Lyn. Eberhardt, Markus Ebrecht, Ronald. Echard, William Echeverría, María del Puy Pe Ecke, Andreas Eckes, Jutta Eckhardt, M Eckhardt, Mária Ecsedi, Zsuzsa Ed.), Ossa-Martínez; Marco Anto Edel Germany GmbH Edexcel (Organization) Edgar, Kate. Edgar, William Edgar-Hunt, Robert Edinburgh University Library. Edith Cowan University. EDITION GORZ Edjabe, Ntone Edling, Anders. Edling, Cecilia Wahlströ Edling, Anders Edlund, Bengt Edström, Olle Edwards, Janet. Edwards, Christine Edwards, Scott Lee Egan, Sean Egea, Susana Egeland, Ånon Egey, Emese Eggenschwiler, Byron Eglinton, Mark Ehmann, Julia Ehrlich, David Ehrlich, Robert Eigeldinger, Jean-Jacques. Eigeldinger, Jean-Jacques Eilish, Billie Eisel, John C. Eisendle, Reinhard Ejeby, Bo Eken, Cecilie Ekenberg, Anders Ekho Verlag Eklund, Christer. Eklund, Karl Johan Elek, Koloh Elgar, Edward Elgar, Alice Elias, Berner Elie, Paul Elixir Piping and Drumming (Firm), Elkins, Elizabeth Elliott, Paul Elliott, David J. Elliott, Richard Ellis, Karen Ellis, Katharine Ellis, Sarah Ellis, Carl Ellis, Sarah Taylor Ellison, Curtis W. Ellison, Barbara Ellsworth, Therese. Ellsworth, Jane Elms, Anthony Előd, Juhász Elowsson, Anders Elphick, Daniel Elsby, Jon Elsea, Peter Elvira-Esteban, Ana Isabel Elvira-Esteban, Ana-Isabel Emile, Wennekes Emília, Barna Emmerson, Simon Emmery, Laura V. Emőke, Sántha Encabo, Enrique. Encabo-Fernández, Enrique Encabo-Fernández, Enrique Ender, Daniel Ender, Daniel. Endō, Tōru Endre, Halmos Endre, Hegedűs Engelbrecht, Henrik Engl, Stefan Engleheart, Murray English, Helen J. English, T. J. English, Lawrence. English Hymnal Co., English National Opera, English National Opera. Englund, Axel Englund, Axel Engström, Andreas Enikő, Gyenge Eno, Brian Enstice, Wayne Eősze, L Eötvös, P Epstein, Dan Epstein, Marcia Jenneth Epting, Chris Érdi, T Erdmann, Hans Erickson, Kris Ericson-Roos, Catarina Erika, Nyerges Erika, Simon Erika, Fernbach Eriksen, Dorthe Eriksen, Jan Eriksson, Gunnar Eriksson, Karin L. Eriksson, Jeanette Eriksson, Karin. Eriksson, Josef Eriksson, Maria Eriksson, Magnus Eriksson, Åke Eriksson, Torbjörn Eriksson, Maria Erlmann, Veit Ernő, Kiss Erricker, Jane Erwin, Max Escuer-Salcedo, Sara Eshbach, Robert Whitehouse Espada, Martín Espeland, Magne I. Espiña-Campos, Yolanda Espínola, Francisco Espinosa, Santiago Esse, Melina Essex, David Esteve-Faubel, José María Esteve-Roldán, Eva Esteve-Roldán, Eva Estévez-Sola, Juan A. Eszter, Gombocz Ethniko kai kapodistriako panepisti̲mio Etter, Brian K. Etxebeste-Espina, Elixabete Etxeverria-Jaime, Jesús European Cantors Association, Éva, Fehér Éva, Kelemen Éva, Bieliczkyné Buzás Éva, Fehérné Sulyok Éva, Kondicsné Kovács Evans, Mark Evans, Timothy Evans, Julie Evans, Steve Evans, Bob Evans, Elfed Evans, David Evans, David T. Evans, Mike Evans, Tristian Everett, Walter Everett, William A. Everett, Andrew Everist, Mark. Everist, Mark Everley, Dave Evertsson, Maria Ewens, Hannah Eybl, Martin. Eybl, Martin Eydmann, Stuart Ezaki, Kimiko Ezquerro-Esteban, Antonio Fabényi, J Faber, Phillip Faber, Phillip. Fábián, Éva Fabian, Dorottya Facci, Serena. Fadipe, Israel A. Fadnes, Petter Frost Fagan, Gerald Fagerström, Eskil Fagius, Jan Fagius, Gunnel Fahlander, Thomas Faiman, David Fairbrass, Fred Fairbrass, Richard Fairchild, Charles Fairclough, Pauline Fairclough-Isaacs, Kirsty Fakir, Abdul Falco, Raphael Falconer, Tim Falkman, Carl Johan Fallon, Robert Falola, Toyin Falthin, Annika Falus, A Fan, Linlin = 范琳琳 Fancourt, Daisy Fang, Xiao = 方晓 Fanni, Hende Fanning, David Fano, Michel Fantappiè, Francesca Fantini, Bernardino. Fargeton, Pierre Fargion, Janet Topp Fariza, Paulina Farkas, Z Farkas, Z Farkas, Iván Farncombe, Tom. Farnsworth, Brandon Farr, Ray Farraj, Yasamin Farrell, Isabel Fassler, Margot Elsbeth Fast, Susan. Fast, Barbara Fatou, Kandé S Faulds, Katrina Faulk, Barry J. Faulkner, Simon Faulkner, Robert Faure, Michel Fauré, Gabriel Fauser, Annegret Fay, Brendan Fazakas, I Fazekas, G Fazekas, Gergely Fazekas, G Fearnley, James Featherstone, Sally Federico, Gabriel Fedoszov, J Fedrová, Stanislava Fein, Michael Fejérvári, Boldizsár Fejérvári, B Fejős, J Fekete, A Fekete, Károly Feldman, Zev. Feldman, Morton. Feldman, Morton Feldman, Heidi Carolyn Feldman, Evan Feldman-Barrett, Christine Jacqueline Feldstein, Ruth Fell, Mark Fell, Alex Fellani, Matin Felton, Dickie. Feneyrou, Laurent Fenlon, Ian Fenlon, Iain Fenton, Kathryn Fényes, G Ferenc, Verseghy Ferenc, Szénási Ferenc, Liszt Ferenc, Rátkai Ferenc, Apró Ferenczi, I Ferge, Béla Ferguson, Paul Ferić, Mihael Fernandes, Cristina Fernández, Gabriel Fernández-de-Latorre, R. Fernández-Manzano, Reynaldo Ferrada-Noli, Nicholas Ringskog Ferraguto, Mark Ferraiuolo, Augusto Ferrari, Brunhild Ferrari, Giordano. Ferreira, Manuel Pedro Ferreiro-Carballo, David Ferrer-Cayón, Jesús Ferrero, Lena Kagg Ferrett, D Ferri-Durà, Jaime. Ferris, William R. Fertel, Rien Ferzacca, Steve Festival de Música Antigua de Úbeda y Baeza Feurzeig, Lisa Feustle, Maristella Fèis Rois. Fhuartháin, Méabh Ní Fiala, Michele Fiddes, Luke Fiegel, Eddi. Field, Kim Fields, Kenneth Fifer, Julian Fifield, Christopher Fifield, Christopher Figueiredo, Marcio Figueroa, Michael A. Filippi, Daniele V. Fillerup, Jessie Fillion, Éric Fink, Jesse Finnerty, Adrian Finney, John Finscher, Ludwig Finzi, Gerald Fiore, Ivana Fiorentino, Giuseppe Fischer, Rebecca Fischer, Paul Fischlin, Daniel. Fischlin, Daniel Fišer, Ernest Fisher, Elizabeth Fisher, Mark Fiskvik, Anne Margrete Fitch, Fabrice FitzGerald, Martin Fitzgerald, Mark Fitzner, Frauke Fitzpatrick, Rob. Fjord, Jens Viggo Flack, Michael Flannagan, Andy Fleet, Paul Fleischer, Rasmus Fleischmann, Ruth Fleischmann, Tilly Fleischmann, Walter Fleming, Michael Jonathan Fleming, Simon Fletcher, Tom Fletcher, K. F. B. Fletcher, Tony. Fletcher, Tony Flintoff, Brian Flom, Jonathan Floquet, Oreste Flores-Fuentes, Juan Floridou, Georgia A. Floros, Constantin Flōrou, Louiza Flotzinger, Rudolf Floyd, James Michael Floyd, J. B. Floyd, Samuel A. Floyd, Richard Flury, Roger Flynn, Amanda Flynn, Patricia Földváry, MI Foley, Catherine E Foley, Catherine E. Foley, Byron Folkehojskolernes Forening i Danmark Fong-Torres, Ben Fong-Torres, Ben. Fonseca, Anthony J. Font-Batallé, Montserrat Fontán-del-Junco, Manuel Fontijn, Claire Anne Foon, Anthony Forbidden City (Nightclub: San Francisco, Calif.) Ford, Robert Ford, Charles Ford, Elizabeth Forde, Eamonn Foreman, Lewis. Forgács, Robert Forkel, Johann Nikolaus Forrest, Arick. Forrest, Nigel. Forsberg, Jan Foršek, Goran Forsell, Jacob Forsén, Arne Forssell, Jonas Forster, Robert Forster, Robert Fortey, Bryn. Fosbraey, Glenn Fosbraey, Glenn. Foss, Hubert J. Foss, Dora. Foster, Stephen Collins Foster, Mick Foster, Mo. Foster-Peters, Kelly-Jo Foulk, Ray Foulk, Caroline Foulkes, Julia L. Foundling Museum, Fouter-Fouter, Vera Fowke, Philip Fowler, Gene Föllmi, Beat A. Fraga-Suárez, Fernando Fraile-Gil, José Manuel. Fraile-Prieto, Teresa Frame, Pete Frampton, Peter Frances-Hoad, Cheryl Francfort, Didier. Franke, Leander Franke, Leander. Frankel, Emile Franklin, Neil Franklin, Dan Franks, Don Franziska, Diehr Fraser, Neil Fraser, Benjamin Fratini-Serafide, Roberto Frayssinet-Savy, Corinne Fredriksson, Niclas Fredriksson, Daniel Freeman, Phil Freeman, Dean Freeman, Peter Freeman, Robert Freestone, Brian D. Frego, R. J. David Frehley, Ace. Freiburghaus, Gabriela French, Stewart French, Mark Frenkel, A Frenz, Barbara Freund, Julia Friberg, Anders Frid, Emma Friddle, David Friedberg, Jeffrey Frieden, Ken Friedl, Erika Friedler, M Friedman, Allan Jay Friedmann, Jonathan L. Friedrich, Á Friehs, Julia Teresa Frierson-Campbell, Carol Friesen, Orin Frigyesi, Judit Frith, Simon Fritsch, Melanie Froehlich, Hildegard C. Frolova-Walker, Marina Frölich, Emilia. Frühauf, Tina Fry, Robert W. Fu, Hong = 傅鈜 Fuchs, Emily Fuchs, Dieter Fuente-Charfolé, José-Luis Fügedi, J Fugelso, Karl Fuhrich, Edda Fuhrmann, Wolfgang Fukuoka, Madoka. Fukuoka, Shōta. Fukushima, Kazuo Fukushima, Mutsumi Fuller, Nicholas Lester Fuller, Sophie Fundación Juan March, Fung, Victor. Furia, Philip G, Németh Gaar, Gillian G. GABARRÓN-TORRECILLAS, Antonio-Francisco Gabbard, Krin Gábor, Vásárhelyi Gábor, Barna Gábor, Eredics Gábor, Turi Gábor, Winkler Gábor, Simon Géza Gábor, Sarbak Gábor, Presser Gábriel, Szoliva Gabriēl, Angelos Gabriella, Gilányi Gaddy, K. R. Gademan, Göran Gádor, Ágnes Gádor, Á Gadpaille, Michelle Gagné, Nicole V. Gagné, David Gaifem, Monica Gaines, Jim Gaitanos, Kōstēs Galán-Bueno, Carlos Galán-Gómez, Santiago Galbraith, Patrick W. Galiana-Gallach, Josep Lluis Galicia-Poblet, Fernando Galilea, Carlos Galindo, João Maurício Galindo-Pozo, Miguel Gall, Zlatko Gall, Gregor Gallagher, Miriam Gallardo, Gemma Gallardo-Saborido, Emilio José Gallego, Antonio Gallet, Bastien Galloway, Vic Galpérine, Alexis Galuszka, Patryk Galvin, Anthony Gambetta, Beppe Gamble, Steven Gammond, Peter Gann, Kyle Gannon, Charles Gant, Andrew Gao, Tian = 高天 Garay, Ramón Garbage (Musical group), Garbayo-Montabes, Francisco-Javier Garber, Michael G. Garcia, Carlos-Benito García, Eliseo Garcia-Arevalo-Alonso, Julia García-Asensio, Enrique García-Gómez, Génesis García-Herrera, Vanessa García-Lorca, Federico García-Mahíques, Rafael García-Manzano, Julia-Esther García-Martínez, Rafael García-Matos-Alonso, María-Carmen García-Molero, Hayda García-Molina, Rafael García-Peinazo, Diego Garcia-Testal, Elena García, Esperanza Rodrígue García-López, Olimpia García-Montalbán, Antonio. Garda, Michela. Gardiner, John Eliot Gardiner, John Eliot Gardiner, Michael C. Gardner, Elysa Gardner, Robert Gardner, Abigail Gardner, Matthew Gárdonyi, Zs Gargagliano, Arlen Garneau, Michel Garner, Anita Faye Garnham, A. M. Garrett, Peter. Garrett, Valerie. Garrido, Sandra Garrido, Waldo Garrido-Aldomar, Miguel Garrido-Domené, Fuensanta Garry, Catherine Garst, John F. Gartz, Thomas Mera Garza, Luis Díaz-San Gasch, Stefan Gaspar-Grandal, Jacobo Gaston-Bird, Leslie Gatenby, Phill Gates, Rachael. Gatsioufa, Paraskevi. Gatti, Tom Gaulier, Armelle Gault, Brent M. Gault, Dermot. Gauthier, David. Gauthier, Mary Gautier, Théophile Gavanas, Anna Gavin, James Gayraud, Agnès Gazarik, Richard Ge Sang Qu Jie = 格桑曲杰 Gebhardt, Nicholas Geck, Martin Geck, Martin. Geesin, Ron Gégény, I Gehlawat, Ajay Gelabert, Cesc Gelbart, Matthew Gembero-Ustárroz, María Gemmell, Keith. Genborg, Catrin Gentil, Nicky Geoffroy-Schwinden, Rebecca Dowd GeoMotion Group. George, Thandi George-Warren, Holly Georgi, Oliver Georgiev, Kiril. Georgii-Hemming, Eva Gerald Coke Handel Foundation, Gerald Coke Handel Foundation. Gergely, Hubai Gergely, Fazekas Gergely, Szilvay Gergely, Z Gerhard, Roberto Germain, Emmanuelle Germano, William P. Gerothanasi, Stamatia Gerup, Martin Gerup, Anders Gethers, Peter Getman, Jessica Giannini, Juri Giannini, Juri Giannopoulos, Emmanouēl Gibbard, Alun Gibbon, Sarah Jane Gibbons, William Gibbs, Christopher H Gibson, Barry. Gibson, Chris Gibson, Kirsten Gibson, Corey Gibson, Colin Gibson, David Giddens, Rhiannon Giddings, Steve Gidman, Jean Giese, Detlef. Gilabert, Gastón Gilányi, G Gilányi, Gabriella Gilbert, Joël Gilbert, W. S. (Willia Gilbert, Susie Gildart, Keith Gilkes, Cheryl Gill, Denise Gill, Andy. Gill, Craig. Gill, Jon Ivan Gillan, Matt Gilles-Kircher, Susanne. Gillespie, Robert Gillett, Christopher Gillies, Richard Louis Gillies, Anne Lorne Gillin, Edward John Gilling, David F. Gilling, Tom Gillon, Les Gilman, Sander L. Gilmore, Tom Gilmore, Ruth Wilson Gilmore, Joe Gilroy, Andrea Gilson, D. Giménez-Morte, Carmen Ginell, Cary Giner, Bruno Ginger, Charlie Giovanni, Varelli Girard, Philippe Girardi, Michele Giray, Selim Giroud, Vincent. Giroud, Vincent Girsberger, Russ Giselbrecht, Elisabeth Gittins, Ian. Gittins, Ian Giuffre, Liz Giuntini, Roberto Giuriati, Giovanni Gladsø, Svein Glass, Philip Glatthorn, Austin Glauert, Amanda Glazer, Mitch. Gleeson, Clare Glennie, Evelyn Gligo, Nikša Glinsky, Albert Glitsos, Laura Glover, Jane Gluck, Bob Glyn, Gareth Glynn, Stephen. Gobbato, Angelo Goddard, Simon Goddard, Michael Goddard, Simon. Godefroy, Cécile Godin, Gérald Goertzen, Chris Goertzen, Valerie Woodring Goialde-Palacios, Patricio Goldberg, Michael Goldberg, Meira Goldberg, Tatjana Golden, Reuel Goldin-Perschbacher, Shana Golding, Rosemary A. Goldman, Jonathan Goldman, Vivien Goldmark, K Goldschmidt, Henrik. Goldschmitt, K. E. Goldsmith, Melissa Ursula Daw Goldstein, Jack. Golia, Maria Golovlev, Alexander Golub, Peter Gombos, L Gombos, L Gombos, László Gómez-Cifuentes, Blanca Gómez-Fernández, Lucía Gomez-Gallego, Alonso Gómez-Muntané, María- Carmen Gomm, Eric Gon, Federico Gonin, Frédéric. Gonnard, Henri. Gonzales, Chilly Gonzales, Chilly Gonzalez, Sara González-Barrionuevo, Herminio González-Lapuente, Alberto González-León, Julia-Edna González-Martínez, Juan-Miguel González-Mira, Pedro González-Ribot, María José Gonzalezné, V Gonzalo, Jaime González, Francisco González-Barba-Capote, Eduardo González-Serrano, Carlos Javier. Good-Perkins, Emily Goodall, Howard. Goodman, Alice Goodman, Elizabeth Goodman, Alice. Goodman, Fred Goody, Matthew Goody, Matthew Goodyear, David Turnbull Gopinath, Sumanth S. Gordienko, Anastasia Gordon, Lisa Gordon, Anna Gordon, Alastair Gorfinkel, Lauren Gorman, Paul Goron, Michael Gottlieb, Jane Gottlieb, Iris Gouk, Penelope. Gouk, Penelope Gould, Jonathan Govan, Chloe. Govan, Chloe Gowen, Bradford Gómez, Francisco Gómez-Castellano, Irene Gómez-Cruz, Camilo. Gómez-Muntané, María del Carmen Gómez-Rodríguez, José-Antonio Götte, Ulli Graakjær, Nicolai Graber, Naomi Grabowski, Stephan Grabócz, Márta Grace, Delilah. Gracon, David Gradowski, Mariusz Graffin, Greg Graham, Ben Graham, Stephen Graham-Jones, Ian Grainger, Percy GRAMMY Museum. Grana, Natalie Douglass Granger, Brian Cornelius Grant, Colin Grant, Nevin Grant, Jane Grapes, Dawn Grapes, Dawn Grasse, Jonathon Grassl, Markus Grassl, Markus. Grau, Anna Kathryn Graves, Eben Graves, Milford Gravestock, Joy. Gray, Timothy Greager, Rosemary Great Britain. Green, Jeffrey. Green, Ben Green, Robert A. Green, Helen Green, Andy Green, Johnny Green, Ian Green, Nick Green, Jenny Green, Alan Green, Jesse Green, Lucy Green, Lucy Green, Laura Gayle Greenacombe, John Greenberg, Yoel Greenberg, Keith Elliot Greene, Taylor Greene, Tom Greene, Jeffrey Greene, Richard Leighton Greenfield, Edward Greenfield, Thomas Allen Greenman, Ben Greer, David Gregor, Neil Gregory, Georgina. Gregory, David Gregory, Glenn Gregory, Georgina Greig, Donald Grenier, Line Grennell, Katherine GRGIĆ, Velimir Gribenski, Fanny Gridley, Mark C. Grieg, Rebecca Grier, James Grierson, Tim. Grierson, Tim Griffin, Michael J. Griffin, Michael Griffiths, Daniel Grigg, Simon Grillo, Jerry Grimaldi, Marco Grimalt, Joan Grimes, Nicole. Grimley, Daniel M. Grimshaw, Mark Gripentrog, Helmuth Griscom, Richard. Grocke, Denise Erdonmez Grogan, Christopher Grogan, Suzie Gróh, Gállné Groos, Arthur. Groote, Inga Mai Groothuis, Marijke Grosen, Peter Grove, George Grover-Friedlander, Michal Grozdits, K Gruber, Gernot Gruhn, Wilfried Grushkin, Paul Grünewald-Schukalla, Lorenz Grzebałkowska, Magdalena Gschwandtner, Harald Gu, Yumie = 谷玉梅 Gudmundsdottir, Helga R. Guerpin, Martin Guerra, Paula Guerriero, Leila Guesdon, Jean-Michel Guesnet, François Guest, John F. Guglielmetti, Yohann Guigné, Anna Kearney Guilbault, Jocelyne Guildhall School of Music and Drama (London, England) Guildhall School of Music and Drama (London, England), Guillaumier, Christina Guillot, Matthieu. Guilloux, F. Guilmard, Jacques-Marie Guiltenane, Christian. Guionnet, Jean-Luc Gullberg, Anna-Karin Gullbrandsson, Robin Gullö, Jan-Olof Gumplowicz, Philippe Gunji, Masakatsu Gunn, Jacky Gunnarson, Anna Charlotta Gunnarsson, Ulrika Gunrem, Michael E. Guns n' Roses (Musical group). Guo, Jie = 郭洁 Gurd, Sean Alexander Gurke, Thomas Gusau, Sa'idu Muhammad Gustafson, Klas Gustafsson, Henrik Gustafsson, Magnus Gustafsson, Lars H. Guthrie, Kate Guthrie, Nora Guthrie, Woody Gutiérrez-Carreras, Pablo Gutiérrez-Carreras, Pablo. Gutiérrez-Cordero, María Rosario Guy, Nancy Guzy-Pasiak, Jolanta Gwizdalanka, Danuta. Gyenge, E Gynne, Göran Gyöngyi, Mátai Gyöngyvér, Hortobágyi Gyöngyvér, Havas Györffy, M György, Solti György, Csobó Péter György, Nagy György, Hegedüs György, Szomory György, Jókúti György, Gyarmati György, Rusznák György, Székely Győri, L Győri, Zsolt Gyula, Ajtonyi Gyula, Hegedűs Gyula, Juhász Haapala, Tuomo Haas, Anita Hackett, Jon Haddon, Alfred C. Haering, Sylvia Ingeborg Haffner, Herbert Hagen, Trever Hageneder, Fred. Hagerman, Frans Hagestedt, Jens Hagiya, Yukiko Haglund, Rolf Haglund, Magnus Hagmann, Lea Hahn, Christopher Haikawa, Mika Hainge, Greg Hair, Ross Hajdók, J Håkanson, Knut Håkansson, Kenny Halász, Péter Halford, Rob Halfyard, Janet K. Hall, Clare Hall, Þorbjörg Daphne. Hallag, Alexander Hallam, Julia Hallam, Susan. Hallgren, Scott W. Halligan, Benjamin. Halligan, Benjamin Halling, Ingmarie Halliwell, Martin. Halliwell, Michael Hallman, Diana R. hAllmhuráin, Gearóid Ó Halper, L Hamanaka, Masatoshi Hamann, Martin Hamann, Donald L. Hamberlin, Larry Hambro, Camilla Hamelman, Steven L. Hamer, Laura Hamilton, Katy Hamilton, Duncan Hamilton, Kenneth Hamilton, Andy Hamilton, David A. Hamlyn, Nick Hammarlund, Rolf Hammarlund, Ingrid Hammarlund, Jan Hammer, Ken Hammerstein, Oscar Hammond, Alan Hammond, Nicholas Hampe, Michael Hampson, Thomas Hampton, Andy Hampton, Nick Hanberry, Gerard Hancock, Herbie Hancox, Grenville Handel House Trust, Hanenberg, Peter Hanke, Maureen. Hanna, Emma Hannah, Jonny Hanns-Werner, Heister Hansén, Stig Hansen, Mads Hansen, Adam. Hansen, Lene Halskov Hansen, Pil Hansen, Kai Arne Hara, Nobuo. Harada, Theresa Harada, Kaori Hardasmal, Sergio Hardi, R Harding, Charlie Harding, J. T. Harding, Phil Hardy, Martha Hargittai, Esther Hargreaves, David J. Hargreaves, Sam Harkins, Paul Harley, John Harmsen, Sophie Harnoncourt, Nikolaus. Harper, Nancy Lee Harper, Sally Harper, Ben Harper, Adam. Harper, Ellen Harper-Scott, J. P. E. Harpham, Geoffrey Galt Harrandt, Andrea Harrán, Don Harries, Judith Harrington, James Harris, Paul Harris, Craig Harris-Warrick, Rebecca Harrison, Peter T. Harrison, Danny Harrison, Sarah Harrison, Brady Harrison, Carol Harrison, Chris Harsent, David Harsløf, Olav Hart, Colin Hart, Chris Hart, Chaz Harte, Frank Hartenberger, Russell Hartl, Karla Hartley, John Hartmann, Astrid Pernille Hartmann, Annette Hartnoll, Paul Hartnoll, Phil Hartse, Joel Heng Hartt, Jared C. Hartyányi, Judit Harvard, Paul Harvey, Peter Harvey, Ryan Harwell, Jonathan H. Harwood, Robert W. Hascher, Xavier Haskins, Rob Hassler-Forest, Dan Haste, Cate Haste, Cate Hasted, Nick. Hasted, Nick Hasted, J. B. Hastey, Britt Hasty, Christopher Hasty, Christopher Francis Hatschek, Keith Hatter, Jane D. Hatzius, Lynn. Haupt, Adam Hauschka, Thomas Haute école de musique (Geneva, Switzerland), Haute école spécialisée de Suisse occidentale, Havas, Ádám Have, Iben Havelková, Tereza Havers, Richard Havránková, Lucie. Hawkey, James Hawkins, Kris Hawkins, Stan Hawkins, Rosa Hawkshaw, Susan Haworth, Rachel Hay, Chris Hayes, Aaron Haynes, Grace Hayslett, Bryan Hayton, Jeff Hayward, Philip Hayward, Mark. Hazlewood, Dave. Hâf, Mererid He, Fang He, Rong = 何荣 He, Yan = 何言 He, Yanshan = 何艳珊 He, Zipu = 何滋浦 Head, Raymond Head, Matthew Head, Paul Heal, Jamie Heath, Chris Heatley, Michael Heber, Noelle M. Heble, Ajay. Heble, Ajay Heble, Edited by. Edited Heckendorff, Nastasia Hédi, Sztanó Hedman, Dag Hedwall, Lennart Hegarty, Paul. Heile, Björn Hein, Morten Hein, Hartmut Hein, Ethan Heine, Christiane Heinemann, Michael. Heintz, Joachim Heintze, James R. Heisser, Jean-François Heister, Hanns-Werner Heisz, Tommy Heldt, Guido Helguera-Villa, Enrique Hellaby, Julian Hellín-Rubio, Inés Hembree, Mark Hemmingsen, Piers A. Henderson, George L. Henderson, Justin Henderson, David Henderson, Amy Henderson, John Hendler, Glenn Hendrickx, Marc Hendrikx, Eric. Hendrikx, Eric Hendrix, Janie Hendrix, Michael Henke, Matthias Henley, Darren. Hennessy, Sarah Henry, Dollie Henry, Pierre Henrysson, Harald Hensher, Philip Henson, David Hentschel, Linn Hentschel, Christian. Hepworth, David Hepworth-Sawyer, Russ Heras, Beatriz Herbert, Peter J. F. Herbert, Ruth Herbert, Trevor Herbert, Martin Herbert, Emily Herbert, Trevor. Herczka, Ferenc Herencsár, V Hergyán, T Herissone, Rebecca. Herle, Anita Herman, Arne Herman, Debbie Herman, Pawel Hermano-Ahullo, Ramón Hermes, Kirsten Hernández-Jaramillo, José Miguel J.M. Hernández-Sonseca, Carmen Hernández-Urculo, Zaida Hernández, Rafael Figueroa Hernández, David Heron-Allen Society. Herpy, Miklós Herren, Graley Herrmann, Timo Jouko Herrmann-Schneider, Hildegard Hersch, Charles Hersh, Kristin Hersh, Kristin. Herstand, Ari Hertzman, Marc A. Herzfeld, Gregor Herzig, Monika Hesmondhalgh, David Hess, Alan Hess, Juliet Hesse, María Hesselink, Nathan Hetény, J Heter, Storm Hewitt, Paolo Heydon, Rachel Heylin, Clinton Heylin, Clinton. Hérault, Catherine. Hibberd, Sarah Hibbett, Ryan Hichens, Mark Hickey, Helen Hickman, Sally. Hickmott, Sarah Hicks, Anthony Hidalgo, Danielle Antoinette Hiekel, Jörn Peter Hiemke, Sven Hiesel, Stefanie. Higgins, Lee Higuchi, Akira Hijleh, Mark Hill, Sarah Hill, Michael. Hill, Kevin Hillman, Neil Hills, Helen Himonides, Evangelos Himonides, Evangelos. Hindemith, Paul Hindemith-Stiftung, Hindle, David Hinson, Maurice Hintermaier, Ernst. Hirai, Mitsuru. Hirai, Nataria emi. Hiramatsu, Hideki. Hirata, Akiko. Hirata, Keiji Hirota, Ritsuko. Hirsch, Lily E. Hirsch, Marjorie Wing Ho, Tung-Hung Ho, Wai-chung Hoad, Catherine Hoag, Melissa E. Hoban, Wieland Hoch, Matthew Hochmiller, Susan Hochradner, Thomas. Hochradner, Thomas Hodge, Daniel White Hodges, Natalie Hodges, David Hodges, Chas Hodges, Donald A. Hodgkinson, Tom Hodgson, Jay Hodkinson, Mark Hoeckner, Berthold Hoefnagels, Anna Hoefnagels, Anna. Hofer, Johann Hoffman, Stewart Hoffmann, Bettina Hoffsten, Louise Hofman-Sretenović, Neda Hofmann, Alex Hogen, Hildegard. Hogg, Katharine Hogmark, Esbjörn Hogwood, Christopher Hojby, Jeanette Holbrook, Ann Norton Holden, Raymond Holden, Wendy Holdhus, Kari Holdhus, Kari. Holgersson, Per-Henrik Hollai, Keresztély Holland, Simon Hollerung, G Holley, Chuck Hollitzer Wissenschaftsverlag Holm-Lupo, Jacob Holman, Peter Holmberg, Henric Holmes, Martin Holmes, Matthew. Holmes, Ramona Holmes, Thom Holmgren, Carl Holmgren, Ola Holmgren, Claes Holmquist, Göran Holmquist, \AAke Holoman, DK Holroyd, Arthur Holt, Thomas J. Holt, Macon Holtsträter, Knut Holzer, Andreas Holzer, Andreas. Homan, Shane Homan, Shane Homer, Sheree Hong, Barbara Blanchard Honing, Henkjan Honrado-Pinilla, Alberto (Ed.) Honrado-Pinilla, Alberto Hood, Alison Hood, Danielle Hook, Peter Hooper, Ellen Hooper, Michael Hoover, Sarah Adams Hoover, Timothy R. Hope, Cat Hope, James Hopkin, Bart Hopkins, Adrian Hopkins, Antony Hopkins, Adrian. Hopper, Jessica Hopwood, Mererid Horák, M Horan, Geraldine Horgas, J Hori, Tomohei. Horlacher, Gretchen Grace Horlor, Samuel Hormigón-Vicednte, Laura Hormigón-Vicente, Laura Horn, Charles E. Horn, David Hornby, Nick. Hornby, Emma Horne, Gerald Horne, Craig. Horne, William P. William Horowitz, Mark Eden Horton, Julian Horton, Peter Horton, Julian Horvat, Hrvoje Horváth, Attila Horváth, A Horváth, Breinichné Horváth, ML Horz, Andrea Hoshino, Yukiyo Hosken, Daniel W. Hoskins, Robin HOskins, Robert Hoskisson, Darin Hoskyns, Barney Hosmer, Brian C. Hosono, Takaoki. hosono, shinji Hotta, Eri Hou, Jiancheng Hou, Lemeng = 侯乐萌 Hough, Stephen Houghton, Mick Housley, Paul Houston, Kerry Houston, Cissy Hovánszki Mária Howard, Deborah. Howard, Stephen Howard, Chris Howard, Keith Howard, Mark Howard, Jack. Howard, Richard Bothway. Howard, David M. Howard, Alan Howden, Martin Howe, Zoë Howe, Richard Howell, Mark Howland, John Hoy, Rory Höhn, Jiří Hölderlin, Friedrich Hrubín, František Hsu, Wei-En Huan Ping Xian Di Fang Zhi Ban Gong Shi = 黄平县地方史志办公室 Huang, Patrick Huang, Jianmin = 黄剑敏 Huber, David Miles Hudes, Quiara Alegría Hudson, Paul Huebner, Steven. Huehns, Colin Huet, Pierre Hughes, Shirley Hughes, David W. Hughes, Marian Beech Hughes, Brian Hughes, Diane Hughes, Owain Arwel Hughes, Charles L. Hughes, Gareth Pritchard Hugill, Andrew Huguet, Joan Campbell Huitker, George. Hultberg, Cecilia K. Hultén, Mårten Nehrfors Humphreys, Alastair Humphries, Glen Humphries, Patrick. Hunsaker, Leigh Anne Hunt, Helena Hunt, John Hunter, David Hunter, Dave Hurley-Glowa, Susan Margaret Hurrell, Nancy Hurwitz, David Huseynova, Aida Hutchence, Tina Hutchinson, Sydney Huygens, Christiaan Hünten, Franz Hyde, Jenni Hyde, Derek Hyden, Steven Hyldgaard, Rikke Hyman, Nicola. Hyman, Robert. Hyōki, Satoru Hytönen-Ng, Elina. Høgel, Sten Hørdum, Søren. Iazzetta, Fernando Ibn Ḥayyān, Abū Marwān H Iddon, Martin Ideguchi, Akinori Ideland, Jens Igbi, Oghenemudiakevwe Iges, José Iges-Lebrancón, José Iglesias-Iglesias, Iván Iglesias-Martínez, Nieves Ignácz, Á Ignácz, Ádám Ihnat, Kati Ikushima, Mikiko Ilari, Beatriz Senoi Ilić, Ivana Ilona, Ferenczi Ilona, Kovács Immler, Christian Impett, Jonathan Impey, Angela Imre, Harangozó Imre, Romsics Imre, Olsvai Information Resources Management Association, Ingalls, Monique Marie Ingalls, Monique Marie. Ingemark, Camilla Asplund Ingham, Chris. Ingham, Chris Ingham, Michael Inglis, Ian Inglis, Brian Ingolfsson., Árni Heimir Ingólfsson, Árni Heimir Ingraham, Mary I. Ingram, Catherine Inomata, Tokiwa Inose, Chihiro Inoue, Takahiro Inōe, Sayuri. Institute of Measurement and Control. International Conference Music Theory and Analysis (9 ; 2011 ; Beograd) International Council for Traditional Music. Study Group on Music and Dance in Southeastern Europe. Symposium (6 ; 2018 ; Sinj) International Music Education Research Centre. International Musicological Society International Society for Music Education. Internationale Richard-Strauss-Gesellschaft Internationale Stiftung Mozarteum Salzburg. Iommi, Tony. Iott, Sheryl Iovene, Paola Ippolito, J. M. Irby, Samantha Ireland, Brian Irons, Yoon Irvine, Thomas Irwin, William Irwin, Colin. Irwin, Colin Isacoff, Stuart Isacsson, Jonas Isakoff, Katia Ishida, Yutaka Isnard, Vincent. Isserlis, S Isserlis, Steven István, Pávai István, Bátori László István, Németh István, Kilián István, Gróf István, Korody-Paku István, Elmer István, Kereszty István, Mustos István, Balázs István, Bogárdi Szabó István, Berczelly István, Gáti Istvandity, Lauren Isusi-Fagoaga, Rosa Ittzés, M Ittzés, Mihály Ittzés, M Ittzésné, K Iturrioz-Petralanda, Nekane Iván, Cs Ivarson, Karin Iverson, Jennifer Ivković, Želimir Ž. Izabella, Bartalis Jaccard, JL Jacke, Christoph Jacks, Will H. Jacks, David Jackson, Laura Jackson, Amy S. Jackson, Andrew Grant Jackson, Seth Jackson, Sam Jackson, Maureen Jackson, Larisa Petrushkev Jackson, Daniel M. Jackson, Paul R. W. Jackson, Jake Jackson-Kew, Meryl Jackson-Tretchikoff, Julie Jacobs-Jenkins, Branden Jacobsen, Stine Lindahl Jacobshagen, Arnold Jacobson, Laurie Jacobsson, Mats Jacobsson, Stig Jacotine, Keshia Jacques, Annie Jaeger, Bertrand Jaffé, Daniel Jagger, Mick Jago, Marian Jakelski, Lisa. Jámbor, F Jambou, Louis James, Martin James, Alex James, Martin James, Barrington Jampol, Joshua. Jan, Steven B. Jancsó, J Janjik, Monika Jurić Jankovich, Richard. Jankowsky, Richard C. János, Weiss János, Sebők János, Sipos János, Béres János, Dombovári János, Fügedi János, Bereczky János, Bibor Máté János, Dézsi János, Szabó Ferenc János, Bojti Jansen, Emile Jansen, Guy Jansson, Sven-Bertil Jansson, Mikael Jansson, Per Åke Jansson, Dag Jara, Víctor Jarbouai, Leila. Jarman, Freya Jarrick, Arne Jarvis, Trevor Jas, Eric Jaschke, Artur C. Jasen, David A. Jauset-Berrocal, Jordi-Àngel Jávorszky, B Jávorszky, BS Jávorszky, Béla Szilárd Jay, Norman JayZ, JayZ Jazzforeningen Jazzinstitut Darmstadt Jäger, Markus Jeanneret, Christine Jedrzejewski, Franck Jefferies, Graeme Jena, Stefan Jena, Stefan. Jenkins, Delyth Jenkins, Willard Jenkins, Mark Jenkins, Jeff Jenkins, Katrina E. Jenkins, Jim Jenkins, Steve Jenkins, Paul Jennex, Craig. Jennings, Sarah Jennings, Ros Jensen, Oskar Cox Jensen, Kurt Balle Jensen, Erik Jensen, Anne Ørbæk Jensen, Jacob Wendt Jensenius, Alexander Refsum Jepson, Louisa Jerković, Berislav Jerold, Beverly Jersild, Margareta Jethro Tull (Musical group), Jewell, Alan. Jian, Miaoju Jiang, Ying = 蒋英 Jimenez, Javier Jiménez, José Luis Jin, Tielin = 金铁霖 JLS (Musical group), Jnr., HOwie Morrison Johann, Lurf Johansen, Geir Johansen, Guro Gravem Johansson, Karin Johansson, Anna Johansson, Carina Johansson, Ola Johler, J John, Elton John, Elton John, Corner John, Graham St. John, Emma John Ireland Charitable Trust. John Merrill Foundation, Johnson, Sherry. Johnson, Stephen Johnson, Mark Johnson, Christopher Johnson, Sherry Johnson, Joan Johnson, Bruce Johnson, Carol Johnson, Jake Johnson, David Johnson, Henry Mabley Johnson, Curtis D. Johnson, Julian Johnson, Alan Johnston, Tom Johnston, Jean Johnston, Roy Johnston, Ben Johnston, A. J. B. Jonasson, Camilla Jonášová, Milada Jones, John Jones, Richard Jones, Jacqueline Jones, Rickie Lee Jones, Gerry Jones, Tudur Huws Jones, Joseph E. Jones, Barry O. Jones, Peter Jones, Kenney Jones, Kimberly A.. Jones, Ellis Jones, Thomas C. Jones, J. S. Jones, Danny Jones, David Wyn Jones, Dylan Jones, Nicholas Jones, Tom Jones, Lesley-Ann Jones, Mark Jones, Lesley-Ann Jonsson, Göran Jonsson, Bengt R. Jorba, Miquel Jordan, W. D. Jordan, Randolph Jordansson, Leif Jorgensen, Ian Jorgensen, Hanna Rose Jornadas de Zarzuela (4ª. 2016. Cuenca) Jovanović, Jelena Jovanovic, Rob. Jovanović, J Joyce, Sandra Joynson, Vernon Joynson, Vernon József, Szécsi József, Krénusz József, Fülöp József, Kozák József, Gál József, Béres József, Terék József, Brauer-Benke Józsefné, Dombi Jóri, Anita Jóri, Anita Ju, Kelin = 巨克林 Jubin, Olaf Judd, Harry Judit, Rácz Judit, Bogár Judit, Pokoly Juhász, Z Juhász, E Juhász, Zoltán Julia, Jaklin Júlia, Torda Julia, Craig-McFeely Júlia, Demeter Julich-Warpakowski, Nina Julien, Pauline Julien, Olivier Julin, Don. Jullander, Sverker Jung, Eunji Jung-Kaiser, Ute Juranić, Zoran Jurecic, Boštjan Jurij, Snoj Juslin, Patrik N. Juslin, Patrik N. Juslin, Patrik N Justice, Deborah Justice, Jacob Jørgensen, Jørgen Wenndorf K., Marquis H. Ka'ai, Tania Kaastra, Linda T. Kabeláč, Miloslav Kabir, Ayesha Kaczmarczyk, Adrienne Kádár, AJ Kagerland, Peter Kahn, Ashley Kahr, Michael Kaijser, Lars Kaiser, Martin Maxmilian Kajanová, Yvetta Kajfeš, Davor Kakubari, Wataru Kaldewey, Helma Kalinak, Kathryn Marie Kalish, Gilbert Kallberg, Jeffrey Kallio, Alexis Anja Kallis, Vasilis Kalman, Julie Kalmár, A Kaltmeier, Olaf Kälvemark, Torsten Kamilla, Dévai Nagy Kamlah, Ruprecht. Kammerchor Stuttgart, Kamp, S Kanbe, Satoru. Kanda, Kunihiko Kane, John Kaneko, Naoki Kaneko, Jun Kanellopoulos, Panagiotis A. Kanellopoulos, Panagiotis A. Kanellopoulou, Jenny Kania, Andrew Kanneh-Mason, Kadiatu Kapilow, Robert Káplán, Szofia Kapp, Reinhard Kapralova Society, Kaprálová, Vítězslava Kapronyi, Teréz Karath, Kym Karczag, M Kardamēs, Kōstas Kardaras, Chrēstos D. Kardos, Leah Karjalainen, Toni-Matti Karl, Kügle Karlin, Jason G. Karlík, Filip Karlsen, Sidsel Karlsen, Sidsel. Karlsson, Ove Karlsson, Katarina A.. Karlsson, Petter Karlsson, Lars Karnes, Kevin Károly, Libisch Károly, Fekete Károly, Sziklavári Karousos, Charalampos Kárpáti, J Karpf, Juanita Kartawidjaja, Yakub E. Karwen, Bernd. Kaschub, Michele Kasinitz, Philip Kasser, Tim Kassler, Michael Kassler, Jamie Croy Kastine, Jeremy Kata, Rácz Katalin, Juhász Katalin, Marczell Katalin, Paksa Katalin, Lázár Katalin, Kim Katalin, Szvitacsné Marton Katalinić, Vjera Katayama, Takeshi. Kathy-Horváth, L Katona, Zoltán Katona, Kerry Katz, Pamela. Katz, Jared Katz, Mark Kauffman, Deborah Kaufman, Will Kaufman, Brian Kawasaki, Mizuho Kay, Maria. Kay, Sarah Kayaki, Tōru Kaye, Lenny Kayes, Gillyanne. Kärjä, Antti-Ville Kärki, Kimi Kealing, Bob Kearney, Mark. Kearns, Robin A. Kearns, Peter Kecskeméti, I Kecskés, A Keefe, Simon P. Keegan, Josephine Kehrer, Lauron J. Keijser, Roland Kelemen, É Kelhoffer, James A. Keller, Hans Kelley, Robin D. G. 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Kimura, Ryō Kinchin-Smith, Sam Kinder, Keith William King, Peter King, Liesl King, Greg King, Elaine King, Julian King, Richard King, Chris Thomas Kinga, Jálics Kinga, Povedák Kingsbury, Paul Kinsella, Ray Kinsley, Lloyd Kirby, Sarah Kirchschlaeger, Peter G. Kirilov, Kalin Kirkland, Kevin H. Kirkman, Phil Kirkman, Andrew Kishikawa, Masanori Kisiel, Marine Kiss, G Kiss, Gábor Kiss, L Kiss-Dobos, L Kitchen, John Kitts, Thomas M. Kitts, Alex. Kiwan, Nadia. Kjaer, Morten Kjelland, James Kjellberg, Erik Kjellberg, Soren Kjus, Yngvar Kjær, Signe Jensen Kladder, Jonathan R. Klaess, John Klape, Michael Klára, Hamburger Klára, Bodza Klára, Móritz Klára, Bajnai Klára, Kisdi Klára, Hamburger Klarin, Suzana Klassen, Judith. Klassen, Judith Klauk, Stephanie Klaus, Illmayer Klause, Inna Klavan, Spencer A. 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Komlós, K Köncse, Heverdle Péterné Kondō, Jō Kong, Siu-hang Konold, Wulf Koo, Sunhee Koops, Lisa Kopanitsanos, Kōnstantinos Kopec, Rudolf Kopecký, Jiří Koppány, Zsolt Koprek, Katarina Kordík, Pavel Kordík, Pavel Kordt, Inge Kordt, Asta Kornberger, Monika Korsakova-Kreyn, Marina Korvig, Hanne Koshikakezawa, Mai. Kosser, Michael Kōstantzos, Giōrgos Kostelanetz, Richard Kotarba, Joseph A. Kotnik, Vlado Kotschack, Jan Kotzor, Günter Kourousēs, Stavros Kovács, A Kovács, M Kovács, J Kovács, József Kovács Eszter Kovarsky, Jerry Kozinn, Allan Köchel, Ludwig König, José Manuel Izq Kraaz, Sarah Mahler Kraebel, A. B. Krahn, Carolin Kramer, Lawrence Kramer, Richard Kramer, Howard. Krapljanov, Marina Perica Krarup, Bertel Kraus, Beate Angelika Krause, S Krause, Bernard L. Kravitz, Lenny Kreitner, Kenneth Kremer, Jon Kreutz, Gunter Kreutz, Gunter Krieg, Gustav A. Kristensen, Erik Laugesen Kristóf, Csengery Kristoferson, Lars A. Kritzas, Vyrōnas Kroeger, Karl Kroeker, Joel Krogh, Mads Krohn, Tarek Kroll, Mark Krolo, KRešimir Kromhout, Melle Jan Kronenburg, Robert Kronenburg, Robert. Kronland-Martinet, Richard Kroó, G Kroupa, Jiří Krowicki, Marek Kröncke, Dietrich. Kröplin, Eckart Krpan, Erika Krueger, Alan B. Krukowski, Damon Krummacher, Christoph Kruse, Joakim Olsson Kruth, John Kubieniec, Jakub Kucinskas, Darius Kuhn, Will Kuijken, Barthold. Kund, Laura Kunitachi College of Music Kunitachi Ongaku Daigaku. Kunitachi-Ongaku-Daigaku. Kurihara, Utako. Kurkela, Vesa Kurth, Ernst Kurtzman, Jeffrey G. Kusz, V Kutschke, Beate Kuuse, Anna-Karin Kuyper-Rushing, Lois. Küssner, Mats B. Kvarnhall, Victor Kym, Min La Barbara, Joan La Chioma, Daniela la Nāśida, Kāmā Labbé, Stéphane Labia, Julien Labozár, A Labrado, silvia Labrador, Germán Lacasse, Serge Lacey, Jordan Lachmann, Frank M. Lacombe, Hervé Lacôte, Thomas Laederich, Alexandra Lafrance, Roger Laing, Dave. Laird, Paul R Laird, Paul R. Lajić, Mihajlović Danka Lajos, Főkövi Lajos, Miller Lakatos, R Laki, P Lalitte, Philippe Laloue, Christine Laloy, Louis Lamb, Andrew Lambe, Stephen Lammers, T. J. Lampert, V Lancashire, Terence Lanctôt, Jacques Lanczkor-Kocsis, K Landau, Carolyn Landerer, Christoph. Lanegan, Mark. Lang, Michael Lang, Zoë Alexis Lang, Jeff Lange, Uffe. Langenbruch, Anna Langford, Jeffrey Alan Langlois, Tony. Lanza, Joseph Lapine, James Lapine, James. Large, Carol Cash Larsen, Christian Larson, Katherine Rebecca Larsson, Christina Larsson, Hugo Laskai, A Laskai, Anna Laskaratos, Andreas Lasocki, David Lasuén, Sergio László, Somfai László, Szalkai László, Böhm László, Molnár László, Harsányi László, Dubrovay László, Stacho László, Domján László, Csányi László, Tóth László, Lakatos László, Dobszay László, Vikárius László, Emmert László, Gombos László, Heltay Lásztity, P Lásztity, Péró Latham, Sean Lathos, James Lattarico, Jean-François. Laubhold, Lars E. Laukvik, Jon. Laurence, Felicity. Lavigne, Laurent Lavocah, Michael Lavranos, Charilaos Law, Michael John Law, Jay Lawlor, Helen Lawrence, Ian Lawrence, Michael Lawson, Francesca R. Sborgi. Lawson, Colin Laxéll, Conny Laxer, Daniel Robert Layden, Joe. Lázár, Katalin Lázaro-López, José-Ángel Le, Tuan Hung Le Colleter, Thomas Le Menestrel, Sara le Pistone, Daniè Le Roux, François Le Vot, Gérard Lea, Kovács Leach, John Leach, Elizabeth Eva Leach, Elizabeth Eva Leach, Robert Leach, Gerald Leaf, David Leal, César Andrés Leary, James P. Leaver, Robin A. Lebrun, Barbara Ledbury, Mark Lederer, Victor Ledesma-Gómez, Francisco Ledsham, Ian Lee, Ric Lee, Michael Lee, Julin Lee, Colin Lee, Jonathan Rhodes Lefferts, Peter Legg, Barnaby. Legge, Nancy J. Leguay, Jean-Pierre Lehmberg, Lisa J. Leibnitz, Thomas Leibnitz, Thomas Leigh, Spencer Leijonhufvud, Susanna Leijonhufvud, Susanna. Leijonhufvud, Jonas Leikin, Anatole Leila, Rásonyi Leistra-Jones, Karen. Lejon, Kjell O. U. Leković, Biljana Leloup, Jean-Yves Lemaire, Frans C Leman, Marc Lemay, Denyse Lempesē, Litsa Lencsés, L Lendvay, Domonkos Leneman, Helen Lenneberg, Hans Lennon, John Lenti, Vincent A. Lenz, Risto León-Ara, Agustín León-Rodríguez, Ángel-Luis Leonard, Maurice. Leonard, Anne Leonard, Kendra Preston Leong, Daphne Leopold, Silke Leppert, Richard D. Lerch-Kalavrytinou, Irmgard Lerena-Gutiérrez, Mario LeRoy, Dan Lesaffre, Micheline Lesner, Frej Vammen Lespinasse, Patricia G. Lester, Paul Lestidau, shane Letchford, Michael Letellier, Robert Ignatius. Letellier, Robert Ignatius Letham, Andy Lethem, Jonathan Levaux, Christophe Leve, James Levenson, Steven Levente, Váradi Levente, Király Leverton, Marc Levey, Marie Therese Levi, Erik. Levine, Victoria Lindsay LeVine, Mark Levinson, Jerrold Levitin, Daniel J. Levitz, Tamara Levy, Daniel Lewenhaupt, Carl-Gustaf Lewin, David Lewin-Lane, Stephanie Lewis, Eric Lewis, Tony Lewis, George Lewisohn, Mark. Lewisohn, Mark Lewitová, Iris Urwin Lewsey, Jonathan Leza-Cruz, José-Máximo Lécroart, Pascal. Lévinas, Michaël. Li, Xiaoti Li, Dan Li, Lizhe = 李丽哲 Li, Mei = 李玫 Li, Xiaoqin = 李晓芹, Xiaoqin Libera, Luca Della Libin, Kathryn L. Libreria musicale italiana, Lichdi, Tilman Licht, Alan. Lídia, Nádori Lidija, BAjuk. Lidskog, Rolf Lie, John Liebersohn, Harry Lifter, Rachel Ligeti, György Ligeti, György Light, Ronald Light, Alan Lih, Emelyn Lih, Ariadne Lihoreau, Tim. Lili, Békéssy Lilla, Tóth Lilliestam, Lars Lin, Jennifer Lin, Hsun Linaberry, Robin Lind, Stephanie Lind, Magnus Lindahl, Andreas. Lindaryd, Christina Lindberg, Erik Lindberg, Boel Lindblad, Adolf Fredrik Lindblad, Katarina Lindgren, Monica Lindmayr-Brandl, Andrea Lindner, Andreas Lindsay, Bruce Lindsay-Douglas, Carole Lindskog, Sven Lindvang, Charlotte Linford, Brian Ling, John. Lingan, John Link, Dorothea Link, John Linnarsson, Bengt "Bella" Lionáird, Iarla. Ó Lipenga, Ken. Lipovac, MArijan Lipscomb, Scott David Lishka, Gerald R. 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Yamada, Chieko Yamada, Takafumi Yamaguchi, Mutsumi Yamakawa, Shizuo Yamamoto, Hiroko Yamamoto, Hiroyuki Yamashita, Hiroaki Yang, Zoua Sylvia Yang, Dingwang = 杨丁旺 Yang, Heping = 杨和平 Yang, Sai = 杨赛 Yang, Xifan = 杨曦帆 Yao, Zhihui = 姚志辉 Yard, Ryan Yawson, Jude Yeaman, G. E. Yearsley, David Gaynor Yearsley, David Gaynor Yeo, Douglas Yewdall, Julian Leonard Yi, Yŏng-mi Yi, Shucheng = 易述程 Yip, Joyce Yoon, Sunmin Yoon, Jean Yordanova, Iskrena Yordanova, Iskrena. York St John University. Yorkshire Association of Change Ringers. Yorkston, James. Yoshida, Tamao Yoshida, Minosuke Yoshida, Yukako. Yoshihara, Mari Yoshikami, Miyuki Yoshizaki, Masaki. You, Jingbo = 尤静波 Young, John Bell Young, Miriama Young, La Monte Young, Rob Young, Toby Young Classical Artists Trust. Young Musician Hebrides (Organization) Ystad, Sølvi Yu, Jun Yu, Danhong = 余丹红 Yuan, Quanyou Yudkin, Jeremy Yue, Kaifeng = 乐开丰 Yun, Isang Yusta, Miguel Ángel Yuste-Martínez, Luis Yusuke, Nakahara Zackrisson, Lasse Zadig, Sverker. Zaeri, Mehrdad Zagorski-Thomas, Simon Zakić, Mirjana Zamora-Caro, Katerine Žanić, Ivo Zapke, Susana Zarate, Rebecca Zatkalik, Miloš Zauner, Michelle Zazulia, Emily Zdanowicz, Gina Zebec, Tvrtko Zeck, Melanie Zeller, Regine. Zembylas, Tasos Zepf, Markus Zeppetelli, John Zerbe, Michael J. 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Zon, Bennett Zondi, Nompumelelo Bernadette Zornica Hagyományőrző Egyesület Zouhar, Vít Zoumpoulakēs, Petros Zsófia, Borz Zsombor, Németh Zsuzsa, Kővágó Zsuzsa, Czagány Zsuzsa, Czagány Zsuzsanna, Erdélyi Zsuzsanna, Pintér Márta Zsuzsanna, Domokos Zsuzsanna, Réfi Zsuzsanna, Glavina Zsuzsanna, Szepesi Zsuzsanna, Bálint Zubillaga, Igor Contreras Zuckermann, Moshe. Zunigo, Xavier. Zurmühl, Sabine Žuvela, Sanja Kiš Zürcher Hochschule der Künste Østergaard, Per Јанковић-Бегуш, Јелена Маринковић, Соња 국남., 배 음악사연구회 川﨑, 瑞穂 Type any Book Miscellaneous Conference Proceedings Journal Website Web Article Audiovisual Thesis Conference Paper Report Journal Article Presentation Term any Year any 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2009 2001 Keyword any 7 (CaQQLa)201-0000282 (CaQQLa)201-0001542 (CaQQLa)201-0004568 (CaQQLa)201-0005777 (CaQQLa)201-0009248 (CaQQLa)201-0010484 (CaQQLa)201-0013983 (CaQQLa)201-0013986 (CaQQLa)201-0017854 (CaQQLa)201-0022164 (CaQQLa)201-0032589 (CaQQLa)201-0038053 (CaQQLa)201-0038355 (CaQQLa)201-0041435 (CaQQLa)201-0046052 (CaQQLa)201-0046054 (CaQQLa)201-0046163 (CaQQLa)201-0053875 (CaQQLa)201-0066316 (CaQQLa)201-0070033 (CaQQLa)201-0081252 (CaQQLa)201-0093787 (CaQQLa)201-0117737 (CaQQLa)201-0164320 (CaQQLa)201-0164324 (CaQQLa)201-0278656 (CaQQLa)201-0343563 (CaQQLa)201-0356887 (CaQQLa)201-0387198 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(OCoLC)fst02021107 (OCoLC)fst02021978 (OCoLC)fst02022009 (OCoLC)fst02023092 (OCoLC)fst02023366 (OCoLC)fst02024003 (OCoLC)fst02027038 (OCoLC)fst02029199 (OCoLC)fst02031393 (OCoLC)fst02032989 (OCoLC)fst02033725 (OCoLC)fst02033891 (OCoLC)fst02033893 (OCoLC)fst02033910 (OCoLC)fst02040679 (RERO)A021003248 (RERO)A021096923 (RERO)A022509224 (RERO)A024797456 (uri) http://id.loc.gov/authorities/subjects/sh2008108258 (uri) http://id.loc.gov/authorities/subjects/sh85088762 (uri) http://id.worldcat.org/fast/fst01033799 13th century 15e siècle 15e siècle. 15th century 15th century. 16. century 16e siècle 16e siècle. 16th century 16th century. 17e siècle 17e siècle-18e siècle 17e siècle. 17th century 17th century. 17the century 18. století. 18.-20. století. 18.century 1814-1918 18e siècle 18e siècle. 18th century 18th century. 18th-20th centuries. 19. century 19.-20. století. 1900-1945. 1901-1910 1911-1920 1914 May 16- Auckland Boys' Choir -- History. Organists -- New Zealand -- Auckland -- Biography. Organists -- New Zealand -- Wellington -- Biography. 1914-1918 New Zealand music and the war; Patriotic music New Zealand History 20th century; World War 1914-1918 New Zealand Songs and music 1915 -2001 Ciricism and interpretation; Maori (New Zealand people) Music; Music New Zealand history and criticism; Puoro. reo 1918-2013 1919 -; Sound recording executives and producers New Zealand Biography; Sound recording industry New Zealand History; 1920-30's 1921-1930 1931-1940 x History and criticism. 1941-1950 1941-1950. 1943- Jackson 1944-2015. Composers -- New Zealand -- Biography. 1951-1960 1951-1960. 1952- anecdotes; Setchell 1955-2011; Popular music New Zealand History 1960-1969. 1961-1969. 1961-1970 1961-1970. 1970-1979. 1971-1980 1971-1980. 1978-1985 1980s 1981-1990 1981-1990. 1983- 1990-.... 1991-2000 1991-2000. 1993- 1996- career in popular music; Popular; music New Zealand 2011 - 2020; Rock musicians New Zealand biography; Singers New Zealand biography 19e siècle 19e siècle. 19th century 19th century. 19th-20th centuries. 20 century Croatia 20. století. 2001-2010 2001-2010. 2011-2020 2011-2020. 20e siecle. 20e siècle 20e siècle. 20th century 20th century & contemporary classical music. 20th century. 21e siècle 21e siècle. 21st century 21st century. 500-1400 500-1400. 600-1500 (Moyen Âge) 880-02 880-03 880-04 880-05 880-06 880-07 880-08 880-09 aat Aboriginal Australians Aboriginal Australians. Academic achievement Academic achievement. Accompaniments. Accordage. 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Auditory perception Auditory perception. Aufführung Auftritt August Abramović Adelburg August Adelburg Abramović Australia Australia |x History Australia. Australian Capital Territory Australie Austria Austria. Authenticité (Philosophie) Authenticity (Philosophy) Authors Authors and music. Authors, American Authors, American. Authors, Austrian Authors, Austrian. Authors, Canadian Authors, English Authors, French-Canadian Authors, French-Canadian. Authors, German Authors, German. Authors. Authorship Authorship. Autism Autism in adolescence Autism in adolescence. Autism in children Autistic children Autobiographie. autobiographies Autobiographies as Topic Autobiographies','Carter, Shayne Autobiographies. autobiography (genre) Autobiography. Autobiography: arts & entertainment Automatic control Automobile racing Automobiles Autonomisation. Autorschaft Autriche Autriche. Avant-garde (Aesthetics) Avant-garde (Music) Avante-garde (Music) New Zealand Awards Ästhetik Background music; Sociology of music Badalić Bagpipe Bagpipe music Bagpipe music, Arranged. Bagpipe music. Bagpipe. Bagpipers Bagpipers. Balkan Peninsula Balkan Peninsula. Ballader Ballades Ballads Ballads, English Ballads, English. Ballads, Japanese. Ballads, Scots Ballads. Ballet Ballet dancers Ballet dancers in art Ballet dancing. Ballet. Ballets Ballets. Ballroom dancing Ballroom dancing. Ballrooms Baloković Band music Bandes dessinées. Bands (Music) Bands (Music) Ireland Banjo Banjo. Bankers Barbados Barbados. Barcelona Bards and bardism. Baritō. Barnes, Jimmy. Baroque Baroque music Baroque music (c 1600 to c 1750). Barroco Barroque Bars (Drinking establishments) Bartók Bartol Đurđević/Jurjević Bass guitar Bass guitarists Batterie (Instrument de musique) Batteurs (Instrumentistes) Battle of Szigetvár Bawdy songs beat music Beatles. Bedeutung. Beethoven, Ludwig van, 1770-1827 Behavior modification. Bel canto Bel canto. Belarus Belarus. Belfast (Northern Ireland) Belgium Bell ringers Benefit performances Benet Casablancas Benjamin Britten Benson Bereavement Berghain Berliner Festspiele. Berlioz, Hector, 1803-1869 Bernard Herrmann Bernholm, Jonas, 1946- Berwald, Franz, 1796-1868 Bestandserhaltung Bible Bible films Bible in music. Bibliographie. Bibliographies & Indexes. bibliography Bibliography of bibliographies. Bibliography. Biblioteca Musical Víctor Espinós Bibliothécaires musicaux Bibliothéconomie musicale bicssc Bif Naked Big bands Binder's volumes (Music) Bio-bibliography Bio-bibliography. Biogaphy. Biographical sources Biographie (Genre littéraire) biographies biographies (literary works) Biographies as Topic Biographies. Biography BIOGRAPHY & AUTOBIOGRAPHY BIOGRAPHY & AUTOBIOGRAPHY / Adventurers & Explorers BIOGRAPHY & AUTOBIOGRAPHY / Artists, Architects, Photographers. 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Birdsongs Birdsongs. bisacsh bisacsh. Black & Asian studies. Black Canadian women Black English (Dialecte) Black English. Black people Black power Black power. Blackface entertainers Blacks Blacks. Bluegrass festivals Bluegrass festivals. Bluegrass music Bluegrass music. Bluegrass musicians Bluegrass musicians. Bluegrasses Bluegrasses. Blues Blues (Music) Blues musicians Blues musicians. Blues-rock music Blues-rock music. Body BODY, MIND & SPIRIT / General BODY, MIND & SPIRIT / Parapsychology / General. Boîte à rythmes Bollinger Bonbons Book industries and trade Books of hours Books of hours. Bop (Music) Bow music Bow songs Bowed stringed instruments Bowie, David, 1947-2016 Bowie, David, 1947-2016. Bowing. Boy bands Boy bands. Boys Brahe, Per, d.y., 1602-1680 Brain Brain stimulation Brain stimulation. Brand name products. Branding (Marketing) branding. Brass band music Brass bands Brass bands. Brass ensembles Brass ensembles. Brass instruments Brass instruments. Brazil Brazil, Southeast Brazil. Brésil Brian Boydell Britanniques. British British & Irish history. British Columbia British Columbia. Broadsides Broadsides. Bruit Bruits. btr Buchanan, Dorothy, 1945 - Buchbinderei. Budapest Buddhism Buddhist chants Buddhist chants. Budgie (musical group) Buildings. Bulgaria Bunkazai hogo. Bunraku. burials Bushi. BUSINESS & ECONOMICS / Careers / General BUSINESS & ECONOMICS / Development / General BUSINESS & ECONOMICS / Economics / Comparative BUSINESS & ECONOMICS / Industries / Media & Communications Industries BUSINESS & ECONOMICS / International / Economics BUSINESS & ECONOMICS / Leadership BUSINESS & ECONOMICS / Management. BUSINESS & ECONOMICS / Nonprofit Organizations & Charities Business Aspects. Butai bijutsu. Buyō-Indoneshia. Byzantine influences. Cabo Verde Cadence Cadiz (Spain) Cahman, Hans Heinrich 1640-1699 Cahman, Johan Niclas, 1670-1737 Cajun music Cajun music. Cajuns California Californie Calligraphy. Calypso musicians Cameroon Cameroon. Cameroun Cameroun. Canada Canada. Canadian poetry Canadian poetry (English) Canary Islands Candy Cantatas Cantatas, Sacred Cantatas, Sacred. Cantatas, Secular. Cantates profanes. Canticles cantor books Cantors Cantors (Church music) Capitalism Capitalism. Capitalist realism (Economic theory) Care and hygiene Career development Caribbean Area Caribbean Area. Carnatic music Carnatic music. Carnival Carnival music; Historical context; Spanish Rebublic Carnival. Carols, English Carols, English (Middle) Carols, German Carols, German. Case studies. Castile Castrati. Castrats. Cataloging of music. Catalogs and collections Catalogs. catalogue of the exhibition Catalogues Catechisms. Catedral de Tarragona Cathedrals Cathedrals; Music chapells; Repertoire; 19th Century Cathedrals; Music chapells; Repertoire; Villancico; Eightheenth Century Catholic Church Catholic Church. Catholics cct Cebu Provincial Detention and Rehabilitation Centre. 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Chanting chants Chants Chants et musique Chants sacrés Chants. Chapelles (Musique) Chapels (Music) Characters and characteristics in opera. Cheesemaking Chefs d'orchestre Chefs d'orchestre. Chefs de police Chiiki shakai. Child development Child development. Children Children in art Children in art. Children of immigrants children songs Children with autism spectrum disorders Children's choirs. Children's drawings Children's drawings. Children's plays, English. Children's plays. Children's poetry, Czech Children's poetry, Czech. Children's songs Children's songs, English Children's songs, English. Children's songs, Scots. Children's songs. Children. Childrens songs Chile Chile. Chills (Musical group) Exhibitions China China. Chine Chine. Chinese Chinese Americans Chinese Americans. Chinese influences. Chiptune Chiptunes Chiptunes. 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Concertos Concertos (Keyboard instrument) Concertos (Piano) Concertos (Viola) Concerts Concerts rock Concerts rock. Concerts. Conditionnement Conditions sociales. Conduct of life. Conducting Conducting. Conductors Conductors (Music) Conductors (Music) - Hungary Conductors (Music) -- New Zealand -- Biography. Conflict of generations Conflict of generations. Conflit interpersonnel Confucian influences. Congo (Democratic Republic) Congress. Congresses Congresses. Congrès. Conjoints Conjunto music Conjunto music. Consciousness. Conservation et restauration. Conservatories of music Conservatories of music. Consolidation and merger of corporations Construction Construction. Consumption (Economics) Contemporary Christian music Contemporary Christian music. 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Coureurs de bois Court music Courts and courtiers Courts and courtiers. Cousins, John, 1943 -career in music Cover versions Cover versions. COVID-19 (Disease) COVID-19 Pandemic, 2020- Creation (Literary, artistic, etc.) Creative ability in business Creative ability in business. Creative ability. Creativity Credo (Music) Credo (Musique) Cree women Création (esthétique) Cricket Crime in music. Crime organisé Criminal psychology. critical edition Criticism and interpretation Criticism and interpretation. Critique musicale Critiques musicaux Croatia Croatia - Medjimurje Croatia Records Croatia. Croatian art music Croatian language Croatian Music Croatian Music Cuture in 19. Century Croatian Music Institute Croatian popular music Croatian traditional music Croatian trditional musical instruments Croatian Writerw Croatie Cross-cultural studies. Crowd funding. Crusades Crusades. Crusell, Bernhard, 1775-1838 CSound (Computer program language) Cuba Cuban Americans Cuban Americans. 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Dance History Dance in motion pictures, television, etc. Dance in opera Dance music Dance music. Dance notation. Dance research Dance teaching Dance therapy Dance. Dance; Audiovisual arts; Copyrights; Law Dance; Choreographers; Women Dance; Choreographers; Women; Letters Dance; Classical dance; Choreographers Dance; Disabilty Dance; Escuela Bolera Dancers Danemark. Dans l'art Danse Danse, Musique de Danses de société Danseuses Data processing Data processing. Deadheads (Music fans) Deaf Deaf musicians. Deafness Death Death in music. Death. Decolonization Decolonization. Deconstruction. Dementia Dementia. Denazification. Denmark Denmark. Denshi ongaku-Rekishi. Denshi ongaku. Depeche Mode Deregulation Deregulation. Design Design and construction. Desire Desire in music. Devčić Natko Devotional literature, Indic Devotional literature, Indic. Décors Déesses hindoues Dépendants dějiny opery Dholi Dialectical behavior therapy. Diaries Diaries. Diario de Barcelona Dictatorship Diction Diction. Dictionaries Dictionaries. Difference (Philosophy) in music. Diffusion of innovations Digital audio editors. Digital electronics. Digital media Digital music players Digital rights management Digital rights management. Digital scores Digitalization Dimmer (musical group) Dinaric Region Dinner theater Dinner theater. Dionysia. Diplomatic relations. Diplomatie culturelle Diplomats Direction chorale. Directories. Dirigenter Disaster relief Disaster relief. Disasters Disc jockeys Disc jockeys. Disco (dans) Rave Modern dansmusik – historia Modern dansmusik – sociala aspekter Populärkultur – historia Disco music Discographie. Discographies. Discography Discography. discourse analysis Discrimination against people with disabilities. Diseases Diseases in opera. Diseases. Disinfection. Diskjockeyer Diskursanalyse Dissemination of music Dissemination of music. Diversity in the workforce Diversity in the workplace Divine office Divine office (Music) Do-it-yourself work Documentary films Dohnányi Domenico Scarlatti Domkyrkor Domnérus, Arne, 1924-2008 Don Juan (Legendary character) Don Quijote Doo-wop (Music) Double bass Double bassists Double bassists. Double Happys (musical group) Double-bassists Douglas Lilburn Dōwa. Dōyō-Nihon. Drama Drama. Dramatic music Dramatic music. Dramatisk och scenisk musik Dramatists, American Dramatists, English Dramatists, German Dramaturgie. Dramaturgy Dramaturgy. Droit d'auteur Droit d'auteur. Drottningar Musik – historia S{\aa}ngerskor – historia Kulturliv – historia Drug addicts Drug addicts. Drugs and popular music. Druids and druidism. Drum Drum and bugle corps. Drum circles Drum circles. drum language. Drum machine Drum machine. Drum set Drum set. Drum. Drummers Drummers (Musicians) dřevěné dechové nástroje. Dublin Dubrovnik dude Dudley Dufva, Petter, 1756-1836 dulcimer Dunedin Choral Society History Dutch Dutch. Dwarfs (Persons) Dylan, Bob, 1941- Dynamics. Dysphonie. Ear training. Early childhood education Early childhood education. Early modern history: c 1450/1500 to c 1700. Early modern, 1500-1700 Early music Early printed books Early works to 1800. East and West in art. East Asia East Asia. East Asians East Indian diaspora. Easter Easter Island Easter music. Easter Rising Eastern Europe Ecomusicology. Economic aspects Economic aspects. Economic conditions Economic conditions. Economic history. Economics, Finance, Business & Management. Economics. Ecrivains québécois eczenas Edition Edo period, 1600-1868. Edo period. Education EDUCATION / General EDUCATION / Higher EDUCATION / Multicultural Education EDUCATION / Special Education / General EDUCATION / Special Education / General. Education and state Education and state. Education, Elementary Education, Elementary. Education, Higher. Education, Humanistic. Education, Primary Education, Primary. Education, Secondary Education, Secondary. Education, Urban. Education. Education; Pedadogy Educational change. Educational sociology Educational sociology. Educational Technology Educational technology. Effect of human beings on. Effects pedals Effects pedals. Effets physiologiques. Effets pysiologiques Eiga ongaku. El Sistema (musikpedagogik) El Sistema (musikpedagogik) – historia election campaigns. Electric guitar Electric guitar makers Electric guitar makers. Electric guitar. Electricity Electroacoustic music Electroacustic music; Sound art; Criticism Electronic apparatus and appliances Electronic composition. Electronic dance music Electronic dance music. Electronic instruments, Digital. Electronic music Electronic music. Electronic musical instrument makers Electronic musical instrument makers. Electronic musical instruments Electronic musical instruments. Electronic reference sources. Electronic sound control. Electronica (Music) Elegiac poetry, English Elegiac poetry, English. Elektroakustisk musik Elektronisk musik Elektronmusikstudion Elementary school teaching. Elever Elgitarr – historia Gitarr – historia Ellington, Duke, 1899-1974-- influenser Elvis Presley Elvis Presley impersonators Elvis Presley impersonators. Embellishment (Vocal music) embne Emeralds Emeralds. Emigration and immigration Emigration and immigration. Emotions Emotions in art. Emotions in children. Emotions in music Emotions in music. Emotions in the performing arts Emotions in the performing arts. Empathy. Employees Empowerment Encyclopedias Encyclopedias. Encyclopédies. End of the world. Engeki-Nihon. Engeki-Roshia. Engelskspråkiga författare-- historia Engineering instruments Engineering instruments. England England, North East England, North East. England, Northern England. English English language English literature English literature. English New Zealand. Hymns English poetry English-speaking countries Enka Enka. Enlightenment Enlightenment. Enregistrements de terrain (Musique) Enrique Enrique Granados Enseignement Enseignement axé sur l'apprenant. Enseignement secondaire. Enseignement supérieur. Enseignement. Ensemble (Exécution musicale) Ensemble playing Ensemble playing. Entertainers Entertainers New Zealand Entertainers New Zealand Biography Entertainers. Entertainment & Performing Arts. Entrepreneurship Entrepreneurship. Entretiens. Environmental aspects Environmental aspects. Equipment and supplies Equipment and supplies. Erard piano. Ergonomi Eric Ericson Eriksson, Josef, 1872-1957 Ernő Dohnányi Errors of usage Esclavage Esclaves Essays. Estland Estonia Estonians Estonians. Etats-Unis ethics (philosophical concept) Ethiopia. Ethiopian Americans Ethiopian Americans. Ethiopians Ethiopians. Ethnic festivals -- New Zealand. Ethnic identity. Ethnic performing arts Ethnic relations. Ethnic Studies Ethnicity in music Ethnicity in music. Ethnological museums and collections Ethnological museums and collections. Ethnology Ethnomusicologie Ethnomusicologie. Ethnomusicology Ethnomusicology. Ethnomusicology; Folklore; Songbooks Etnicitet Etnologi Musiketnologi Kulturmiljöv{\aa}rd Folkmusik Folkmusikuppteckningar eucharist Eurasia Eurasia. Eurasie. Europe Europe, Central Europe, Eastern Europe, Eastern. Europe. European influences. Eurovision Song Contest Eurythmics. Evangelicalism Evangelicalism. Evangelists Evangelists. Events (Philosophy) Evolutionary computation. Evolutionary psychology. Examinations Examinations. Executors and administrators Executors and administrators. Exercices (Éducation musicale) exercises etc. Exécution Exécution (musique) Exécution. Exhibition catalogs exhibition catalogue Exhibitions Exhibitions. Exoticism in music. Expériences paroxystiques. Expression (Philosophy) Expression in art. Extreme metal (Music) Écoles secondaires Écomusicologie. Écosse. Écoute (Philosophie) Écrits de musiciens rock. Écrivaines noires américaines. Écrivains autrichiens Éditeurs audionumériques. Éditeurs de musique Édition Éducation holistique. Éducation humaniste. Éducation. Église catholique Église luthérienne Église luthérienne. Églises protestantes. Électronica (Musique) Électrophones États arabes États-Unis États-Unis (Sud) États-Unis. Éthiopie. Éthiopiens Étude et enseignement Étude et enseignement. Études de cas. Facsimiles. Facteurs d'orgues Facteurs liés à l'âge. Facture Facture. Faculty of Music in Belgrade Fair use (Copyright) Fairy tales Faith. Fame Families Families. Family relationships Fan magazines Fan magazines. Fandangos Fanfares (Orchestres) Fängelser Musik och samhälle Fans (Persons) Fantasy fiction Fantasy fiction. Fantasy films Fantasy games. Fanzines Farm life Farmers Fascism and culture Fascism and culture. Fascism and music Fascism and music. Fascisme et musique Fashion Fashion designers Fashion in art. fast Fathers and daughters Fathers and daughters. Fathers and sons Fathers and sons. Faust (Legendary character) Fågelsång. Feasts for the Blessed Virgin Mary. Federico García Lorca Feliks Petančić Femininity in music. Femininity in popular culture Femininity in popular culture. Feminism Feminism & Feminist Theory. Feminism and literature Feminism and literature. Feminism and music Feminism and music. Femmes dans l'industrie musicale. Femmes dans la musique. Femmes mécènes de la musique Femmes sauvages dans la littérature. Femmes violonistes Fender guitar Fender guitar. Fernsehproduzent. Festivals Festivals de musique Festivals. Féminisme et musique. Fiddle tunes Fiddle tunes. Fiddlers Fiddlers. Fiddling Field recordings Fife and drum corps Fife and drum corps music Fife and drum corps music. Fife and drum corps. Fifre et tambour, Musique de Filipino American youth Filipino Americans Film Film adaptations. Film catalogs. Film composers Film composers. Film music Film soundtracks Film soundtracks. Film theory & criticism,Film: styles & genres,Opera. Film, Musique de Filmmusik Filmmusik Animerad film Publiker Filmmusik, USA. Filmmusik. Filmska umjetnost filosofi Musik – sociala aspekter Finance, Personal. Fingering Fingering. Finland Finlandssvenskar Finn, Liam Finn, Neil Flageolet Flamenco Flamenco dancers; Biographies Flamenco dancers; Homosexuality; Gender studies Flamenco music Flamenco singers Flamenco; Ethnomusicology; Work songs Flight in art. Flöjt Musikframträdanden Florida Floride Flute Flute music Flute music. Flute players Flute players. Flûte à bec Flying Nun Records - History 20th century Flying Nun Records - History; Sound recording industry - New Zealand - History; Rock musicians - New Zealand; Music trade - New Zealand - history Flying Nun Records history Folk art Folk art. folk custom Folk dance folk dance in Hungary Folk dance music Folk dance music. folk dance research Folk dancing Folk dancing, Irish Folk dancing, Irish. Folk dancing, Scottish. Folk dancing. folk epics folk instrument Folk music folk music collection Folk music festivals Folk music festivals. folk music history Folk music Hungarian folk music research Folk music Southern Slavs in Hungary Folk music symphosyum Folk music, Irish. Folk music. folk musical instruments Folk musicians Folk musicians. folk musicof South Slavs in Hungary Folk poetry, Arabic Folk poetry, Bakhtiari. Folk poetry, Greek (Modern) Folk poetry, Italian Folk poetry, Italian. Folk singers Folk singers. Folk songs Folk songs, Aboriginal Australian Folk songs, Arabic Folk songs, Bakhtiari. Folk songs, Chinese Folk songs, Czech Folk songs, Czech. Folk songs, English Folk songs, English. Folk songs, Indonesian Folk songs, Indonesian. Folk songs, Japanese Folk songs, Japanese. Folk songs, Kannada. Folk songs, Korean Folk songs, Ladino Folk songs, Ladino. Folk songs, Manx. Folk songs, Nenets Folk songs, Old French Folk songs, Scots Folk songs, Scots. Folk songs, Scottish Gaelic Folk songs, Welsh. Folk songs. Folk-rock music Folk-rock music. folkdance Folkliga koraler Folklore Folklore. Folklorists Folkmusik Folkmusik Spelmän Folkmusik-- historia Folkmusik-- sociala aspekter folksongs folktradition Folkvisor-- forskning Fonds d'archives. Food in music Food in music. Football (Soccer Association Football) Forecasting. Foreign influences. FOREIGN LANGUAGE STUDY / Multi-Language Phrasebooks. Förenta staterna Forests and forestry. formal analysis Formation. Former Yugoslav republics Former Yugoslav republics. Foster children Fourrures Fragmente. fragments. France France, Southern France, Southern. France. Francoism Francoist dictatorship Franjo Ksaver Kuhač = Franz Ksaver Koch Frankrike Franz Joseph (František) Gläser Franz Xaver Kleinheinz Französisch Frederick May Free jazz Free jazz. French influences. French language French poetry French poetry. French. Friendship Friendship. From Scratch(Musical Group) Fue. Functor theory. Fundamentalism Fundamentalism. Funds Preservation Funeral consultants Funeral music Funeral music. Funeral service Funk (Music) Funk musicians Fur trade Fur trade. Fur traders Futurism (Literary movement) Futurism (Music) Fuzzy logic. Gagaku Gagaku. gaita Gakufu-Rekishi. ganga Gangsta rap (Music) Gangsters Gangsters. Garamut García family Gardberg, Tom, 1941- Gasshō. Gay culture Gay culture. Gay men Gay men. Gay musicians Gay musicians. Gay musicologists Gehörslära Geijutsu-Indoneshia. Geishas. Geistliche Musik. Gender Gender identity in music Gender identity in music. Gender nonconformity Gender nonconformity. Gender studies Gender studies, gender groups. Gender studies: women. Gender studies; Pedagogy Gender-nonconforming people Gender-nonconforming people. General & world history. General certificate of education examination (Great Britain) General. Generation Y. Generation Z Genetic algorithms. Genres & Styles genusaspekter. George Frideric Handel Georgia Gerald Dawe German influences. German language German literature German literature. German poetry German speaking countries German. Germany Germany (East) Germany (West) Germany. Gesang Geschlechterrolle Gestes dans la musique. Gestion numérique des droits Gestion. Gesture in music. Géorgie (État) Gēmu sofuto. Ghana Ghana. Ghāna Ghāna. Gidayūbushi. gipsy musicians Girei. Girl groups (Musical groups) Gitarrer-- historia Giuseppe Verdi Glam metal (Music) Glam rock (Music) - New Zealand - History and criticism Glam rock music Glam rock music - History and criticism - New Zealand Glam rock music. Glam rock musicians Glasgow glazbeni nakladnici - Hrvatska - 20/21. st. Glee clubs Glee clubs. Globalisierung Globalization Globalization. Gluck-Piccinni controversy. gnd God (Christianity) Godfrey Gong Gospel Gospel music Gospel music. Gospel musicians Gospel musicians. Gospel singers Gospel singers. Govori Grading and marking (Students) Grainger, Percy, 1882-1961 Grammar. Grande-Bretagne Grande-Bretagne. Graphic novels. Greager, Richard, Great Britain Great Britain. Greece Greece. Greek Americans Greek influences. Greek literature Greek music Greek poetry, Modern Greek poetry, Modern. Greeks gregorian Gregorian chants Gregorian chants. Group identity Group identity in the performing arts Group identity. Groupes rock Groupes vocaux Groupies Growth Growth. Grunge (Musique) Grunge music Grunge music. gtt Guadeloupe Guadeloupe. Guerre mondiale, 1939-1945 Guidebooks. Guides touristiques (Personnes) Guinbri Guinea. Guitar Guitar makers Guitar makers. Guitar music Guitar music (Blues) Guitar music (Rock) Guitar music. Guitar teachers Guitar. Guitare Guitare, Musique de. Guitaristes Guitarists Guitarists. Gullahs Gunnar, Eriksson, 1936- Guralnick, Peter Gymnasieskolan Gypsy musicians Hagström Hainichi mondai. Haiyū. Håkanson, Knut, 1887-1929 Hallucinations and illusions. Handbooks, manuals, etc. Hardcore (Music) Hardcore (Musique) Hardcore musicians Harmonica Harmonica music. Harmonica players Harmonica players. Harmonicistes Harmonie (musique) Harmonie. Harmony Harmony of the spheres. Harmony. Harp Harp music Harpistes Harpists Harpists. Harpsichord Harpsichord. Harpsichordists Hassaniyya dialect Hate groups. Hawaii. Hayes, Roland, 1887-1977. hälsoaspekter. HEALTH & FITNESS / Healthy Living HEALTH & FITNESS / Work-Related Health Health and hygiene. Health aspects Health aspects. Health facilities Hearing Hearing Aids Hearing aids. Hearing impaired. Hearing. Heavy Metal Heavy metal (Music) Heavy metal (Musique) Heian period, 794-1185 Heike monogatari. Heritage tourism Heroines in opera. Higashinihon daishinsai. higher education. Hindu goddesses Hindu goddesses. Hindu music Hindu music. Hinduism Hindustani music Hindustani music. hip-hop Hip-hop dance Hip-hop in art. Hip-hop. Hiphop (musik) Samhällskritik Feminism Antirasism Musiksociologi Musik – sociala aspekter Hispanic Americans Histoire Histoire et critique Histoire et critique. Histoire. Histoires, intrigues, etc. Historia historia. Historically informed performance (Music) Historiographie Historiography historiography Croatia Historiography. History History & Criticism. HISTORY / Africa / South / Republic of South Africa. HISTORY / African American HISTORY / Asia / General HISTORY / Australia & New Zealand. HISTORY / Europe / France. HISTORY / Europe / Great Britain / General. HISTORY / Europe / Spain & Portugal HISTORY / Europe / Western HISTORY / General. HISTORY / Jewish HISTORY / Latin America / South America. HISTORY / Modern / General HISTORY / Oceania. HISTORY / Social History HISTORY / Social History. HISTORY / United States / 19th Century. HISTORY / United States / 20th Century. HISTORY / United States / General HISTORY / United States / State & Local / South (AL, AR, FL, GA, KY, LA, MS, NC, SC, TN, VA, WV) History and criticism History and criticism. History and criticsm. History and critisicm. History in literature. History in opera. History in popular culture History in popular culture. History of music history of opera History. Högstadiet Holistic education. Holistic Health Holocaust survivors Holocaust, Jewish (1939-1945) Homages Homeland in music. Homes and haunts. Homes. homoit Homosexualité et musique. Homosexuality Homosexuality and music. Homosexuality and popular music Homosexuality and popular music. Homosexuality. Hongrie Hongrie. Honnête homme Horn (Musical instrument) Horror films Horror films. Horses Hospital care. Hospital patients Hospitalers Hospitalers. Hospitals Hospitals. House music House music. Hōgaku-Rekishi. Hōgaku. hrvatska poezija - 20/21. st. - antologije http://id.loc.gov/authorities/subjects/sh2008106048 http://id.loc.gov/authorities/subjects/sh85069833 http://id.worldcat.org/fast/871620 http://id.worldcat.org/fast/871649 http://id.worldcat.org/fast/982165 http://id.worldcat.org/fast/982175 http://id.worldcat.org/fast/982185 https://id.kb.se/term/sao/Kultur https://id.kb.se/term/sao/Kulturhistoria https://id.kb.se/term/sao/Musik https://id.kb.se/term/sao/Musikhistoria https://id.kb.se/term/sao/Nazism%20och%20musik https://id.kb.se/term/sao/Orgel https://id.kb.se/term/sao/Propaganda--historia https://id.kb.se/term/sao/Reggae https://scigraph.springernature.com/ontologies/product-market-codes/I13022 https://scigraph.springernature.com/ontologies/product-market-codes/I14002 https://scigraph.springernature.com/ontologies/product-market-codes/I18067 https://scigraph.springernature.com/ontologies/product-market-codes/I21000 https://scigraph.springernature.com/ontologies/product-market-codes/I22005 https://scigraph.springernature.com/ontologies/product-market-codes/I24032 Huang zhong (Musical instrument) hudba hudebniny hudební kritici hudební kritika hudební sbírky hudební skladatelé hudební skladatelky hudební vzdělávání hudební život hudebníci Hugo Badalić Human body Human body in music. Human body. Human evolution. Human geography. Human rights Human rights workers Human rights workers. Human rights. Human sacrifice in opera. Human-animal relationships Human-computer interaction. Humaniora och konst. Humanism Humanism in music Humanism in music. Humanism. Humanisme dans la musique. Humanists Humanities and the Arts. Humor in music. Humor. Hungarian hungarian composers Hungarian folk music Hungarian Folk songs Hungarian folksongs Hungarian music life hungarian musiciians hungarian musicology hungarian pop music Hungarian song Hungary Hungary. Hurdy-gurdy. Husband and wife. Hydroponics Hymnes Hymnes. Hymns Hymns, English Hymns, English. Hymns, Pitjantjatjara. Hymns, Welsh. Hymns. IAML Ian McGillis Iberian Peninsula Iceland Iconography Identification Identification (Religion) Identification. Identité sexuelle dans la musique. Identity (Psychology) in adolescence Identity (Psychology) in adolescence. Identity politics. Identity. Ideology Igor Illinois Illumination of books and manuscripts. Illustrators Imagery (Psychology) Imagination. Imitation (Littérature) Imitation in literature. Immigrants Immigrants. Impresarios Impression Impression. Imprésarios Improvisation (Music) Improvisation (Musique) Improvisation in art Ina Boyle Incas Incas. Inclusive education Inde Inde (Sud) Inde. Indexes. India India, South. India. Indian influences. Indian women activists Indian women singers Indians of North America Indie culture. Indie pop music Indigenous musicians Indigenous peoples Individual Composer & Musician. Individual composers & musicians, specific bands & groups. Indonesia Indonesia. Industrial music Industrial music. Industrie Industrie de la musique et du son. Industrie. Influence (Literary, artistic, etc.) Influence africaine. Influence américaine. Influence. Information literacy Information resources Informatique. Ingénieurs du son Inlärning Inscriptions. Installations sonores (Art) Institute of Registered Music Teachers of New Zealand Institute of Registered Music Teachers of New Zealand history Institutional care institutional history Instruction & Study Instruction and study Instruction and study. Instrumental music Instrumental music. instrumental works Instrumentation and orchestration Instrumentation and orchestration. Instrumentation et orchestration Instruments à clavier Instruments à cordes Instruments de musique Instruments de musique électroniques Intangible property Intelectual property Intellectual life Intellectual life. Intellectual property Intelligence artificielle. Intercultural communication Intercultural communication. Interfaith worship. Interior decoration Interior decoration. Intermediality. International relations. International trade. Internationalism Internationalism. Interpersonal conflict Interpersonal conflict. Interpretation Interpretation (Phrasing, dynamics, etc.) Interpretation and construction Interpretation and construction. Interracial adoption Intertextuality. Interviews Interviews. Inuit Invective in music. Iolo Morganwg iPad (Computer) iPhone (Smartphone) iPod (Digital music player) Iran Iraq Ireland Ireland. Irish Irish American soldiers Irish American soldiers. Irish American. Irish Americans Irlandais Irlandais. Irlande Irlande. Irony in music. Irving, Dorothy, 1927- Islam Islam Semiotik Hiphop Islam. Islamic arts Islamic countries Islamic countries. Islamic influences. Islamic music Islamic music. Islands. Isle of Man Isle of Man. Israel Israel. Israël. Italian language Italian Opera Italian poetry Italian poetry. Italie Italie. Italy Italy. Itálie Ivan Kukuljević Sakcinski Ivan pl. Zajc Ivan Zajc Jacinto Guerrero Jacinto Valledor Jack Jam bands Jam bands. Jamaica Jamaica. Jamaicans Jamaïque Jamaïque. James Goodman James Wilson Japan Japan. Japanese drama Japanese drama. Japanese influences. Japanese literature Japanese poetry Japon. Japonism Järnbruk-- historia Jay-Z. Jazz Jazz au cinéma. Jazz clubs Jazz dance. Jazz dans la littérature. Jazz festivals jazz history in Hungary Jazz history in Spain Jazz in Croatia Jazz in literature. Jazz in motion pictures. Jazz musicians Jazz Musicians - New Zealand jazz musicians - New Zealand - anecdotes; Clark Jazz musicians. Jazz New Zealand jazz record history Jazz singers Jazz singers. jazz theory Jazz vocals Jazz-- historia Jazz. Jazzklubbar Jazzmusiker Jazzmusiker Basister Tonsättare Jefferies, Graeme Jelena Zrinska=Ilona Zrínyi Jenny Jeux vidéo, Musique de Jew's harp Jewelry Jewelry theft Jewelry theft. Jewelry. Jewish composers Jewish composers. Jewish jazz musicians Jewish music Jewish musicians Jewish musicians. Jewish studies. Jewish theater Jews Jews in the performing arts Jews, German Jews, German. Jews. jlabsh/4 Joan Denise Moriarty Job stress. Joe Dolan John Barry John Beckett John Buckley John Egan Jojk Folkmusikuppteckningar Josep Mestres-Quadreny Journalism (Film & Media) Journalism. Journalists Jōruri Jōruri-Rekishi. Jōruri. Judaism Judaïsme. Judenverfolgung Jugaku. Jugoton Juifs Jukebox musicals Jukebox musicals. Jungian psychology. Jusqu'à 1500 Jusqu'à 1901 Jusqu'à 1931 Justice sociale Justice sociale. Juvenile Juvenile literature. K-pop Kabuki Kabuki music Kabuki music. Kabuki plays Kabuki plays. Kabuki-Rekishi. Kabuki. Kageki. Kagura Kagura. Kaitito waiata reo Korero taumata Kaiwaiata. Kamengeki. Kansas Karl Goldmark Kashu. Kayō. Keiongaku. Kentucky Kenya Kenya Nairobi Kenya. Kerry Kevin (trumpeter) - anecdotes - Keyboard instrument music Keyboard instrument music. Keyboard instruments Keyboard instruments. Keyboard music Keyboard players Keyboards (Music) Keybord music Kildare Kinematografija Kirchenmusik Kirtana (Hinduism) Klangfärg Improvisation (musik) Preparerat piano Klangkunst. Klapa singing Klarinettister Klassische Musik Klassische Musik. Klassisk musik Konserter (framträdanden) Pianister Scenframträdanden Nervsystemet Prestations{\aa}ngest Klassisk musik-- historia Klassisk musik-- mottagande Klezmer music Klezmer music. Knowableness. Knowledge, Theory of (Religion) Knowledge, Theory of. Kokusai bunka kōryū. Komponist Komponistin Komposition (musik) Komposition Musikframträdanden Kompositörer Konserter (framträdanden) Rock Könsmaktsordning Könsroller Konst Konst. Konstfilosofi Konstmusik Konstnärlig forskning Konstnärligt skapande Konzert Kördirigering Korea Korea (South) Korea. Korean Americans Korean language materials. Körer-- historia Körledning Körsång-- forskning Körsångng Körs{\aa}ng – sociala aspekter Körs{\aa}ng – psykologiska aspekter Kōrero taumata. Kŏmunʼgo music Kŏmunʼgo music. Kranjčević Vladimir Kropp och själ Kultur. Kulturell identitet Migration Musik – sociala aspekter Kulturförderung Kulturhistoria. kulturni kapital ; vrijednosti ; mladi ; kulturna potrošnja ; glazbeni ukus ; televizijske preferencije ; Jadranska Hrvatska (cultural capital ; values ; youth ; cultural consumption ; taste in music ; television preferences ; Adriatic Croatia) Kulturpolitik Kulturpolitik Offentliga sektorn Musikliv Kurt Weil Kuyō. Künste Kvarner Kvinnliga musiker Kvinnliga tonsättare Kvinnliga tonsättare Tonsättare Kvinnoförtryck Musik – historia – genusaspekter Kvinnor i musiken – historia Kvinnlighet – historia Kärlekss{\aa}nger – historia – genusaspekter Kwansei Gakuin Glee Club Kyōdo geinō. kyōdogeinō Kyōgen Kyōgen plays Kyōgen plays. Kyōgen-Rekishi. Kyōgen. Kyrkomusik Kyrkomusik – historia Kyrkomusiker. Kyrkos{\aa}ng Kyrkomusik Labor productivity Labour law Laienspiel Landscape architecture. Landscapes in music. Language Language acquisition. Language and languages Language and languages. LANGUAGE ARTS & DISCIPLINES LANGUAGE ARTS & DISCIPLINES / Alphabets & Writing Systems. LANGUAGE ARTS & DISCIPLINES / Composition & Creative Writing LANGUAGE ARTS & DISCIPLINES / Grammar & Punctuation. LANGUAGE ARTS & DISCIPLINES / Linguistics / General. LANGUAGE ARTS & DISCIPLINES / Linguistics / Syntax. LANGUAGE ARTS & DISCIPLINES / Publishing LANGUAGE ARTS & DISCIPLINES / Readers. LANGUAGE ARTS & DISCIPLINES / Spelling. Language. Large type books. Larsson Gothe, Mats, 1965- Last years of a person's life. Latin America Latin America. Latin drama (Comedy) Law LAW / Jurisprudence Law and legislation Law and legislation. Lawyers lcgft Leadership. Learning Learning disabled children Legacies Legal status, laws, etc. Leisure Lent Lenten music Leonard Cohen Lesbian musicians Lesbian musicians. Letters Letters. Lésions et blessures. LGBT LGBT Studies. LGBT. LGBTQ+ musicians. Liberalism Libraries and minorities Libraries and minorities. Libraries. Librarinaship Library Library fund raising Library fund raising. Library outreach programs libreto Librettists Libretto Libretto Librettologi Libretto. Librettos Librettos. Licenses lidové hudební nástroje Lied Lieu (Philosophie) Life cycle, Human Lifestyle, sport and leisure / Sports and outdoor recreation / Active outdoor pursuits / Walking, hiking, trekking likovi kao alegorija nacije Lindblad, Adolf Fredrik, 1801-1878 Lindh, Björn J:son, 1944-2013 Lisa; Pearl (musical group Listening Listening (Philosophy) Listening. Literacy LITERARY COLLECTIONS / Essays. Literary collections. LITERARY CRITICISM LITERARY CRITICISM / American / Asian American & Pacific Islander. LITERARY CRITICISM / American / General LITERARY CRITICISM / American / General. LITERARY CRITICISM / European / English, Irish, Scottish, Welsh LITERARY CRITICISM / European / English, Irish, Scottish, Welsh. LITERARY CRITICISM / Feminist. LITERARY CRITICISM / General. LITERARY CRITICISM / Modern / General. LITERARY CRITICISM / Poetry Literary sources Literary themes, motives. Literatur Literature Literature on music. Literature, Modern Literature, Modern. Littérature Liturgical drama; Religious festivities; Oral tradition liturgical songs Liturgics. Liturgie. Liturgies liturgy. Livres d'heures Livret (Musique) Ljudeffekter Ljudevit Gaj Ljudkonst Loggers Logging. Logiciels. Logistik Streamad media Programvara Musikbranschen – tekniska aspekter Loisir loneliness Longitudinal studies. Lorde Loss (Psychology) Louisiana Louisiane Love poetry, Scottish. Love songs Ludwig van Luis de Pablo Lullabies. Lumber trade. Lur (Iranian people) Lute Lutheran Church Lutheran Church. Luthiers Lyric writing (Popular music) Lyricists Lyricists. Lyrics. Maček Ivo Machine learning. Madrid Madrigal. Madrigaler. Madrigalkomödie. Madrigals Madrigals. Maintenance and repair Maintenance and repair. Makerspaces Maksimilijan Vrhovac Malawi Malawi. Malaysia Male actors. Male musicians Male singers Male singers. Malec Ivo Malerei Malta Malta. Män Man-woman relationships. Management. Mandolin Mandolinists Mandolinists. Manners and customs Manners and customs. Manuel de Falla manufacture of musical instruments. Manuscripts Manuscripts, German Manuscripts, German. Manuscripts, Latin (Medieval and modern) Manuscripts. Manuscrits latins médiévaux et modernes Maori (New Zealand people) Maori (New Zealand people), Maori in the performing arts Maori; Maori (New Zealand people) - music; wood instruments - New Zealand; Birds - New Zealand - songs and music Marcus, Greil Markedness (Linguistics) Marketing Marketing. Marque (Linguistique) Marriage. Marshall Islands Marshall Islands. Marshallais Marshallese Martin P. anecdotes Martin, Hans, 1934- Masculinité dans la musique. Masculinity Masculinity in music. Maskanda Maskanda. Mass Mass (Music) Mass media Mass media and music Mass media and music. Mass media; Broadcasting Massachusetts Masses Mastering (Sound recordings) Materialität. materiality. 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Found 650 results Author
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Campbell, Edward , and Peter O'Hagan
. The Cambridge Stravinsky Encyclopedia
. United Kingdom : Cambridge : Cambridge University Press, 2020.
Nakagawa, Stephanie , and Allen Clark
. Canadian Opera Anthology : Soprano, Volume 1
. Vol. 1. Canada: Kawartha Lakes, ON : Counterpoint Music Library Services, 2021.
https://cpmusiclibrary.ca/highlights/hl-2020-opera-anthology-soprano-v1/ (link is external)
.
Cleveland, Susannah , and Joe C Clark
. Careers In Music Librarianship Iii : Reality And Reinvention
. Vol. no. 33. United States: [United States] : Music Library Association ; Middleton, Wisconsin : A-R Editions, 2014.
Cleveland, Susannah , and Joe C Clark
. Careers In Music Librarianship Iii : Reality And Reinvention
. Vol. no. 33. United States: [United States] : Music Library Association ; Middleton, Wisconsin : A-R Editions, 2014.
Shaw, Misti , Susannah Cleveland , Lisa M Woznicki ,
Chuck Peters , Melissa E Wertheimer , Matthew Testa , Ruthann Boles McTyre , et al.
. Careers In Music Libraries Iv
. Vol. v. 39. [Middleton, Wisconsin, United States]: Music Library Association;A-R Editions, 2022.
Shaw, Misti , Susannah Cleveland , Lisa M Woznicki ,
Chuck Peters , Melissa E Wertheimer , Matthew Testa , Ruthann Boles McTyre , et al.
. Careers In Music Libraries Iv
. Vol. v. 39. [Middleton, Wisconsin, United States]: Music Library Association;A-R Editions, 2022.
Shaw, Misti , Susannah Cleveland , Lisa M Woznicki ,
Chuck Peters , Melissa E Wertheimer , Matthew Testa , Ruthann Boles McTyre , et al.
. Careers In Music Libraries Iv
. Vol. v. 39. [Middleton, Wisconsin, United States]: Music Library Association;A-R Editions, 2022.
Shaw, Misti , Susannah Cleveland , Lisa M Woznicki ,
Chuck Peters , Melissa E Wertheimer , Matthew Testa , Ruthann Boles McTyre , et al.
. Careers In Music Libraries Iv
. Vol. v. 39. [Middleton, Wisconsin, United States]: Music Library Association;A-R Editions, 2022.
Coghlan, Alexandra
. Carols From King's : The Stories Of Our Favourite Carols From King's College /
. United Kingdom : London : BBC Books, 2019.
Šedivá, Eliška , and Andy Letham
. Catalogus Collectionis Operum Artis Musicae Comitis Clam-Gallas
. Vol. X/1-4. 1. vydáníst ed. Czech Republic : Prague: Narodni Knihovna CR, 2018.
Delisle-Crevier, Patrick , and François Couture
.
Céline Dion
. Vol. 10. Canada: Montréal, Québec : Petit homme, 2016.
Chrisp, Pete
. The Chain : 50 Years Of Fleetwood Mac /
. United Kingdom : [Solihull, West Midlands] :Danann Publishing Ltd, 2017.
Chrisp, Pete
. The Chain : 50 Years Of Fleetwood Mac /
, 2017.
Anthony, Barry. , and Michael. Chaplin
. Chaplin's Music Hall : The Chaplins And Their Circle In The Limelight /
. United Kingdom ; United States : London ; New York : I.B. Tauris, 2012.
Anthony, Barry. , and Michael. Chaplin
. Chaplin's Music Hall : The Chaplins And Their Circle In The Limelight /
, 2012.
Southey, Roz , and Eric Cross
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. United Kingdom : Manchester : Manchester University Press, 2020.
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. Paris, France: Premières Loges,, 2021.
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. Christiaan Huygens : Écrits Sur La Musique Et Le Son /
. Paris, France: Hermann, 2021.
Studwell, William E , Charles P Conrad , and Bruce R Schueneman
. Circus Songs : An Annotated Anthology /
. United Kingdom : London : Routledge, 2020.
Culshaw, Peter
. Clandestino : In Search Of Manu Chao /
. United Kingdom: London : Profile, 2013.
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. The Clash Takes On The World : Transnational Perspectives On The Only Band That Matters /
. United States: New York : Bloomsbury Academic, 2017.
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Interview with Jerry Yanz, Director of Audiology, Hansaton Acoustics
Topic: Hansaton Rechargeable Hearing Aids 1382 AudiologyOnline Interview
Interview with Jerry Yanz, Director of Audiology, Hansaton Acoustics
Jerry Yanz, PhD, FAAA
Interviews
Hearing Aids - Adults
Interview with Jerry Yanz, Director of Audiology, Hansaton Acoustics
Topic: Hansaton Rechargeable Hearing Aids
Jerry Yanz
SMAKA:
Today I have Jerry Yanz from Hansaton talking with us about what's new with Hansaton. First off, Jerry, can you tell me about your background and your role at Hansaton?
Sure thing. I'm the Director of Audiology here at Hansaton USA. In a startup company like ours, any title requires a person to wear many hats, and this one is no exception. My primary role, however, in addition to interacting with engineers on R&D issues, is to develop education and training programs for staff and customers. In this position I draw from 16 years of experience in a variety of roles in the hearing aid industry.
After finishing my Ph.D. at University of Iowa and before joining the industry, I spent a number of years in academia and the audiology clinic. Fitting many patients with hearing aids piqued my interest in new technology and motivated my switch to the industry side of our field. I refer to these years in the industry as my third life in audiology, and, with all of the technology that's developed recently, it's been a rewarding role.
It's an exciting time for us at Hansaton with the release of our new AQ in-the-ear hearing system.
SMAKA:
Yes, I'm sure it is! I got to see the AQ system at AudiologyNOW! What was the feedback from the show?
YANZ:
Extremely positive. We came back from the show energized by the feedback from professionals who got to see the AQ system firsthand.
As you know, Carolyn, for many years, both professionals and consumers have known that a rechargeable hearing aid is a good idea. The unfortunate reality, though, is that over the years the available rechargeables have been plagued with problems and have not been as successful as we might wish. With our AQ hearing system, we've been able to solve those long-standing problems.
AQ is a smart, inductive recharging system. Let me describe what that means. An inductive coil inside the charging station sends a current to an inductive coil inside the hearing aid, which recharges the battery.
The battery is completely sealed inside AQ custom products, which offers several benefits. First, it removes the rather unattractive battery door from the faceplate of the hearing aid, giving AQ a smooth, natural appearance in the ear, improved even further by a custom sculpted contour. Eliminating the battery door reduces the potential for moisture to get into the inner workings of the instruments. Moisture ingress is one of the leading causes of instrument failure, and the battery compartment is a point of considerable moisture ingress. As a bonus, we'll never again see a broken battery door.
In addition to these benefits, AQ instruments provide improved ease of use. Many patients, especially those in our major age demographic, older people, have trouble handling tiny batteries. With AQ, this obstacle to successful hearing aid use is removed, along with the nuisance factor. There are a lot of people who are going to be very pleased with an instrument like this. You just put it in your ear in the morning and forget about it.
SMAKA:
Jerry, you explained that the AQ hearing system is charged via induction. Can you describe what the patient needs to do to charge his or her AQ hearing aids?
Hansaton's new AQ in-the-ear charging system
YANZ:
Yes, it's very simple. To charge AQ instruments, you simply drop them into a little cup in the charging station. The cups are custom-shaped based on the patient's ear shape, using the same impressions that the instruments themselves are made from.
Drop it in the cup, and a little red LED begins to glow through the faceplate of the hearing aid to show the patient that it is entering its charge cycle. Charging takes roughly two to four hours, depending on the amount of charge needed to bring the battery up to full charge. When that full charge is achieved, the red light goes out to tell the patient the hearing aids are ready to go again for another full day. And a full day means 20 to 30 hours of operation per charge. (I don't know many people who wear their hearing aids 30 hours at a time, but now they have that option.)
Smart circuitry enables communication between the hearing aid and the charger. It turns off the charger when the battery is 100% charged, so there's no possibility of over-charging. It also turns the hearing aid off when it drops into the charger so that you're not using up battery at the same time you're charging it. Each aid also comes with a travel case that automatically turns the aid off to prevent losing a battery charge when the aid is not is use.
To help maintain the relationship between patient and audiologist, the charger counts the number of times the hearing aid has been charged. After it's been charged 200 times, it brings up a little signal on the display in the middle of the charging station, which is a reminder to the patient it is time to go back and see the hearing professional for cleaning and service.
SMAKA:
That is so cool. Two to four hours to recharge and 20 to 30 hours of use? Can you get my iPhone to work that way?
[laughs]
YANZ:
[laughs]
Right! You bring up another one of the traditional problems with rechargeable hearing aids. There have been promises about the operating time of a rechargeable battery, and if you talk to people who've actually used them, the reality often doesn't meet the claims. They may claim 16 hours;you might get 8.
In our case, the engineers designing AQ have been adamant that the battery needed to get 20 to 30 hours of operating time per charge. That's obviously a critical variable,.
Another issue with earlier rechargeable hearing aids was the memory of the batteries. They would only maintain the operating time designed into them if, and only if, they were allowed to fully discharge and fully recharge each and every time. Shortening the discharge time or the charge time would compromise the operating time of the battery. The more times it happened, the more that memory would be compromised. So what started out as a 12-hour operating time may become 10 hours, 8 hours, 6 hours, and eventually becomes unusable.
That problem has been solved in the AQ design by virtue of the smart charging and the communication between the battery and the charging unit. That's something that is refreshingly different from the norm that most people associate with rechargeable systems.
Reliability of the charging station is also important. The AQ charging system has no moving parts, no contacts to corrode or wear out, no mechanical parts to give way.
It's interesting - I just visited with some folks at an audiology clinic yesterday. I asked them about rechargeables, and they described the other systems they'd used. Their technician, who does hearing aid troubleshooting, rolled her eyes when she heard the word "rechargeable". She said didn't want to even deal with rechargeable systems because they've been so problematic. We have a happy surprise for her in the AQ.
I also have a friend who uses a pair of rechargeable BTEs from another manufacturer. I called him up and asked, "How are they working for you?" He said, "Well, I don't bother with the charger, it's too much of a nuisance. I just change the batteries." These are the kinds of issues people have had historically with rechargeable systems, which were all considered during the design and development process with AQ. This innovation is not only an outstanding hearing instrument, but an outstanding rechargeable hearing system that will change people's notions of what a rechargeable hearing system can be.
SMAKA:
What about long-term battery life with AQ?
YANZ:
That's a great point, and a very important variable to consider. AQ has a five-year battery, and to stand behind that we're giving a six-year battery guarantee.
So if the battery dies any time in the first six years, we will replace it at no charge.
SMAKA:
Excellent. I have a question about the 200-charge reminder. Is that a courtesy reminder that a check-up is due?
YANZ:
Yes, that's right. The appearance of the 200-day reminder has no effect on the operation of the hearing instrument, the battery or the recharging unit. It is, as you said, a courtesy reminder. You can ignore it if you want to, or you can go in and have your audiologist or hearing professional clean and check your instruments. The professional will make sure everything's up to par, and then reset the counter in your charging unit. It'll come up again in 200 days.
SMAKA:
Just like in your car, when it's time to change your oil or you're due for a check-up.
YANZ:
Exactly. In fact, the reminder is an icon of a wrench.
SMAKA:
You mentioned that this is an in-the-ear system. What models are available?
YANZ:
Full Shell, Half-Shell and In-the-Canal (ITC) models are available.
Hansaton AQ ITC
SMAKA:
Actually, when you look just at audiograms, you can fit many patients that you see in a typical practice with a full shell model. Offering the canal is a nice cosmetic bonus. What kind of technology does AQ feature?
YANZ:
That's another area we focused on in this product development. There is absolutely no compromise on the feature set in this instrument. AQ has a full range of adaptive features, including a speech detection algorithm, noise reduction algorithm, multichannel directionality, active feedback block, active wind block, impulse noise management system, situation optimization - the full array of digital processing features that you expect in a premium instrument.
Along with that, we have full wireless capability in all three technology levels of the AQ. That means that we can have Bluetooth communication from our cell phone, television, stereo, and iPod.
In addition to external wireless input, by ordering the icom-2 wireless option, there is ongoing wireless communication between the two instruments. That means that if the instrument on one side decides, with some smart processing in the DSP, that a directional response is needed, both ears are going to adopt that directional pattern. Or if it identifies a speech and noise signal, it's going to optimize the adaptive features for speech and noise, and it's going to synchronize that adaptation between the two sides of the head.
Research has shown that binaural synchronization is a very desirable feature, both in terms of improved localization and in terms of patient preference.
SMAKA:
You've mentioned three different technology levels. Can you explain?
YANZ:
Sure. We're calling these First Class, Business Class and Comfort Class. The differences are partly in the number of processing channels and bands. In the First Class we have 16 channels and 16 bands for the ultimate in selectivity - that is, selectivity of frequency response adjustment at the time of fitting, and selectivity in the speech and noise algorithm operations.
Business Class has 12 channels and 12 bands;Comfort Class, 8 channels and 8 bands. Even at the Comfort Class level it's very sophisticated processing. Beyond those differences in channels and bands, there are some differences in the number of different levels that we can adopt when we set up the various adaptive features, so there will be greater resolution in the adaptive features in the first-class product.
SMAKA:
Sure, that makes sense. Jerry, how is the Bluetooth connectivity established?
YANZ:
I'm glad you asked that question. There are some common misunderstandings about Bluetooth and hearing aids. Bluetooth is a very important wireless communication protocol, but so far Bluetooth chips are too big and too power-hungry to go into a hearing aid. Maybe they will someday. Bluetooth keeps changing at a phenomenally fast pace because of the millions of people all over the world who are using it, and it is, by design, an inexpensive technology.
With AQ, we have Bluetooth connectivity to the Media remote, which then sends a near-field digital inductive signal up to both hearing aids. One neat thing about that is that the receiver inside the hearing aid is a small ferrite core coil that serves as an antenna to pick up this near-field digital inductive signal in both ears.
So if I'm listening to music, I would use the Bluetooth advanced audio distribution profile - that's a music profile that gives me full stereo in my hearing aids. There've been many times when I've been sitting here at my desk with my iPod attached to the Media Transmitter - it's a little matchbox-sized transmitter that transmits Bluetooth up to ten meters, to my Media remote. The Media remote in turn sends this nice, clean, broadband stereo signal to the two hearing aids. It's like having wireless earphones to listen to music.
SMAKA:
Getting back to Hansaton as a company, since it may be a relatively new name to some of our readers, it has been in business over 50 years, but is new to the U.S. market.
YANZ:
Yes. Hansaton USA is a startup company, and we have all of the energy and enthusiasm of a startup company. We're a very compatible group of people on board here and it's a fun place to be. But unlike most startup companies, we have the backing of a well-established company with tried and true technology, which distributes products in over 70 countries. It's a really nice combination of those two different identities.
When people ask me what's different about Hansaton, there are three key words that define what we're all about: communicate, collaborate, and celebrate. Communication is key, and we are dedicated to very straightforward communication with our customer base so everyone is on the same page. It's all about knowing and meeting expectations.
Clear communication and clear expectations lead to a meaningful collaboration. After all, a manufacturer and audiologist are working toward the same goal - a successful patient outcome.
When our collaboration leads to a successful outcome - a win-win-win outcome for patient, practitioner and manufacturer - then it's time to celebrate together.
SMAKA:
When will AQ be available?
YANZ:
You can order AQ now. It's already available.
SMAKA:
Perfect. Thanks again, Jerry, for talking with me today. We wish you much success with the AQ hearing system. Please say hello to Bob for me.
YANZ:
You're very welcome, and I will do that. Thanks for having me today.
Jerry Yanz, PhD , FAAA Senior Trainer in the Education and Training Department at Starkey LabsJerry L. Yanz, Ph.D., is a Senior Trainer in the Education and Training Department at Starkey Labs. After earning a Bachelor’s degree from Stanford University, he went on to earn Master’s and Doctoral degrees in speech and hearing sciences from the University of Iowa. Before entering the hearing aid industry in 1994, he served on the audiology faculty at the University of Minnesota and was Director of Audiology at the St. Paul Hearing Clinic in St. Paul, Minnesota. In his current role at Starkey, he brings those previous experiences to bear on the tasks of delivering meaningful educational programs to hearing professionals, writing articles for professional journals and participating in hearing aid research and development. Dr. Yanz is a Fellow of the American Academy of Audiology and holds memberships in the American Speech-Language-Hearing Association, Minnesota Speech-Language-Hearing Association and the American Auditory Society.
| https://www.audiologyonline.com/interviews/interview-with-jerry-yanz-director-1382 |
Flora (5): Trees
(a) Bodhi: (II. 4. 20; p. 84)– [Holy Fig tree:] Though Pipal’s popular synonyms are Pippala and Aśvattha, the particular mention of Bodhi lends a clue...
Flora (5): Trees
(a) Bodhi: (II. 4. 20; p. 84)–
[Holy Figtree:]
ThoughPipal’s popular synonyms are Pippalaand Aśvattha, the particular mention of Bodhilends a clue to the religion and the time ofAmaraas later toBuddhism.
For only after the advent of Buddhism, the tree got the status of Bodhimeaning ‘that which enlightens’.
Recording this feature of the tree,Kṣīrasvāminsays that it is endowed with energy to enlighten or impartknowledgeand thus beneficial in all aspects–
bodhidrumo bodhisatvākhyaḥ sarvopakāritvāt |
Caladala:
Kṣīrasvāmin explains the stalk of theleafis thin and the leaf being thick is wafted gently by breeze. Theleavesin contact with each other makes a clappingnoiseand earns the name caladala–
tanu vṛntatvād guruparṇatvāt svalpe'pi vāte caladalaḥ |
Apaplava:
Kṣīrasvāmin observes that etymologists call Bodhias Apaplava–
āpaplava iti nairuktāḥ |
Apaplavameans 'that which leaps'. Aśvatthapropagates by taking anything as its substratum and starts growing there. Probably the etymologists refer to this characteristic feature of Bodhi. The leaves of Aśvatthaare thick innaturewith its conspicuous form of pointed tip. According to Kṣīrasvāmin the Holy Fig tree in Deśīis called Patrāṇi.
It is common knowledge that Viṣnuresides in Aśvatthatree and hence considered very auspicious indicated by terms Keśavāvāsaand maṅgalya.
(b) Udumbara(II. 4. 22; p. 85)–
[Fig tree:]
The wasp that enters theflowersforhoneyget trapped inside and remain inside the fruits and dies. Hence the fig tree is known as jantuphalaor kṛmiphala. The unripe fruits when crushed exude milk thus named hemadugdhaka. Their twigs are used in sacrifices earning the name yajñāṅgato the tree.
(c) Plakṣa(II. 4. 32; p. 88)–
[Wavy leaved fig tree:]
It is interesting to note that one variety of Plakṣais termed jaṭī. Perhaps this indicates that the thick stems of the tree that loop round and grows.
(d) Vaṭa(II. 4. 32; p. 88)–
[The Banyan:]
Nyagrodha, Bahupādaand vaṭaare synonyms mentioned in AmarakośaKṣīrasvāmin adds from Dhanvantari Nighaṇṭu(5. 76) the terms likeraktaphala, vanaspatiand vaiśravaṇāvāṣa. Though Banyan tree puts forth flowers it is hardly seen and hence termed vanaspati. Only the dark red coloured fruits are conspicuous and hence the synonym raktaphalais used here.
(e) Āragvadha(II. 9. 23-4; p. 85):
It is also termed rājavṛkṣa–a majestic tree. According to Kṣīrasvāmin the synonym caturaṅgulais denotive of the long leguminous pod perhaps measuring upto fouraṅgulas–
caturaṅgulaparvā |
According to Kṣīrasvāmin the asterism Revatīis the Goddess ofdiseasesand hence the synonym ārevatathatwhich cures ferver–
revatī rogadevatā ārevatyam bhavaārevataḥ|
ārevate jvaro'nena vā | rebṛ plavagatau |
(f) Lodhra(II. 4. 33; p. 88):
Amarakośa [1]mentions six words for lodhra. Kṣīrasvāmin opines that Lodhracomprises of red and white varieties. The white variety of lodhraare known as gālavaand śābarawhile the red is called tiriṭa, tilvaand mārjana–
ādyau śvetalodhre tiriṭādyā raktalodhre |
(g) Guggulu(II. 4. 34; p. 88-9)–
[Indianbdellium:]
Kṣīrasvāmin opines that the wordgugguludenotes its property of alleviating the vāta roga– guḍati rakṣati vātārogādgugguluḥ|
InAyurvedaguggulu extracts are used mainly in the treatment of rheumatism.
Indian bdellium gum is an irregular roundish glistening mass and is an opaque reddish brown when dry and is aromatic. This reddish brown colour of the gum is probably referred to as kālaniryāsain Dhanvantari Nighanṭu(3. 127).
(h) Airāvatī(II. 4. 38; p. 90)–
[Orange:]
Kṣīrasvāmin describes that the colour of orangefallinginto the blended hue of red and yellow, akin to the colour of the lightning called irāvatī–
irāvatyavidyutāivāyaṃ raktatvādairāvataḥ |
(i) Kūṭaśālmalī(II. 4. 47; p. 92)–
[Blacksilkcottontree:]
Explaining the term ' kūṭaśālmalī', Kṣīrasvāmin points out that it is the black silk cotton tree that was used in warfare. He adds that it was thrown from forts on the enemy’s army for scattering them [2]—
kūṭena kutsitatvaṃ dyotyate durgāderhi parasainyadalanārthaṃ sā kṣipyate ||
However there is no mention of which part of the black silk cotton tree was used for this purpose.
(j) Khadira–(II. 4. 50; p. 93)–
[Acacia Catechu:]
Amarakośagives gāyatrīand bālatanayaas other synonyms for khadira.
Kṣīrasvāmin rightly observes that Amarasiṃha’s reading of the term bālapatraas bālaputra, is defenitely an error since the reading in Dhanvantri(I. 123) and dvyarthareveal it as bālapatra–
bālapatroyavāsakhadiraśceti( ā dra2/64) ?[™]rtheṣu |
dhanvantaripāṭhamadṛṣṭvā bālaputrabhrāntyā granthakṛdbālatanayamāha |
āha ca khadiro raktasāraśca gāyatrīdantadhāvanaḥ|
kaṇṭakībālapatraśca jihmaśalyaḥ kṣitikṣamaḥ ||
(k) Āmalakī Tiṣyaphalā(II. 4. 58; p. 95)–
[Emblica officinalis, Indian gooseberry:]
Kṣīrasvāmin explains that Lakshmī resides ināmalakīpermanently and hence the fruit is synonymous with auspiciousness ( tiṣya)–
tiṣyam maṅgalyam phalamasyāstiṣyaphalā nityamāmalake lakṣmīriti ||
(l) Karkandhūḥor Badarī(II. 4. 37; p. 89) [3]
Jujube: Amarakośagives nine synonyms for jujube, but does not differentiate the name of the tree from fruit. Kṣīrasvāmin specifies that the first three names denote the tree while the rest denote the fruit, whereas the word ghoṇṭāspecifies both.
A deviation from the rule of fruits being neuter gender is witnessed here in ghoṇṭābeing feminine–
ātra ādyastrayo vṛkṣārthāḥ ānye phalārthāḥ ghoṇṭā tūbhayaspṛk |
Substantiating his view Kṣīrasvāmin quotes the text ofIndu–
yathenduḥ–
badarīsnigdhapatrā ca rāṣṭravṛddhikarī tathā |
phalaṃtasyāḥ smṛtaṃ kolaṃ kokilaṃphenilaṃkuham ||
lolaṃsūkṣmaphalaṃ tattu jñeyaṃkarkandhukandukam |
svāduḥkaṭuḥsiñcatikā tacca kolaṃ phalaṃmatam||
Here Kṣīrasvāmin observes that Dhanvantari(5/96) does not specify the tree or fruit but gives the synonyms in general–
dhanvantariḥsāmānyenāha–
badaraṃkokilaṃ kolaṃsauvaraṃphenilaṃkulam|
karkandhuḥkandukaṃsvāduḥ kaṭuḥ siñcatikāguḍā||
He also remarks that the fruit of koliwas generally known as kolikamand the physicians denote it as kokilam(because of the linguistic aspect of metathesis) –
koliphalatvātkolikamiti ca sabhyaḥpāṭhaḥkokilamiti tuvaidyāḥ|
(m) Vīravṛkṣa(II. 4. 43; p. 91)–
[Marking nut:]
Explaining the word Kṣīrasvāmin mentions that this tree is called so as it is painful to even touch the tree–
viśeṣeṇerayati vīrāṇāṃ vā vṛkṣo duḥsparśatvāt |
Rough handling might cause some exudation from the tree.
(n) Iṅgudī(II. 4. 46; p. 92):
This tree is also known as tāpasataru. Since the oil from this tree is used by ascetics in theforest, Kṣīrasvāmin suggests that the tree is called tāpasataru–
tāpasāhyaraṇyesyāḥ snehamupabhuñjata | [4]
(o) Govandanī(II. 4. 56; p. 93):
Govandanīis given as a synonym to priyaṅgu. Kṣīrasvāmin observes that the text of Indu (3/28) reads the word as gaurvandanī.
The word gundrā( priyaṅgu) is given in tryartha kośaas erakā, priyaṅguand śarā–
tryarthe gundrā erakāpriyaṅguḥśarā ca |
Similarly according to dvyarthakoṣa(3/35) priyakadenotes all the three viz.,asana, priyaṅguand kadamba–
priyako'sanaḥpriyaṅguḥ kadambaśceti |
In dyarthakoṣa(2/71) gandhaphalinīmeans priyaṅguand campakakalikā.
(p) Panasa(II. 4. 61; p. 96)–
[Jackfruit:]
Kṣīrasvāmin remarks thatDurgareads it as Paṇasaand it is generally called Kaṇṭhakayukta phala, the thorny fruit. It is also called Mahāsarga–
paṅāsa itidurgaḥ|
lokoktyā kaṇṭakayuktaphalaḥ | mahāsargo'pi |
(q) Picumanda(II. 4. 63; p. 96)–
[NeemorMargosa:]
It is a synonym ofnimba. Kṣīrasvāmin observes that the word should be picumarda(literally meaning that which alleviates leaprosy) and the followers of Śuśrutacall it pavaneṣṭaas it is held as sacred and worshipped–
pavaneṣṭo'pi sauśrutāḥ | śāśvatastu hiṅguniryāsaśabdo'yaṃ nimbe hiṅgurase'pi ca |candranandanastu śukamālakamāha |
Footnotes and references:
[1]:
gālavaḥśābarolodhrastiriṭas tilva mārjanau |
[2]:
Dr.Savitrisaxenain the Geographical Survey of the Purāṇas(p. 580) metions that Kūṭaśālmalīis aspeciesof silk-cotton tree. She describes that the tree has short thorns and is regarded as one of the severalweaponsused in a battle. Probably because of it's thorny feature of the tree it was used in warfare to scatter the enemy army.
[3]:
karkandhūr badarīkoliḥkolaṃkuvalaphenile |sauvīraṃbadaraṃ ghoṇṭā
[4]:
Cf. Abhijñānaśākuntalam(II. 10):... tapasvina iṃgudītailacikkaṇaśīrṣasya... |
| https://www.wisdomlib.org/hinduism/essay/amarakoshodghatana-of-kshirasvamin-study/d/doc1151644.html |
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Glutamate and Amyloid β-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms | Journal of Neuroscience
Development/Plasticity/Repair
Glutamate and Amyloid β-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms
Journal of Neuroscience 1 October 2003, 23 (26) 8967-8977; DOI: https://doi.org/10.1523/JNEUROSCI.23-26-08967.2003
Hiromi Hiruma
Departments of 1 Physiology and 2 Biochemistry, Kitasato University School of Medicine, Sagamihara 228-8555, Japan
Takashi Katakura
Departments of 1 Physiology and 2 Biochemistry, Kitasato University School of Medicine, Sagamihara 228-8555, Japan
Sanae Takahashi
Departments of 1 Physiology and 2 Biochemistry, Kitasato University School of Medicine, Sagamihara 228-8555, Japan
Takafumi Ichikawa
Departments of 1 Physiology and 2 Biochemistry, Kitasato University School of Medicine, Sagamihara 228-8555, Japan
Tadashi Kawakami
Article
Figures & Data
Article Figures & Data
Figures
Tables
Figure 1.
Effects of glutamate and its agonists on the number of particles transported in neurites of cultured rat hippocampal neurons. A, C, E, Percentage changes in the number of transported particles of control (the value before application) induced by 26 min application of 100 μ mglutamate ( A), 100 μ mNMDA ( C), and 100 μ mAMPA ( E). Note that the number of transported particles was rapidly reduced by these drugs and restored by removal of the drugs. B, D, F, Concentration dependence of reduction in the number of transported particles induced by glutamate ( B), NMDA ( D), and AMPA ( F). The value obtained at 20 min after each application of the drugs is expressed as a percentage of control (the value before application). Data in all panels are expressed as mean ± SD of five neurons. Error bars represent SD. * p< 0.05; ** p< 0.005; *** p< 0.0005 compared with control (100%).
Figure 3.
Figure 2.
Effects of Aβ 25-35and jasplakinolide, an actin-polymerizing agent, on the number of particles transported in neurites of cultured rat hippocampal neurons. A, C, Percentage changes in the number of transported particles of control (the value before application) induced by 26 min application of 20 μ mAβ 25-35( A) and 0.5 μ mjasplakinolide ( C). Note that the number of transported particles was rapidly and progressively reduced by both drugs and not restored after removal of the drugs. B, Concentration dependence of reduction in the number of transported particles induced by Aβ 25-35. The value obtained at 20 min after each application of various concentrations of Aβ 25-35is expressed as a percentage of control (the value before application). Data in all panels are expressed as mean ± SD of five neurons. Error bars represent SD. * p< 0.05; ** p< 0.005; *** p< 0.0005 compared with control (100%).
Figure 4.
Effects of glutamate and Aβ 25-35under various conditions. Data represent percentage changes in the number of transported particles of control (the value before application). Glutamate (100 μ m) ( A, C, E) and Aβ 25-35(20 μ m) ( B, D, F) were applied after treatment with a combination of 20 μ mMK-801, an NMDA receptor antagonist, and 100 μ mCNQX, an AMPA receptor antagonist ( A, B), in Ca 2+-free solution ( C, D), and after treatment with 5 μ mlatrunculin B, an actin depolymerizer ( E, F). Each data point indicates the mean ± SD of the values obtained from five neurons. Error bars represent SD. * p< 0.05; ** p< 0.005; *** p< 0.0005 compared with control (100%).
Figure 5.
Rhodamine-phalloidin staining of actin filaments in cultured hippocampal neurons. Neurons were stained with rhodamine-phalloidin after treatment of drugs dissolved in HEPES-buffered solution. A, Control (treatment with HEPES-buffered solution alone for 30 min). B, Treatment with 100 μ mglutamate for 30 min. C, Treatment with 20 μ mAβ 25-35for 30 min. D, Treatment with 20 μ mAβ 25-35for 30 min followed by washout for 30 min. E, Treatment with 5 μ mlatrunculin B for 30 min. F, Simultaneous treatment with 20 μ mAβ 25-35and 5 μ mlatrunculin B for 30 min. Scale bar, 20 μm.
Photographs representing properties of various Aβ fragments. A, B, Precipitates detected under light microscopy in Aβ 25-35solution ( A) and in incubated Aβ 1-40solution ( B). Aβ 25-35produced cotton-like precipitates ( A), and incubated Aβ 1-40formed fiber-like or amorphous precipitates ( B). Scale bar, 10 μm. C-E,SDS-PAGE profiles of various Aβ fragments. F, G, Rhodamine-phalloidin staining of intracellular actin filaments in hippocampal neurons treated with Aβ 31-35( F) and with incubated Aβ 1-42( G). Aβ 31-35(20 μ m) and incubated Aβ 1-42(20 μ m) formed intracellular actin aggregates. Scale bar, 20 μm.
Tables
Figures
Table 1.
Properties and effects of various Aβ fragments
Aβ fragment Precipitates detected under light microscopy Structural properties analyzed by SDS-PAGE Intracellular actin aggregation Effects on axonal transport Aβ 15-20 amide − Low molecular weight forms (<1 kDa) − No effect Aβ 31-35 − Low molecular weight forms (<1 kDa) + Inhibitory Aβ 25-35 + Low molecular weight forms (~1 kDa) + Inhibitory Aggregates Fresh Aβ 1-40 − Monomers − No effect Incubated Aβ 1-40 + Monomers − No effect Aggregates Fresh Aβ 1-42 − Monomers − No effect Pentamers Hexamers Incubated Aβ 1-42 − Monomers + Inhibitory Pentamers Hexamers High molecular weight forms (30-100 kDa)
Aβ fragments dissolved in HEPES-buffered salt solution, pH 7.4, at a concentration of 20 μM were used for light microscopic analysis, intracellular actin observation with rhodamine-phalloidin, and axonal transport study under video-enhanced microscopy. Ten micrograms of each Aβ fragment dissolved in an aqueous solution were subjected to SDS-PAGE. +, Detected; −, not detected.
Hiromi Hiruma , Takashi Katakura , Sanae Takahashi , Takafumi Ichikawa , Tadashi Kawakami
Journal of Neuroscience 1 October 2003, 23 (26) 8967-8977; DOI: 10.1523/JNEUROSCI.23-26-08967.2003
Keywords
glutamate
amyloid β-protein
actin
Ca 2+
cultured hippocampal neurons
| https://www.jneurosci.org/content/23/26/8967/tab-figures-data |
ALFREDO T. ROMUALDEZ v. SANDIGANBAYAN
GR No. 152259, (2004-07-29)
EN BANC
[ GR No. 152259, Jul 29, 2004 ]
ALFREDO T. ROMUALDEZ v. SANDIGANBAYAN +
DECISION
479 Phil. 265
EN BANC
[ G.R. No. 152259, July 29, 2004 ]
ALFREDO T. ROMUALDEZ, PETITIONER, VS. THE HONORABLE SANDIGANBAYAN (FIFTH DIVISION) AND THE PEOPLE OF THE PHILIPPINES, RESPONDENTS.D E C I S I O N
PANGANIBAN, J.:
Repetitive motions to invalidate or summarily terminate a criminal indictment prior to plea and trial, however they may be named or identified -- whether as a motion to quash or motion to dismiss or by any other nomenclature -- delay the administration of
justice and unduly burden the court system. Grounds not included in the first of such repetitive motions are generally deemed waived and can no longer be used as bases of similar motions subsequently filed.
Section 5 of the Anti-Graft Law is constitutional. It penalizes certain presidential relatives who "intervene, directly or indirectly, in any business, transaction, contract or application with the Government." This provision is not vague or "impermissibly broad,"
because it can easily be understood with the use of simple statutory construction. Neither may the constitutionality of a criminal statute such as this be challenged on the basis of the "overbreadth" and the "void-for-vagueness" doctrines, which apply only to free-speech
cases.
The Case
Before us is a Petition for
Certiorari
[1]
under Rule 65 of the Rules of Court, seeking to set aside the November 20, 2001
[2]
and the March 1, 2002
[3]
Resolutions of the Sandiganbayan in Criminal Case
No. 13736. The first Resolution disposed thus:
"WHEREFORE, for lack of merit, the Motion to Dismiss is hereby DENIED. The arraignment of the accused and the pre-trial of the case shall proceed as scheduled."
[4]
The second Resolution denied reconsideration.
The Facts
The facts of the case are narrated by the Sandiganbayan as follows:
"[The People of the Philippines], through the Presidential Commission on Good Government (PCGG), filed on July 12, 1989 an information before [the anti-graft court] charging the accused [with] violation of Section 5, Republic Act No. 3019,
[5]
as
amended. The Information reads:
'That on or about and during the period from July 16, 1975 to July 29, 1975, in Metro Manila, Philippines, and within the jurisdiction of [the Sandiganbayan], said [petitioner], brother-in-law of Ferdinand E. Marcos, former President of the
Philippines, and therefore, related to the latter by affinity within the third civil degree, did then and there wil[l]fully and unlawfully, and with evident bad faith, for the purpose of promoting his self-interested [sic] and/or that of others, intervene directly or indirectly,
in a contract between the National Shipyard and Steel Corporation (NASSCO), a government-owned and controlled corporation and the Bataan Shipyard and Engineering Company (BASECO), a private corporation, the majority stocks of which is owned by former President Ferdinand E.
Marcos, whereby the NASSCO sold, transferred and conveyed to the BASECO its ownership and all its titles and interests over all equipment and facilities including structures, buildings, shops, quarters, houses, plants and expendable and semi-expendable assets, located at the
Engineer Island known as the Engineer Island Shops including some of its equipment and machineries from Jose Panganiban, Camarines Norte needed by BASECO in its shipbuilding and ship repair program for the amount of
P
5,000,000.00.
'Contrary to law.'
"On December 27, 1996, the accused filed his first 'MOTION TO DISMISS AND TO DEFER ARRAIGNMENT' claiming that no valid preliminary investigation was conducted in the instant case. He asserts that if a preliminary investigation could be said to have been conducted, the same
was null and void having been undertaken by a biased and partial investigative body.
"On January 9, 1997, [the Sandiganbayan], through the First Division, issued an order giving the accused fifteen days to file a Motion for Reinvestigation with the Office of the Special Prosecutor.
"[Petitioner] questioned said order before the Supreme Court via a petition for Certiorari and Prohibition with prayer for temporary restraining order. On January 21, 1998, the Supreme Court dismissed the petition for failure to show that [the Sandiganbayan] committed
grave abuse of discretion in issuing the assailed order.
"On November 9, 1998, the [petitioner] filed with the Office of the Special Prosecutor a Motion to Quash.
"On September 22, 1999, x x x Special Prosecution Officer (SPO) III Victorio U. Tabanguil, manifested that the prosecution had already concluded the reinvestigation of the case. He recommended the dismissal of the instant case. Both the Deputy
Special Prosecutor and the Special Prosecutor approved the recommendation. However, Ombudsman Aniano A. Desierto disagreed and directed the prosecutors to let the [petitioner] present his evidence in Court.
"Subsequently, [petitioner] filed on October 8, 1999 his second 'MOTION TO QUASH AND TO DEFER ARRAIGNMENT'.
"On February 9, 2000, the [Sandiganbayan] denied the motion for lack of merit.
"On June 19, 2001, [the] accused filed a 'MOTION FOR LEAVE TO FILE MOTION TO DISMISS'. On June 29, 2001, the [Sandiganbayan] admitted the motion and admitted the attached (third) Motion to Dismiss.
"The [Motion to Dismiss] raise[d] the following grounds:
'I. THE CONSTITUTIONAL RIGHT TO DUE PROCESS OF
LAW OF [PETITIONER] WAS VIOLATED DURING THE PRELIMINARY INVESTIGATION STAGE IN THE FOLLOWING WAYS:
'A. NO VALID PRELIMINARY INVESTIGATION
WAS CONDUCTED IN THE INSTANT CASE; AND
'B. THE PRELIMINARY INVESTIGATION WAS
CONDUCTED BY A BIASED AND PARTIAL INVESTIGATOR
'II. THE CONSTITUTIONAL RIGHT OF [PETITIONER] TO BE
INFORMED OF THE NATURE AND CAUSE OF THE ACCUSATION AGAINST HIM WAS VIOLATED
'III. PURSUANT TO ARTICLE VII, SECTION 17 OF THE 1973
CONSTITUTION, [PETITIONER] IS IMMUNE FROM CRIMINAL PROSECUTION
'IV. THE CRIMINAL ACTION OR LIABILITY HAS BEEN
EXTINGUISHED BY PRESCRIPTION'" [6]
Ruling of the Sandiganbayan
The Sandiganbayan explained that all the grounds invoked by petitioner, except the third one, had already been raised by him and passed upon in its previous Resolutions.
[7]
In resolving the third ground, the anti-graft court pointed out that Section 17 of
the 1973 Constitution became effective only in 1981 when the basic law was amended. Since his alleged illegal intervention had been committed on or about 1975, the amended provision was inapplicable to him.
[8]
In denying the Motion for Reconsideration filed by petitioner, the Sandiganbayan passed upon the other grounds he had raised. It ruled that his right to a preliminary investigation was not violated, because he had been granted a reinvestigation.
[9]
It
further held that his right to be informed of the nature and cause of the accusation was not trampled upon, either, inasmuch as the Information had set forth the essential elements of the offense charged.
[10]
Hence, this Petition.
[11]
The Issues
In his Memorandum, petitioner assigns the following errors for our consideration:
"Whether or not the Honorable Sandiganbayan erred and gravely abused its discretion amounting to lack of, or in excess of jurisdiction
In not dismissing and/or quashing Criminal Case No. 13736 despite clear and incontrovertible evidence that:
Section 5 of Republic Act No. 3019 is unconstitutional because its vagueness violates the due process right of an individual to be informed of the nature and the cause of the accusation against him;
Section 5 of Republic Act No. 3019 is unconstitutional because it violates the due process right of an individual to be presumed innocent until the contrary is proved;
The constitutional right of petitioner x x x to be informed of the nature and the cause of the accusation against him was violated;
The constitutional right to due process of law of petitioner x x x was violated during the preliminary investigation stage in the following ways:
No valid preliminary investigation was con-ducted for Criminal Case No. 13736; and
The preliminary investigation was conducted by a biased and partial investigator.
The criminal action or liability has been extinguished by prescription; and
Pursuant to Article VII, Section 17 of the 1973 Constitution, petitioner x x x is immune from criminal prosecution.
And
In light of the foregoing, in denying petitioner['s] x x x right to equal protection of the laws." [12]
Simply stated, the issues are as follows: (1) whether Section 5 of Republic Act 3019 is unconstitutional; (2) whether the Information is vague; (3) whether there was a valid preliminary investigation; (4) whether the criminal action or liability has been extinguished by
prescription; and (5) whether petitioner is immune from criminal prosecution under then Section 17 of Article VII of the 1973 Constitution.
The Court's Ruling
The Petition has no merit.
First Issue:
Constitutionality of Section 5,
Republic Act 3019
Petitioner challenged the constitutionality of Section 5 of RA 3019 for the first time in the Sandiganbayan through a Supplemental Motion to Dismiss. Attached to his December 7, 2001 Motion for Reconsideration of the Order denying his Motion to Dismiss was this
Supplemental Motion which was, in effect, his third motion to quash.
[13]
We note that the Petition for Certiorari before us challenges the denial of his original, not his Supplemental, Motion to Dismiss.
Upon the denial of his original Motion to Quash on February 9, 2000, petitioner could have filed a motion for reconsideration of the denial. Had reconsideration been turned down, the next proper remedy would have been either (1) a petition for certiorari
[14]
-- if there was grave abuse of discretion -- which should be filed within 60 days from notice of the assailed order;
[15]
or (2) to proceed to trial without prejudice to his right, if final judgment is rendered against him, to raise the same
questions before the proper appellate court.
[16]
But instead of availing himself of these remedies, he filed a "Motion to Dismiss" on June 19, 2001.
Impropriety of
Repetitive Motions
There is no substantial distinction between a "motion to quash" and a "motion to dismiss." Both pray for an identical relief, which is the dismissal of the case. Such motions are employed to raise preliminary objections, so as to avoid the necessity of proceeding to
trial. A motion to quash is generally used in criminal proceedings to annul a defective indictment. A motion to dismiss, the nomenclature ordinarily used in civil proceedings, is aimed at summarily defeating a complaint. Thus, our Rules of Court use the term
"motion to quash" in criminal,
[17]
and "motion to dismiss" in civil, proceedings.
[18]
In the present case, however, both the "Motion to Quash" and the "Motion to Dismiss" are anchored on basically the same grounds and pray for the same relief. The hairsplitting distinction posited by petitioner does not really make a difference.
By filing a Motion to Dismiss, petitioner submitted in effect a prohibited second motion to quash. A party is not permitted to raise issues, whether similar or different, by installment. The Rules abhor repetitive motions. Otherwise, there would be no end to
preliminary objections, and trial would never commence. A second motion to quash delays the administration of justice and unduly burdens the courts. Moreover, Rule 117 provides that grounds not raised in the first motion to quash are generally deemed
waived.
[19]
Petitioner's "Motion to Dismiss" violates this rule.
Constitutionality of
the Challenged Provision
If only for the foregoing procedural lapses, the Petition deserves to be dismissed outright. However, given the importance of this case in curtailing graft and corruption, the Court will nevertheless address the other issues on their merit. Petitioner challenges the
validity of Section 5 of Republic Act 3019, a penal statute, on the ground that the act constituting the offense is allegedly vague and "impermissibly broad."
It is best to stress at the outset that the overbreadth
[20]
and the vagueness
[21]
doctrines have special application only to free-speech cases. They are not appropriate for testing the validity of penal statutes. Mr.
Justice Vicente V. Mendoza explained the reason as follows:
"A facial challenge is allowed to be made to a vague statute and to one which is overbroad because of possible 'chilling effect' upon protected speech. The theory is that '[w]hen statutes regulate or proscribe speech and no readily apparent construction
suggests itself as a vehicle for rehabilitating the statutes in a single prosecution, the transcendent value to all society of constitutionally protected expression is deemed to justify allowing attacks on overly broad statutes with no requirement that the person making the
attack demonstrate that his own conduct could not be regulated by a statute drawn with narrow specificity.' The possible harm to society in permitting some unprotected speech to go unpunished is outweighed by the possibility that the protected speech of others may be deterred
and perceived grievances left to fester because of possible inhibitory effects of overly broad statutes.
This rationale does not apply to penal statutes. Criminal statutes have general in terroremeffect resulting from their very existence, and, if facial challenge is allowed for this reason alone, the State may well be prevented from enacting laws against
socially harmful conduct. In the area of criminal law, the law cannot take chances as in the area of free speech.
x x x x x
x x x x
In sum, the doctrines of strict scrutiny, overbreadth, and vagueness are analytical tools developed for testing "on their faces" statutes in free speech cases or, as they are called in American law, First Amendment cases. They cannot be made to do service when what is
involved is a criminal statute. With respect to such statute, the established rule is that 'one to whom application of a statute is constitutional will not be heard to attack the statute on the ground that impliedly it might also be taken as applying to other persons or
other situations in which its application might be unconstitutional.' As has been pointed out, 'vagueness challenges in the First Amendment context, like overbreadth challenges typically produce facial invalidation, while statutes found vague as a matter of due process
typically are invalidated [only] 'as applied' to a particular defendant.'"
[22]
(underscoring supplied)
"To this date, the Court has not declared any penal law unconstitutional on the ground of ambiguity."
[23]
While mentioned in passing in some cases, the void-for-vagueness concept has yet to find direct application in our jurisdiction. In
Yu Cong
Eng v. Trinidad,
[24]
the Bookkeeping Act was found unconstitutional because it violated the equal protection clause, not because it was vague.
Adiong v. Comelec
[25]
decreed as void a mere Comelec
Resolution, not a statute. Finally,
Santiago v. Comelec
[26]
held that a portion of RA 6735 was unconstitutional because of undue delegation of legislative powers, not because of vagueness.
Indeed, an "on-its-face" invalidation of criminal statutes would result in a mass acquittal of parties whose cases may not have even reached the courts. Such invalidation would constitute a departure from the usual requirement of "actual case and controversy" and permit
decisions to be made in a sterile abstract context having no factual concreteness. In
Younger v. Harris,
this evil was aptly pointed out by the U.S. Supreme Court in these words:
[27]
"[T]he task of analyzing a proposed statute, pinpointing its deficiencies, and requiring correction of these deficiencies before the statute is put into effect, is rarely if ever an appropriate task for the judiciary. The combination of the relative remoteness
of the controversy, the impact on the legislative process of the relief sought, and above all the speculative and amorphous nature of the required line-by-line analysis of detailed statutes, x x x ordinarily results in a kind of case that is wholly unsatisfactory for deciding
constitutional questions, whichever way they might be decided."
For this reason, generally disfavored is an on-its-face invalidation of statutes, described as a "manifestly strong medicine" to be employed "sparingly and only as a last resort." In determining the constitutionality of a statute, therefore, its provisions that have
allegedly been violated must be examined in the light of the conduct with which the defendant has been charged.
[28]
As conduct -- not speech -- is its object, the challenged provision must be examined only "as applied" to the defendant, herein petitioner, and should not be declared unconstitutional for overbreadth or vagueness.
The questioned provision reads as follows:
"Section 5.
Prohibition on certain relatives
. It shall be unlawful for the spouse or for any relative, by consanguinity or affinity, within the third civil degree, of the President of the Philippines, the Vice-President of the
Philippines, the President of the Senate, or the Speaker of the House of Representatives, to intervene, directly or indirectly, in any business, transaction, contract or application with the Government: Provided, That this section shall not apply to any person who, prior to the
assumption of office of any of the above officials to whom he is related, has been already dealing with the Government along the same line of business, nor to any transaction, contract or application already existing or pending at the time of such assumption of public office,
nor to any application filed by him the approval of which is not discretionary on the part of the official or officials concerned but depends upon compliance with requisites provided by law, or rules or regulations issued pursuant to law, nor to any act lawfully performed in an
official capacity or in the exercise of a profession."
Petitioner also claims that the phrase "to intervene directly or indirectly, in any business, transaction, contract or application with the Government" is vague and violates his right to be informed of the cause and nature of the accusation against him.
[29]
He further complains that the provision does not specify what acts are punishable under the term
intervene
, and thus transgresses his right to be presumed innocent.
[30]
We disagree.
Every statute is presumed valid.
[31]
On the party challenging its validity weighs heavily the onerous task of rebutting this presumption.
[32]
Any reasonable doubt about the validity of the law should be resolved in favor of its
constitutionality.
[33]
To doubt is to sustain, as tersely put by Justice George Malcolm. In
Garcia v. Executive Secretary
,
[34]
the rationale for the presumption of constitutionality was explained by this Court thus:
"The policy of the courts is to avoid ruling on constitutional questions and to presume that the acts of the political departments are valid in the absence of a clear and unmistakable showing to the contrary. To doubt is to sustain. This presumption is
based on the doctrine of separation of powers which enjoins upon each department a becoming respect for the acts of the other departments. The theory is that as the joint act of Congress and the President of the Philippines, a law has been carefully studied and determined
to be in accordance with the fundamental law before it was finally enacted."
[35]
In the instant case, petitioner has miserably failed to overcome such presumption. This Court has previously laid down the test for determining whether a statute is vague, as follows:
"x x x [A] statute establishing a criminal offense must define the offense with sufficient definiteness that persons of ordinary intelligence can understand what conduct is prohibited by the statute. It can only be invoked against that species of legislation
that is utterly vague on its face,
i.e.
, that which cannot be clarified either by a saving clause or by construction.
"A statute or act may be said to be vague when it lacks comprehensible standards that men of common intelligence must necessarily guess at its meaning and differ in its application. In such instance, the statute is repugnant to the Constitution in two (2) respects -
it violates due process for failure to accord persons, especially the parties targeted by it, fair notice of what conduct to avoid; and, it leaves law enforcers unbridled discretion in carrying out its provisions and becomes an arbitrary flexing of the Government
muscle.
[36]
But the doctrine does not apply as against legislations that are merely couched in imprecise language but which nonetheless specify a standard though defectively phrased; or to those that are apparently ambiguous yet fairly applicable to certain
types of activities. The first may be 'saved' by proper construction, while no challenge may be mounted as against the second whenever directed against such activities.
[37]
With more reason, the doctrine cannot be invoked where the assailed statute is
clear and free from ambiguity, as in this case.
"The test in determining whether a criminal statute is void for uncertainty is whether the language conveys a sufficiently definite warning as to the proscribed conduct when measured by common understanding and practice.
[38]
It must be stressed, however,
that the 'vagueness' doctrine merely requires a reasonable degree of certainty for the statute to be upheld - not absolute precision or mathematical exactitude, as petitioner seems to suggest. Flexibility, rather than meticulous specificity, is permissible as long as the
metes and bounds of the statute are clearly delineated. An act will not be held invalid merely because it might have been more explicit in its wordings or detailed in its provisions, especially where, because of the nature of the act, it would be impossible to provide all
the details in advance as in all other statutes."
[39]
A simpler test was decreed in
Dans v. People
,
[40]
in which the Court said that there was nothing vague about a penal law that adequately answered the basic query "What is the violation?"
[41]
Anything beyond -- the hows and
the whys -- are evidentiary matters that the law itself cannot possibly disclose, in view of the uniqueness of every case.
[42]
The question "What is the violation?" is sufficiently answered by Section 5 of RA 3019, as follows:
The offender is a spouse or any relative by consanguinity or affinity within the third civil degree of the President of the Philippines, the Vice-President of the Philippines, the President of the Senate, or the Speaker of the House of Representatives; and
The offender intervened directly or indirectly in any business, transaction, contract or application with the government.
Applicability of
Statutory Construction
As to petitioner's claim that the term
intervene
is vague, this Court agrees with the Office of the Solicitor General that the word can easily be understood through simple statutory construction. The absence of a statutory definition of a term used in a
statute will not render the law "void for vagueness," if the meaning can be determined through the judicial function of construction.
[43]
Elementary is the principle that words should be construed in their ordinary and usual meaning.
"x x x. A statute is not rendered uncertain and void merely because general terms are used therein, or because of the employment of terms without defining them;
[44]
much less do we have to define every word we use. Besides,
there is no positive constitutional or statutory command requiring the legislature to define each and every word in an enactment. Congress is not restricted in the form of expression of its will, and its inability to so define the words employed in a statute will not
necessarily result in the vagueness or ambiguity of the law so long as the legislative will is clear, or at least, can be gathered from the whole act x x x.
"x x x [I]t is a well-settled principle of legal hermeneutics that words of a statute will be interpreted in their natural, plain and ordinary acceptation and signification,
[45]
unless it is evident that the legislature intended a technical or special
legal meaning to those words.
[46]
The intention of the lawmakers - who are, ordinarily, untrained philologists and lexicographers - to use statutory phraseology in such a manner is always presumed."
[47]
The term
intervene
should therefore be understood in its ordinary acceptation, which is to "to come between."
[48]
Criminally liable is anyone covered in the enumeration of Section 5 of RA 3019 -- any person who intervenes in any manner in any
business, transaction, contract or application with the government. As we have explained, it is impossible for the law to provide in advance details of how such acts of intervention could be performed. But the courts may pass upon those details once trial is
concluded. Thus, the alleged vagueness of
intervene
is not a ground to quash the information prior to the commencement of the trial.
In sum, the Court holds that the challenged provision is not vague, and that in any event, the "overbreath" and "void for vagueness" doctrines are not applicable to this case.
Second Issue:
Allegedly Vague Information
Other than arguing on the alleged intrinsic vagueness of
intervene
, petitioner further contends that the Information itself is also unconstitutionally vague, because it does not specify the acts of intervention that he supposedly performed.
[49]
Again, we disagree.
When allegations in the information are vague or indefinite, the remedy of the accused is not a motion to quash, but a motion for a bill of particulars.
[50]
The pertinent provision in the Rules of Court is Section 9 of Rule 116, which we quote:
"Section 9.
Bill of particulars
. -- The accused may, before arraignment, move for a bill of particulars to enable him properly to plead and prepare for trial. The motion shall specify the alleged defects of the complaint or information and
the details desired."
The rule merely requires the information to describe the offense with sufficient particularity as to apprise the accused of what they are being charged with and to enable the court to pronounce judgment.
[51]
The particularity must be such that persons of
ordinary intelligence may immediately know what is meant by the information.
[52]
While it is fundamental that every element of the offense must be alleged in the information,
[53]
matters of evidence -- as distinguished from the facts essential to the nature of the offense -- need not be averred.
[54]
Whatever facts
and circumstances must necessarily be alleged are to be determined by reference to the definition and the essential elements of the specific crimes.
[55]
In the instant case, a cursory reading of the Information shows that the elements of a violation of Section 5 of RA 3019 have been stated sufficiently. Likewise, the allegations describe the offense committed by petitioner with such particularity as to enable him to
prepare an intelligent defense. Details of the acts he committed are evidentiary matters that need not be alleged in the Information.
Third Issue:
Preliminary Investigation
Clearly, petitioner already brought the issue of lack of preliminary investigation when he questioned before this Court in GR No. 128317 the Sandiganbayan's Order giving him 15 days to file a Motion for Reinvestigation with the Office of the Special Prosecutor.
[56]
Citing
Cojuangco v. Presidential Commission on Good Government
,
[57]
he undauntedly averred that he was deprived of his right to a preliminary investigation, because the PCGG acted both as complainant and as
investigator.
[58]
In the case cited above, this Court declared that while PCGG had the power to conduct a preliminary investigation, the latter could not do so with the "cold neutrality of an impartial judge" in cases in which it was the agency that had gathered evidence and subsequently filed
the complaint.
[59]
On that basis, this Court nullified the preliminary investigation conducted by PCGG and directed the transmittal of the records to the Ombudsman for appropriate action.
It is readily apparent that
Cojuangco
does not support the quashal of the Information against herein petitioner. True, the PCGG initiated the present Complaint against him; hence, it could not properly conduct the preliminary investigation. However, he
was accorded his rights -- the Sandiganbayan suspended the trial and afforded him a reinvestigation by the Ombudsman. The procedure outlined in
Cojuangco
was thus followed.
The Sandiganbayan's actions are in accord also with
Raro v. Sandiganbayan
,
[60]
which held that the failure to conduct a valid preliminary investigation would not warrant the quashal of an information. If the information has already been
filed, the proper procedure is for the Sandiganbayan to hold the trial in abeyance while the preliminary investigation is being conducted or completed.
[61]
Fourth Issue:
Prescription
The issue of prescription was the principal basis of the Motion to Quash filed by petitioner with the Sandiganbayan on October 8, 1999.
[62]
Such issue should be disregarded at this stage, since he failed to challenge its ruling debunking his Motion within
the 60-day period for the filing of a petition for certiorari. A party may not circumvent this rule by filing a subsequent motion that raises the same issue and the same arguments.
Furthermore, it is easy to see why this argument being raised by petitioner is utterly unmeritorious. He points out that according to the Information, the offense was committed "during the period from July 16, 1975 to July 29, 1975." He argues that when the
Information was filed on July 12, 1989,
[63]
prescription had already set in, because the prescriptive period for a violation of Republic Act No. 3019 is only ten (10) years from the time the offense was allegedly committed. The increase of this
prescriptive period to fifteen (15) years took effect only on March 16, 1982, upon the enactment of Batas Pambansa Blg. 195.
[64]
Act No. 3326, as amended,
[65]
governs the prescription of offenses penalized by special laws. Its pertinent provision reads:
"Sec. 2. Prescription shall begin to run from the day of the commission of the violation of the law, and if the same not be known at the time, from the discovery thereof and the institution of judicial proceedings for
its investigation and punishment.
"The prescription shall be interrupted when proceedings are instituted against the guilty person, and shall begin to run again if the proceedings are dismissed for reasons not constituting jeopardy."
Consistent with the provision quoted above, this Court has previously reckoned the prescriptive period of cases involving RA 3019 (committed prior to the February 1986 EDSA Revolution) from the
discovery
of the violation.
[66]
In
Republic
v. Desierto
, the Court explained:
"This issue confronted this Court anew, albeit in a larger scale, in
Presidential Ad Hoc Fact-Finding Committee on Behest Loans v. Desierto
. In the said recent case, the Board of Directors of the Philippine Seeds, Inc. and Development Bank of the
Philippines were charged with violation of paragraphs (e) and (g) of Section 3 of RA No. 3019, by the Presidential
Ad Hoc
Fact-Finding Committee on Behest Loans, created by then President Fidel V. Ramos to investigate and to recover the so-called 'Behest Loans',
where the Philippine Government guaranteed several foreign loans to corporations and entities connected with the former President Marcos. x x x In holding that the case had not yet prescribed, this Court ruled that:
'In the present case, it was well-nigh impossible for the State, the aggrieved party, to have known the violations of RA No. 3019 at the time the questioned transactions were made because, as alleged, the public officials concerned connived or conspired with the
'beneficiaries of the loans.' Thus, we agree with the COMMITTEE that the prescriptive period for the offenses with which the respondents in OMB-0-96-0968 were charged
should be computed from the discovery of the commission thereof and not from the day of such
commission
.
x x x x x x x x x
'People v. Duque is more in point, and what was stated there stands reiteration: In the nature of things, acts made criminal by special laws are frequently not immoral or obviously criminal in themselves; for this reason, the applicable statute requires that if the
violation of the special law is not known at the time, the
prescription begins to run only from the discovery thereof, i.e., discovery of the unlawful nature of the constitutive act or acts
.' (Italics supplied)
"There are striking parallelisms between the said Behest Loans Case and the present one which lead us to apply the ruling of the former to the latter.
First
, both cases arose out of seemingly innocent business transactions;
second
, both were
'discovered' only after the government created bodies to investigate these anomalous transactions;
third
, both involve prosecutions for violations of RA No. 3019; and,
fourth
, in both cases, it was sufficiently raised in the pleadings that the
respondents conspired and connived with one another in order to keep the alleged violations hidden from public scrutiny.
"This Court's pronouncement in the case of
Domingo v. Sandiganbayan
is quite relevant and instructive as to the date when the discovery of the offense should be reckoned, thus:
'In the present case, it was well-nigh impossible for the government, the aggrieved party, to have known the violations committed at the time the questioned transactions were made because both parties to the transactions were allegedly in conspiracy to perpetuate
fraud against the government. The alleged anomalous transactions could only have been discovered after the February 1986 Revolution when one of the original respondents, then President Ferdinand Marcos, was ousted from office. Prior to said date, no person would have
dared to question the legality or propriety of those transactions. Hence,
the counting of the prescriptive period would commence from the date of discovery of the offense, which could have been between February 1986 after the EDSA Revolution and 26 May 1987 when the
initiatory complaint was filed.
'"
[67]
The above pronouncement is squarely applicable to the present case. The general rule that prescription shall begin to run from the day of the commission of the crime cannot apply to the present case. It is not legally prudent to charge the State, the aggrieved party,
with knowledge of the violation of RA 3019 at the time the alleged intervention was made. The accused is the late President Ferdinand E. Marcos' brother-in-law. He was charged with intervening in a sale involving a private corporation, the majority stocks of which
was allegedly owned by President Marcos.
Prior to February 1986, no person was expected to have seriously dared question the legality of the sale or would even have thought of investigating petitioner's alleged involvement in the transaction. It was only after the creation
[68]
of
PCGG
[69]
and its exhaustive investigations that the alleged crime was discovered. This led to the initiation on November 29, 1988 of a Complaint against former President Marcos and petitioner for violation of the Anti-Graft and Corrupt Practices
Act. Consequently, the filing of the Information on July 12, 1989 was well within the prescriptive period of ten years from the
discovery
of the offense.
Fifth Issue
Immunity from Prosecution
Petitioner argues that he enjoys derivative immunity, because he allegedly served as a high-ranking naval officer -- specifically, as naval aide-de-camp -- of former President Marcos.
[70]
He relies on Section 17 of Article VII of the 1973 Constitution, as
amended, which we quote:
"The President shall be immune from suit during his tenure. Thereafter, no suit whatsoever shall lie for official acts done by him or by others pursuant to his specific orders during his tenure.
"x x x x x
x x x x"
As the Sandiganbayan aptly pointed out, the above provision is not applicable to petitioner because the immunity amendment became effective only in 1981 while the alleged crime happened in 1975.
In
Estrada v. Desierto
,
[71]
this Court exhaustively traced the origin of executive immunity in order to determine the extent of its applicability. We explained therein that executive immunity applied only during the incumbency of a
President. It could not be used to shield a non-sitting President from prosecution for alleged criminal acts done while sitting in office. The reasoning of petitioner must therefore fail, since he derives his immunity from one who is no longer sitting as
President. Verily, the felonious acts of public officials and their close relatives "are not acts of the State, and the officer who acts illegally is not acting as such but stands on the same footing as any other trespasser."
In sum, petitioner utterly fails to show that the Sandiganbayan gravely abused its discretion in issuing the assailed Resolutions.
[72]
On the contrary, it acted prudently, in accordance with law and jurisprudence.
WHEREFORE
, the Petition is
DISMISSED
, and the questioned Resolutions of the Sandiganbayan
AFFIRMED
. Costs against petitioner.
SO ORDERED.
Davide, Jr., C.J., Quisumbing, Carpio, Austria-Martinez, Carpio-Morales, Callejo, Sr.,
and
Azcuna, JJ.,
concur.
Puno, Ynares-Santiago,
and
Sandoval-Gutierrez, JJ.,
in the result.
Corona, J.,
on leave.
Tinga, J.,
in the result. Please see separate opinion.
Chico-Nazario, J.,
no part. Ponente of assailed SB Resolutions.
[1]
Rollo, pp. 3-55.
[2]
Id., pp. 56-62.
[3]
Id., pp. 63-68. Fifth Division. Penned by Justice Minita V. Chico-Nazario (chairman), with the concurrence of Justices Ma. Cristina G. Cortez-Estrada and Francisco H. Villaruz Jr. (members).
[4]
Sandiganbayan Resolution, p. 5; rollo, p. 62.
[5]
Anti-Graft and Corrupt Practices Act.
[6]
Sandiganbayan Resolution, pp. 1-3; rollo, pp. 56-60.
[7]
Id., p. 60.
[8]
Ibid.
[9]
Id., p. 64.
[10]
Id., p. 66.
[11]
This case was deemed submitted for resolution on March 6, 2003, upon this Court's receipt of petitioner's Memorandum, signed by Atty. Enrico Q. Fernando. The Memorandum of the Office of the Ombudsman, signed by Deputy Special Prosecutor Robert E.
Kallos, Director Rodrigo V. Coquia, and Special Prosecution Officer Elvira C. Chua, was received by this Court on January 30, 2003. The Memorandum of the Office of the Solicitor General, signed by Solicitor General Alfredo L. Benipayo, Assistant Solicitor General Alexander
G. Gesmundo, and Associate Solicitor Raymond C. de Lemos, was received on February 19, 2003.
[12]
Petitioner's Memorandum, p. 6.
[13]
On October 8, 1999, petitioner had already filed a Motion to Quash, which was denied by the Sandiganbayan on February 9, 2000. Then on June 19, 2001, he filed a Motion to Dismiss.
[14]
A motion for reconsideration is generally required prior to the filing of a petition for certiorari to allow the tribunal an opportunity to correct its assigned errors (
Lasco v. United Nations Revolving Fund for Natural Resources
Exploration
, 241 SCRA 681, 684, February 23, 1995;
Butuan Bay Wood Export Corp. v. CA
, 297 SCRA 297, 305, April 28, 1980). Being interlocutory, the order denying a motion to quash is not appealable. The Order may, however, be reviewed in the
ordinary course of law by an appeal from the judgment after trial. (
Tan Jr. v. Sandiganbayan
, 354 Phil. 463, 470, July 10, 1998;
Cruz v. CA
, 194 SCRA 145, 152, February 18, 1991;
Bulaong v. CA
, 181 SCRA 618, 622, January 30, 1990;
Gamboa v. Cruz
, 162 Phil. 642, 652, June 27, 1988.)
[15]
§4, Rule 65 of the Rules of Court.
[16]
Tan Jr. v. Sandiganbayan
, 354 Phil. 463, 470, July 10, 1998;
Cruz v. CA
, 194 SCRA 145, 152, February 18, 1991;
Bulaong v. CA
, 181 SCRA 618, 622, January 30, 1990.
[17]
Governed by Rule 117.
[18]
Under Rule 16.
[19]
§9, Rule 117 of the Rules of Court, states: "The failure of the accused to assert any ground of a motion to quash before he pleads to the complaint or information, either because he did not file a motion to quash or failed to allege the same in
said motion, shall be deemed a waiver of any objections except those based on the grounds provided for in paragraphs (a), (b), (g) and (i) of section 3 of this Rule." The exceptions refer to the following grounds: the facts do not constitute an offense, lack of
jurisdiction over the offense charged, extinction of the offense or penalty, and double jeopardy.
[20]
"The overbreadth doctrine x x x decrees that 'a governmental purpose may not be achieved by means which sweep unnecessarily broadly and thereby invade the area of protected freedoms.'" Separate Opinion of Mr. Justice Vicente V. Mendoza in
Estrada
v. Sandiganbayan
, 421 Phil. 290, 430, November 19, 2001 (citing
NAACP v. Alabama
, 377 U.S. 288, 307, 12 L. Ed. 2d 325, 338 [1958];
Shelton v. Tucker
, 364 U.S. 479, 5 L. Ed. 2d 231 [1960]).
[21]
The void-for-vagueness doctrine states that "a statute which either forbids or requires the doing of an act in terms so vague that men of common intelligence must necessarily guess at its meaning and differ as to its application, violates the first
essential of due process of law." Separate Opinion of Mr. Justice Mendoza in
Estrada v. Sandiganbayan
421 Phil. 290, 429-430, November 19, 2001 (citing
Connally v. General Constr. Co
., 269 U.S. 385, 391, 70 L. Ed. 328 [1926]; in turn cited in
Ermita-Malate Hotel and Motel Operators Ass'n v. City Mayor
, 20 SCRA 849, 867 [1967]).
[22]
Separate Opinion of Mr. Justice Mendoza in
Estrada v. Sandiganbayan
, supra.
[23]
Separate Opinion of Mr. Justice Panganiban in
Estrada v. Sandiganbayan
, supra.
[24]
271 US 500, June 7, 1926.
[25]
207 SCRA 712, March 31, 1992.
[26]
270 SCRA 106, March 19, 1997.
[27]
401 U.S. 37, 52-53, 27 L. Ed. 2d 669, 680 (1971), per Black, J.
[28]
Separate Opinion of Mr. Justice Mendoza in
Estrada v. Sandiganbayan
, supra.
[29]
Petitioner's Memorandum, p. 9.
[30]
Id., p. 11.
[31]
Heirs of Juancho Ardona v. Reyes
, 210 Phil. 187, 207, October 26, 1983;
Peralta v. Commission on Elections
, 82 SCRA 30, 55, March 11, 1978;
Ermita-Malate Hotel & Motel Operations Association, Inc. v. Hon. City Mayor
of Manila
, 127 Phil. 306, 314, July 31, 1967.
[32]
Estrada v. Sandiganbayan
, supra;
Heirs of Juancho Ardona v. Reyes
, supra;
Peralta v. Commission on Elections
, supra.
[33]
Heirs of Juancho Ardona v. Reyes
, supra;
Peralta v. Commission on Elections
, supra.
[34]
204 SCRA 516, December 2, 1991.
[35]
Id., p. 523, per Cruz, J.
[36]
Citing
People v. Nazario
, 165 SCRA 186, 195-196, August 31, 1988.
[37]
Ibid.
[38]
Citing
State v. Hill
, 189 Kan 403, 369 P2d 365, 91 ALR 2d 750.
[39]
Estrada v. Sandiganbayan
, supra, p. 352, per Bellosillo, J.
[40]
349 Phil. 434, January 29, 1998.
[41]
Id., p. 462, per Romero, J.
[42]
Ibid.
[43]
Caltex v. Palomar
, 18 SCRA 247, September 29, 1966,
Estrada v. Sandiganbayan
, supra, p. 443.
[44]
Citing 82 CJS 68, p. 113;
People v. Ring
, 70 P. 2d 281, 26 Cal. App 2d Supp. 768.
[45]
Citing
Mustang Lumber, Inc. v. Court of Appeals
, 257 SCRA 430, 448, June 18, 1996.
[46]
Citing
PLDT v. Eastern Telecommunications Phil., Inc
., 213 SCRA 16, 26, August 27, 1992.
[47]
Estrada v. Sandiganbayan
, supra, pp. 347-348.
[48]
Webster's Third New International Dictionary, 1993 ed., p. 11.
[49]
Petitioner's Memorandum, p. 14.
[50]
Dans v. People
, supra, p. 461.
[51]
Estrada v. Sandiganbayan
, 427 Phil. 820, 858, February 26, 2002;
People v. Arcillas
, 348 SCRA 729, 733, December 27, 2000;
U.S. v. Go Chanco
, 23 Phil. 641, 645, December 28, 1912.
[52]
People v. Arcillas
, supra.
[53]
Naya v. Abing
, 398 SCRA 364, 369, February 27, 2003;
Estrada v. Sandiganbayan
, supra;
Balitaan v. CFI of Batangas, Branch II,
201 Phil. 311, 322, July 30, 1982.
[54]
Balitaan v. CFI of Batangas, Branch II
, supra, p. 323;
People v. Arbois
, 138 SCRA 24, 32, August 5, 1985.
[55]
Naya v. Abing
, supra, p. 369;
Estrada v. Sandiganbayan
, supra, p. 859;
Balitaan v. CFI of Batangas, Branch II
, supra, p. 322.
[56]
Sandiganbayan Resolution, dated November 20, 2001, p. 2 (supra, p. 59); Office of the Special Prosecutor's Comment, p. 5 (rollo, p. 201); Comment of the Office of the Solicitor General, p. 8 (rollo, p. 224).
[57]
190 SCRA 226, October 2, 1990.
[58]
Petitioner's Memorandum, pp. 21-22.
[59]
Cojuangco v. Presidential Commission on Good Government
, supra, p. 255; See also
Republic v. Desierto
, 416 Phil. 59, 65, August 23, 2001.
[60]
390 Phil. 917, July 14, 2000.
[61]
Id., p. 941.
[62]
Sandiganbayan Resolution dated February 9, 2000; rollo, p. 158.
[63]
Petitioner's Memorandum, p. 24.
[64]
Ibid.
[65]
An Act to Establish Periods of Prescription for Violations Penalized by Special Acts and Municipal Ordinances and to Provide When Prescription Shall Begin to Run.
[66]
Salvador v. Desierto
, GR No. 135249, January 16, 2004;
Presidential Ad Hoc Fact-Finding Committee on Behest Loans v. Desierto
, 415 Phil. 723, August 22, 2001.
[67]
Republic v. Desierto
, supra, pp. 76-78, per De Leon Jr., J.
[68]
On February 28, 1986, by virtue of Executive Order No. 1.
[69]
This Commission was tasked with the recovery of all ill-gotten wealth accumulated by former President Ferdinand E. Marcos, his immediate family, relatives, subordinates and close associates, during his administration; the investigation of cases of
graft and corruption; and adoption of safeguards and institution of adequate measures to prevent the occurrence of corruption.
[70]
Petitioner's Memorandum, p. 31.
[71]
353 SCRA 452, 516-524, March 2, 2001, per Puno, J.
[72]
Land Bank of the Philippines v. Court of Appeals
, supra;
De Baron v. Court of Appeals
, 368 SCRA 407, 415, October 26, 2001;
Intestate Estate of Carmen de Luna v. Intermediate Appellate Court
, 170 SCRA 246, 254,
February 13, 1989;
Butuan Bay Wood Export Corp. v. Court of Appeals
, 97 SCRA 297, 303, April 28, 1980.
tags
Facts Issues Ruling Principles
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U.S. Patent: 6231607 - Bone graft substitute and its preparation - May 15, 2001
4861733 Aug., 1989 White.
5084051 Jan., 1992 Tormala et al. 606/77.
5152836 Oct., 1992 Hirano et al.
5747390 May., 1998 Cooper et al. 442/59.
5885540 Mar., 1999 Fulmer et al. 423/11.
Foreign Patent Documents
3925185 May., 1990 DE.
0705802 Apr., 1996 EP.
0705802 Oct., 1996 EP.
9523775 Sep., 1995 WO.
Primary Examiner: Milano; Michael J.
Assistant Examiner: Phan; Hieu
Attorney, Agent or Firm: Greer, Burns & Crain, Ltd.
Claims
What is claimed is:
1. A composition of matter, being a solid ceramic mass and comprising
.beta.-TCP, hydroxy apatite and a substantial amount of .alpha.-TCP.
2. A composition according to claim 1, wherein the concentration of
.alpha.-TCP is within the range of 5-40% (w/w).
3. A process for the preparation of a composition of matter useful as a
bone substitute, comprising the steps of:
(a) preparing a mixture of ionic calcium, phosphate, aspartic acid and
carbonate;
(b) subjecting the mixture to microwave irradiation;
(c) quenching the irradiated mixture; and
(d) filtering the mixture so as to separate between the filtrate and a cake
and drying the cake.
4. A process according to claim 3, further comprising:
(e) compressing the dried cake; and
(f) heating the compressed cake to a temperature of at least 650.degree. C.
5. A process according to claim 3, wherein the mixture prepared in step (a)
comprises calcium chloride, sodium phosphate, L-Aspartic acid and sodium
carbonate.
6. A process according to claim 3 comprising admixing a carbonate salt in
particulate solid form to the cake obtained in step (d).
7. A process according to claim 3, comprising grinding the cake obtained in
step (d).
8. A process according to claim 4, wherein the step of heating the
compressed cake further comprises maintaining a temperature essentially
constant for a period of time.
9. A composition of matter obtained by the process of claim 3.
10. The composition of matter of claim 1, wherein said composition of
matter is a bone graft substitute.
11. A composition of matter obtained by the process of claim 4.
12. A composition of matter obtained by the process of claim 5.
13. A composition of matter obtained by the process of claim 6.
14. A composition of matter obtained by the process of claim 7.
15. A composition of matter obtained by a process of claim 8.
16. The composition of matter of claim 2, wherein the composition of matter
is a bone graft substitute.
17. The composition of matter of claim 9, wherein the composition of matter
is a bone graft substitute.
18. The composition of matter of claim 1, wherein said composition of
matter is a ceramic formed by heating to no more than approximately
750.degree. C.
Description
FIELD OF THE INVENTION
The present invention relates to the preparation of artificial bone or bone
graft substitutes. In particular, it relates to hydroxyapatite ceramics
which are suitable for this purpose.
BACKGROUND OF THE INVENTION
There are many advantages in using bone graft substitutes over
transplantable allografts which include avoidance of the danger of
transmitting infectious diseases to the host, they are less expensive and
are more readily available. However, the mechanical strength of available
substitutes is substantially lower than allografts, they lack elasticity
and exhibit a poor osteoinductive capability.
During the last two decades porous, calcium and phosphate-based ceramics
were developed as synthetic bone graft substitutes. Past works have shown
that these substitutes are biocompatible and are easily fabricated in a
variety of sizes and shapes. These ceramic compositions of matter
typically comprise hydroxyapatite (hereinafter: "HA") and tricalcium
phosphate (hereinafter: "TCP") or a mixture (hereinafter: "HA+TCP")
thereof.
Synthetic apatites mixed with tricalcium phosphate are widely used in bones
and teeth transplantation. Following preparations, the HA+TCP is usually
subjected to a mechanical treatment in which the material is ground and/or
pressed to obtain a required porosity, hardness or shape, partially
overcoming the problems associated with the bone graft substitutes
discussed above.
However, the requirement to obtain a good quality bone graft substitute
still exists, as well as the need to simplify the mechanical treatment
stage.
It is an object of the present invention to provide a bone substitute being
suitable for use as a transplantable graft.
It is a further object of the invention to provide a process for preparing
such a bone substitute.
Other objects of the invention will become apparent from the following
description.
SUMMARY OF THE INVENTION
In accordance with the invention a novel process for the preparation of a
composition of matter useful as a bone graft substitute has been
developed. The novel process which constitutes one facet of the invention,
yields a composition of matter, which is novel per se, and which
constitutes another facet thereof. For reasons which are not yet fully
elucidated, the novel composition of matter of the invention possesses
improved properties in its use as a bone graft substitute.
The present invention provides, by a first of its aspects, a composition of
matter useful as a bone graft substitute. The composition of matter of the
invention comprises a mixture of tricalcium phosphate (TCP) and
crystallized hydroxy apatite (HA) and is a solid mass typically formed so
as to be suitable for transplantation. The composition of matter of the
invention is unique in that rather than having essentially only the .beta.
form of TCP (.beta.-TCP), it comprises both .alpha.- and .beta.- TCP.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an x-ray diffraction ("XRD") spectrum showing the diffractogram
of a powder product prepared in accordance with the invention prior to
compression and final heating steps (after the filtering step (d) of the
process);
FIG. 2 is the Fourier Transform Infra Red ("FTIR") spectrum of the same
product shown in FIG. 1;
FIG. 3 is an XRD spectrum of a pellet made by two minutes grinding of the
product shown in FIGS. 1 and 2, pressing under 4 tons/cm.sup.2 and
sintered at 700.degree. C. (this product is referred to herein as
"HA-SAL2");
FIG. 4 are SEM ("scanning electron microscope") photographs of human
osteocytes seeded on ceramic HA-SAL2:
FIGS. 4A and 4B are 2 days after seeding;
FIG. 4C is 14 days after seeding;
FIG. 4D is 21 days after seeding; and
FIG. 5 is a comparison of the mineral content at a site of induced bone
defects implanted with either HA-SAL2 or the commercial product Zimmer HA
of Zimmer Inc., Warsaw, USA.
DETAILED DESCRIPTION OF THE INVENTION
The present invention thus provides a composition of matter, beings a solid
ceramic mass and comprising .beta.-TCP, hydroxy apatite (HA) and a
substantial amount of .alpha.-TCP.
The term "substantial amount" should be understood as meaning an amount
which is present in the composition of matter in noticeable quantities,
i.e. not trace amounts. A substantial amount of .alpha.-TCP meaning an
amount within the range of 5-40%, preferable within the range of 10-30%.
The concentration above and further below in the text will at times be
given in "%". A concentration of an ingredient given in "%" means weight
units of the ingredient in 100 weight units of the total composition
(including that ingredient).
The presence of .alpha.-TCP in this ceramic composition of matter is
evidenced, for example, in that the x-ray diffraction ("XRD") spectrum
main reflection is at 2.theta.=30.71.degree. and further reflections are
peaked at 24.10.degree. and 12.01.degree., which are characteristics of
this form and do not appear in either .beta.-TCP and HA x-ray
difractograms.
In accordance with the invention a novel process for the preparation of
bone graft substitute composition matter has been developed, which
constitutes another aspect of the invention. This process comprises the
following steps:
(a) preparing a mixture of ionic calcium, e.g. calcium chloride, phosphate,
e.g. NaH.sub.2 PO.sub.4, an amino acid in either monomeric or polymeric
form, e.g., L-aspartic acid and carbonate, e.g. NaHCO.sub.3 ;
(b) subjecting said mixture to microwave irradiation;
(c) quenching the irradiated mixture; and
(d) filtering the mixture so as to separate between the filtrate and a cake
and drying the cake.
According to an embodiment of the invention, the above process may further
comprise the following steps:
(e) compressing the dried cake, e.g. under a pressure of 2-6 tons/cm.sup.2
; and
(f) heating the compressed cake to a temperature of at least 650.degree.
C., e.g. to a temperature within the range of about 670-750.degree. C., to
obtain a hard ceramic mass.
Step (a) is typically carried out under controlled pH conditions, at a pH
of about 7.0-8.0, preferably a pH range of about 7.3-7.5.
The microwave irradiation may typically be at a wavelength of about 2.45
GHz, at an intensity of about 700 to 1000 W, for about 5 minutes. The
subsequent quenching step may be at a temperature of about 0.degree. C.
for about 30 minutes.
It should be understood that these conditions are given herein as an
example only.
By a preferred embodiment of the invention, the process further comprises
admixing an agent for controlling the porosity of the sintered product
such as a carbonate salt, e.g. NH.sub.4 HCO.sub.3, in a particulate solid
form, to the cake obtained in step (d). The amount of carbonate salt added
to the dried cake is typically within the range of about 5-30% by weight
of the obtained mixture, preferably about 20%. Furthermore, by another
preferred embodiment, the dried cake or the mixture obtained after the
addition of the carbonate salt is ground prior to compression.
The powder obtained in step (d) may be used directly as bone graft, and
therefore comprises another aspect of the present invention.
The Ca.sup.+2 concentration added in step (a) is typically within the range
of about 5.times.10.sup.-3 to about 5.times.10.sup.-2 M and the
concentration of phosphate is typically within the range of about
3.times.10.sup.-3 to about 2.times.10.sup.-2 M; preferred Ca.sup.-2
concentration is about 1.times.10.sup.-2 and preferred phosphate
concentration is about 6.times.10.sup.-3 M.
The aspartic acid used is preferably of the L form and its concentration in
the mixture prepared in step (a) is about 10 to about 50 ppm, preferably
about 25 ppm.
The carbonate concentration of in the mixture prepared in step (a) of the
process of the invention is preferably about 150 to about 600 ppm. In
accordance with the present invention, it was found that changing the
carbonate concentration at step (a) allows to control the extent of HA to
TCP conversion of the product of sep (f).
The heating in step (f) of the process is typically applied for a period of
time sufficient to obtain the hardness and porosity which make the
material useful as a bone substitute. The time of applied heating may also
be used to advantage of controlling the final properties of the
composition of matter.
EXAMPLES
Preparation Method:
Two types of solutions were prepared in a 1% Trizma buffer (pH=7.4): (A)
CaCl.sub.2 of 10.times.10.sup.-3 M and (B) NaH.sub.2 PO.sub.4 of
6.times.10.sup.-3 M. To each one of these solutions L-Aspartic acid was
added to a final concentration of 25 ppm, and NaHCO.sub.3 was added to
final concentrations of 150 ppm.
250 ml of each of the two types of solutions A and B, were mixed rapidly
together in a 1000 ml beaker and put into a microwave (Sharp 700 w) at
maximum power for 5 minutes.
The hot irradiated mixture was then quenched in an ice bath for 30 mins,
and the precipitate was filtered through a milipore filter (having a pore
size of 0.45 .mu.), washed and dried at 55.degree. C. overnight.
A limited amount of a product cake was obtained this way (about 210 mg) and
this procedure was repeated several times to obtain a sufficient quantity
for further analysis. The products of these batches were then collected,
mixed with NH.sub.4 HCO.sub.3 (20 wt %) and ground for 2 mins. (Addition
of NH.sub.4 HCO.sub.3 at this stage was made so as to provide the sample
with a suitable porosity after being heated).
Then, portions of 200 mg each were put into a pellet dye (Graseby Specac)
and compressed under pressure of 4 tons/cm.sup.2. The so formed pellets
were then heated to 700.degree. C. in a standard oven for one hour.
Thereafter, the samples were all analyzed by XRD and FTIR methods.
Analyses
X-ray analyses were carried out by using a Philips X-ray powder
diffractometer of monochromatic Cu K.alpha. radiation.
FTIR analyses were performed using a Nicolet 510 FTIR spectrophotometer.
The amount of carbonate in the samples was estimated from the FTIR spectra
according to a method described in.sup.[1] which is hereby incorporated by
reference.
CHEMICAL RESULTS
The material HA-SAL2 according to the present application has been used
both as a powder and as a sintered porous ceramic. The two products differ
from each other with respect to crystallinity of the hydroxy-apatite
phase, which may be seen from the undifferentiated peak of 2.theta. in the
32.degree.-33.degree. range of the powder as shown in FIG. 1, and the
differentiated peaks of the sintered product in the same region, presented
in FIG. 3. The x-ray diffractogram of the powder resembles closely the
diffractogram of bone mineral.
Another noticeable difference between both products is their
crystallography. During the sintering process, part of the initial HA
powder undergoes transformation to TCP. The transformation to .beta.-TCP
was expected, in accordance with the prior art, however, under the process
conditions described above, the appearance of .alpha.-TCP was not
expected.
Within the interval 2.theta.=30.degree.-33.degree., the following peaks as
presented in FIG. 3 were found: (i) 31.77.degree., 32.20.degree., and
32.90.degree. of the main diffractions hydroxyapatite (JCPDS-ICDD 9-432),
(ii) 31.03.degree., the main diffraction of .beta.-TCP (JCPDS-ICDD 9-169)
and (iii) at 30.71.degree. the main diffraction of (.alpha.-TCP
(JCPDS-ICDD 29-359). The identification of the last mentioned polymorph,
was corroborated by the distinguishing(, reflections of
2.theta.=12.01.degree. and 24.10.degree. in an extended diffractogram of
the same pellets (not shown).
The ratio between .alpha.- and .beta.- TCP polymorphs depend upon various
parameters, some of which are chemical, whereas the others are a function
of the operating conditions. Thus, under standard operating conditions the
balance between both polymorphs may depend upon the amount of NaHCO.sub.3
added to the reaction mixture in step (a). The balance further depends
upon the operating parameters such as the pressure applied prior to
sintering, the grinding of the powder (grinding intensity and duration),
temperature and sintering period.
Upon heating the powder to 700.degree. C., the carbonate and H.sub.2 O
peaks of the ceramic materials at 1400 to 1600 cm.sup.-1 are considerably
weakened, whereas the 1035 cm.sup.-1 and 565 to 633 cm.sup.-1 peaks of
phosphate compounds remain unchanged.
The transition from the powder to the porous sintered ceramic involves the
addition of NH.sub.4 HCO.sub.3. This substance is completely decomposed
upon heating to 700.degree. C., leaving large pores in the product's
structure.
The use of the composition of the present invention in biological tests and
in animal model can be made with both products, namely, the powder and the
sintered ceramic. The selection of the particular state of the material is
determined in accordance with the specific application.
In the following examples ceramic discs produced from HA-SAL2 powder were
used in the biocompatibility tests, whereas the powder form was used in
the animal model studies. The characterization of the initial powder used
is given by its XRD spectrum (FIG. 1) and FTIR spectrum (FIG. 2).
Morphological Appearance and Growth of Human Bone Cells on HA-SAL2
Human bone derived cells were seeded on discs of HA-SAL2 specified under
"Chemical Results", and examined by SEM after 2, 14 and 21 days of
culture. Ultrastructural observation indicated that the cells had
anchored, attached and spread onto the discs within 2 days after seeding
(FIG. 4A). The cells were well spread, displaying a flat configuration and
good contact with neighboring cells (FIG. 4B). Within 14 days after
seeding, the cells had colonized large areas of the substrate surface
(FIG. 4C). They maintained physical contact with one another through
multiple extensions, and formed a multilayer sheet. They overlapped and
superimposed, making it difficult to distinguish the borders of individual
cells. Cells seeded at higher density took less time to cover the apatite
surface, although there were variations from one culture batch to another.
No signs of cytotoxicity or cell degenerations were evident throughout the
experiment. The cells retained their typical broad and flattened
morphology and exhibited good culture organization.
Concurrent with continuous cultivation of the human bone derived cells,
formation of extracellular matrix ("ECM") containing fibrous material
secreted by the osteoblasts could be observed (FIG. 4B). It has not been
yet identified or distinguished as collagen. Globular masses on the cell
surface of bone cells in culture were also observed (FIG. 4D). It has been
suggested that the mineralization begins with matrix vesicles and is
followed by additional mineral deposition on collagen fibrils.
The ceramic surfaces of HA-SAL2 did not exhibit microscopic degradation or
altered surface morphology resulting from their interaction with the
cultured cells and/or incubation in protein containing medium for the
duration of the experiments.
Light microscopic and SEM examination of the periphery of the specimens and
the outgrowth of the cells on the culture dishes showed no signs of
toxicity throughout the rest period. The cells were well spread,
maintained contact with neighboring cells, and formed a well organized
monolayer. Mineralized bone-like nodules were detected by Alizarine red
staining in the culture growing at the periphery of the apatite disc
(generally detectable after 10 days of culturing).
Mineralization of HA-SAL2 Implanted in Rat Tibiae
According to sporadic clinical reports, HA ceramics have been used for
filling bone defects in tibial plateau fractions and in bone tumor
surgery. However, it was difficult to follow healing progression in these
patients. In .sup.[3], the use of DEXA in vivo for detecting small changes
of mineral content (MC) within a ceramic implant in a surgical model was
demonstrated. This publication is incorporated herein by reference. In
accordance with the model, HA cylinders were implanted in rat proximal
tibiae and followed for 13 weeks. In order to determine whether the MC
changes obtained in vivo by the DEXA technique are comparable with changes
determined by invasive techniques commonly used to evaluate bone healing,
the alkaline phosphatase (ALP) activity within the implants was measured
during callus formation. The increase in ALP activity within the implants
was found to precede the increase in mineral content as measured
non-invasively by the DEXA technique. This was consistent with the timing
of ALP activity in respect to mineralization as it occurs during fracture
healing. HA-SAL1 (a preliminary preparation of the HA-SAL series)
cylindrical implants of 3 mm diameter and 5 mm length were shaped and
autoclaved. The results showed that DEXA imaging is useful in measuring
bone ingrowth in small ceramic HA implants in vivo, despite the high
mineral content background of the implant scaffold.sup.[3].
The previously described surgical model was used with some
modifications.sup.[3]. In a new set of experiments, Sabra female rats
weighing 250 gr were anesthetized and holes of 3 mm diameter were drilled
in the right tibial metaphysis, 3 mm below the collateral ligaments
insertion. HA-SAL2 powder was put in these holes, the contralateral empty
holes, as control defects, were omitted since they were found to be
inappropriate controls.
Bone defects implanted with HA-SAL2 powder were examined for MC at
different time intervals during, 110 post implantation (days and compared
to Zimmer HA (FIG. 5). The base line MC for each implanted defect was
determined on Day 1 post implantation and designated "100%". MC was
measured seven times post implantation (throughout the experiment). The MC
change (MCC) for each implant consists of the ratio between the measured
MC at each time interval and its own Day 1 MC value. In FIG. 2 the mean
MCC.+-.SEM is expressed in percent deviation from the 100% base line MC.
On day 110 a maximum mean increase exceeding 50% in the MC of the HA-SAL2
implants, was observed. This resulted from apposition of healing
fractured-bone callus on the surface of the powder HA-SAL2 which showed
progressive mineralization. Lower MCC was obtained while using implants
prepared from the product of Zimmer company, which served as controls. The
substantial mineralization onto the HA-SAL2 surface, despite the lack of
macropores, is indicative of its biocompatibility in vivo.
REFERENCES
1. Featherstone , J. D. B. et al., Caries Res., 18:65, (1975).
2. Conistantz, B. R. et al., Science, 267:1796-1799, (1995).
3. Mosheiff, R., et al., Biomaterials, 13:(7)462-466, (1992). Top | http://www.everypatent.com/comp/pat6231607.html |
The African Lungfish (Protopterus Dolloi): Ionoregulation and Osmoregulation in a Fish out of Water - DocsLib
Wilfrid Laurier University Scholars Commons @ Laurier Biology Faculty Publications Biology 2007 The African Lungfish (Protopterus dolloi):
Wilfrid Laurier University Scholars Commons @ Laurier
Biology Faculty Publications Biology
2007
The AfricanLungfish(Protopterusdolloi): Ionoregulation and Osmoregulation in aFishout of Water
Michael P. Wilkie Wilfrid Laurier University,[email protected]
Tammie P. Morgan McMaster University
Fernando Galvez Louisiana State University
Richard W. Smith McMaster University
Makiko Kajimura McMaster University
Follow this and additional works at: https://scholars.wlu.ca/biol_faculty
Recommended Citation Wilkie, Michael P.; Morgan, Tammie P.; Galvez, Fernando; Smith, Richard W.; Kajimura, Makiko; Ip, Yuen K.; and Wood, Chris M., "The African Lungfish (Protopterus dolloi): Ionoregulation and Osmoregulation in a Fish out of Water" (2007). Biology Faculty Publications. 45. https://scholars.wlu.ca/biol_faculty/45
This article is available at Scholars Commons @ Laurier: https://scholars.wlu.ca/biol_faculty/45 99
The African Lungfish (Protopterus dolloi): Ionoregulation and Osmoregulation in a Fish out of Water
Michael P. Wilkie1,2,* content observed after 20 wk of air exposure. The possibility Tammie P. Morgan1 that muscle acted as a “water reservoir” during air exposure Fernando Galvez1,3 was supported by the 20% decline in body mass observed dur- Richard W. Smith1 ing subsequent reimmersion in water. This decline in body mass Makiko Kajimura1 was equivalent to 28 mL water in a 100-ganimaland was very Yuen K. Ip4 close to the calculated net water gain (approximately 32 mL) Chris M. Wood1 observed during the 20-wk period of air exposure. Tritiated 1Department of Biology, McMaster University, Hamilton, water and unidirectional ion fluxes on air-exposed lungfish Ontario L8S 4K1, Canada; 2Department of Biology, Wilfrid revealed that the majority of water and ion exchange was via Laurier University, Waterloo, Ontario N2L 3C5, Canada; the ventral body surface at rates that were initially similar to 3 3 Department of Biological Sciences, Louisiana State aquatic rates. The H-H2O flux declined over time but increased University, Baton Rouge, Louisiana 70803-1715; 4Department upon reimmersion. We conclude that the slender lungfish body of Biological Science, National University of Singapore, Kent surface, including the gills, has relatively low permeability to Ridge, Singapore 117543, Republic of Singapore water and ions but that the ventral surface is an important site of osmoregulation and ionoregulation. We further propose that Accepted 8/28/2006; Electronically Published 11/15/2006 an amphibian-like combination of ventral skin water and ion permeability, plus internal urea accumulation during air ex- posure, allows P. dolloi to extract water from its surroundings and to store water in the muscle when the water supply becomes ABSTRACT limited. Although urea production and metabolism in lungfish have been thoroughly studied, we have little knowledge of how in- ternal osmotic and electrolyte balance are controlled during estivation or in water. We tested the hypothesis that, compared Introduction with the body surface of teleosts, the slender African lungfish (Protopterus dolloi) body surface was relatively impermeable to The sixspeciesof lungfish (subclass:Sarcopterygii) belong to water, Naϩ, and ClϪ due to its greatly reduced gills. Accordingly, the familiesCeratodontidae(Australian lungfish;Neoceratodus3 we measured the tritiated water ( H-H2O) flux in P. dolloi in forsteri),Lepidosirenidae(South American lungfish; Lepidosiren 3 water and during air exposure. In water, H-H2O efflux was paradoxa), and Protopteridae, which comprises the four species comparable with the lowest measurements reported in fresh- of African lungfish belonging to thegenusProtopterus (P. ae- water teleosts, with a rate constant (K) of 17.6% body water thiopicus, P. amphibius, P. annectens, P. dolloi; see Graham 1997 hϪ1. Unidirectional ion fluxes, measured using 22Naϩ and 36ClϪ, for review). The Protopteridae are distributed across tropical indicated that Naϩ and ClϪ influx was more than 90% lower Africa, and these obligate air breathers have been subject to than values reported in most freshwater teleosts. During air intense scrutiny by respiratory physiologists interested in the exposure, a cocoon formed within 1 wk that completely covered evolution and development of air breathing invertebrates(e.g., the dorsolateral body surface. However, there were no distur- Smith 1931; McMahon 1970; Johansen et al. 1976a; Laurent et bances to blood osmotic or ion (Naϩ,ClϪ) balance, despite al. 1978; Perry et al. 2005). The African lungfish are also re- seven- to eightfold increases in plasma urea after 20 wk. Up to nowned for their ability to enter a prolonged (up to 4 yr) state 13-fold increases in muscle urea (on a dry-weight basis) were of torpor or estivation during periods of extreme drought (e.g., the likely explanation for the 56% increase in muscle water Smith 1931; Janssens 1964; DeLaney et al. 1974). With the onset of the dry season, some lungfish burrow into the mud and * Corresponding author. Address for correspondence: Department of Biology, secrete a mucus cocoon that surrounds the body to reduce Wilfrid Laurier University, 75 University Avenue West, Waterloo, Ontario N2L desiccation (see Fishman et al. 1986 for review). During both 3C5, Canada; e-mail:[email protected] and air exposure, nitrogenous wastes are also con- Physiological and Biochemical Zoology 80(1):99–112 2007 ᭧ 2007 by The verted to and stored in the body as urea, rather than as the University of Chicago All rights reserved 1522-2152/2007/8001-6065$15 00 more toxic ammonia (Smith 1930, 1931; Janssens 1964; Jans- 100 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood sens and Cohen 1968; DeLaney et al. 1974, 1977; Chew et al. contact with the moist substrate (Chew et al. 2003; Wood et 2003, 2004; Loong et al. 2005; Wood et al. 2005). Only P. al. 2005). Because humid conditions are essential for survival annectens is reported to estivate in nature on a regular basis under such circumstances, we predicted that water and ion (Greenwood 1986), but all African lungfish have the ability to uptake would take place across the ventral body surface. To 3 ϩ Ϫ secrete a cocoon and to enter an estivation-like state when test this hypothesis, H-H2O and unidirectional Na and Cl denied access to water in the laboratory. Although nitrogenous flux measurements were performed on acutely (4–8 h) and waste production and excretion during estivation have been chronically (1 wk–6 mo) air-exposed lungfish that were sus- studied extensively, less is known about how internal ion and pended over a water bath that was in contact with only the osmotic balance is maintained in lungfish during periods of ventral body surface. These studies were also accompanied by water shortage. The goal of this study was to determine how measurements of plasma nitrogen stores (ammonia, urea, tri- the slender lungfish P. dolloi controls internal osmotic and elec- methylamine oxide), osmolality and ion concentrations, and trolyte balance while in water and during periods of limited water and urea content of muscle to assess how effectively the water availability due to air exposure. lungfish defended osmotic and ionic status during prolonged In most freshwater fish species, the gills are the major site air exposure. of ion exchange (Perry 1997; Marshall 2002), but they are also the major route of water entry due to the large surface area Material and Methods generated by numerous filaments containing secondary lamel- ExperimentalAnimalsand Holding lae (Evans 1979). The gills of lungfish, however, are greatly reduced and characterized by a lack of gill filaments and sec- Adult slender African lungfish averaging 156 g in mass ondary lamellae on the anterior gill arches and relatively low (range p 56–274 g), originally captured in western Africa, were numbers of these structures on the posterior arches (Laurent purchased from a tropical fish dealer in Singapore and then et al. 1978; Burggren and Johansen 1986). As a result, in juvenile air-shipped to McMaster University, in Hamilton, Ontario, in and adult life stages, the gills play a relatively minor role in gas plastic bags that were partially filled with water and had an 1 exchange, with most O2 ( 80%) uptake occurring via the lungs overlying air phase that was saturated with oxygen. The lungfish (McMahon 1970; Johansen et al. 1976a; Perry et al. 2005). were subsequently held individually in static 10-L covered Based on these facts, a key objective of this study was to test aquaria, containing approximately 2 L of warm (25Њ–28ЊC) the hypothesis that the gills and general body surface (skin) of water, and subject to a 12L : 12D photoperiod. Because African P. dolloi were relatively impermeable to water, Naϩ, and ClϪ lungfish are obligate air breathers, aeration of the water was while the animals were submerged in water. We tested this not necessary, but the water was supplemented with Instant hypothesis by measuring rates of exchangeable water turnover Ocean, resulting in [Naϩ] ∼2.0 mmol LϪ1,[ClϪ] ∼1.8 mmol between P. dolloi and its environment by tracking the appear- LϪ1, and [Ca2ϩ] ∼1.2 mmol LϪ1;pH∼7.8; and hardness ∼170 3 ance of radioactive H-H2 O in the water after its injection into ppm, which minimized the incidence of fungal infections and the intraperitoneal (IP) cavity (Evans 1967; Potts et al. 1970). overall stress. The lungfish were fed bloodworms (chironomid Unidirectional Naϩ and ClϪ flux rates were also determined by larvae) three times per week, but non-air-exposed lungfish measuring the changes in water radioactivity after the external (aquatic) were starved for 3–5 d before experiments to mini- addition of 22Naϩ and 36ClϪ (Wood 1988; Wilkie et al. 1998) mize possible artifacts that feeding might have introduced to 3 to determine basal rates of ion exchange across the body surface ion or H-H2O measurements. This also permitted more mean- of P. dolloi. ingful comparisons between aquatic and air-exposed lungfish, All of the African lungfish are amphibious, and P. dolloi lives which do not feed while estivating. All experimental and hold- in marginal, swampy habitat (Greenwood 1986) where it could ing procedures used followed Canadian Council on Animal be subject to short periods of air exposure while stranded in Care guidelines and were approved by the McMaster University puddles or during temporary aerial excursions. Under such Animal Care Committee. circumstances, the gills would be inoperative due to the collapse of secondary lamellae and fusion of gill filaments on the pos- Experimental Protocol and Air Exposure terior arches (Sturla et al. 2002). An ability to continue uptake of water and/or ions from the limited water remaining in their Air exposure was achieved by completely draining each holding habitat by using other routes/mechanisms could therefore pro- chamber (25cm # 18.5 cm) and then adding back 20 mL of long lungfish survival by minimizing the severity of osmotic water (same composition as above) to create a film of water and ionic disturbances. To examine this possibility, we took on the bottom of each chamber. The animals were sprayed advantage of the ability of P. dolloi to survive out of water for every sixth day with a fine mist of water to maintain high prolonged periods by entering an estivation-like state charac- relative humidity throughout the air-exposure period (1 wk–6 terized by the secretion of a cocoon that envelops the animal’s mo). To minimize disturbance, air-exposed animals were held dorsolateral body surface while the ventral surface remains in under constant darkness, but they were inspected twice per day, Osmoregulation and Ionoregulation in the African Lungfish 101 except on weekends (once per day). Under these conditions, exposed animals were injected in a similar manner, but damage it was noted that cocoon formation began within 1–2 d of to the cocoon was minimal because the site of injection (ventral initiating air exposure, and after approximately 1 wk, a clearly body surface) lacked this covering. After injection, the aquatic discernible cocoon could be seen covering the animal’s dor- or air-exposed lungfish were transferred to the appropriate ex- 3 solateral body surface. Of the 45 lungfish that were exposed to perimental chamber for measurement of the H-H2O flux. The air for 1 wk or longer, 42 survived air exposure and reimmer- experimental chambers either contained 2.5 L of nonradioactive sion in water. water (aquatic controls) or comprised a mesh screen upon which the lungfish was placed, overlying 1.3 L of water. After Experiment 1: Effects of Air Exposure on Osmotic, Ionic, and the 1-h postinjection period, water samples (10 mL) were col- Nitrogenous Waste Balance. Lungfish were held under aquatic lected at 0, 1, 2, 4, 6, 8, 10, 12, and 18 h. Water efflux was 3 (control) or terrestrial (air exposure) conditions for 1, 4, or 20 calculated based on the appearance of the radioactive H-H2O 3 wk. At the conclusion of each period, blood samples (50–500 in the water. As an additional check of our protocol, H-H2O mL) were collected by caudal puncture using 26-gauge insulin influx and efflux were compared using two subgroups of acutely syringes that were prerinsed with Naϩ-heparin (1 mg mLϪ1); (short-term; 4 h) or chronically (long-term; 6 mo) air-exposed the samples were subsequently centrifuged at 10,000 g for 3 lungfish. Unlike efflux, water influx determinations were based 3 min to separate the plasma from the corpuscular portion. on the disappearance of H-H2O radioactivity following the Where sufficient blood was available (1200 mL), hematocrit was addition of 10 mCi isotope to the underlying water. To verify also determined using Naϩ-heparinized capillary tubes centri- that changes in water radioactivity were not due to evaporation, fuged for 5 min at 6,000 g. Plasma was transferred to 500-mL water samples were also taken from chambers spiked with 3H- Ϫ Њ centrifuge tubes, frozen in liquid N2, and stored at 80 C until H2O (as above) but containing no fish. analyzed for plasma osmolality, ions (Naϩ,ClϪ), and nitroge- To determine whether subsequent reimmersion resulted in 3 nous compounds (ammonia, urea, and trimethylamine oxide net stimulation of whole-body water turnover, H-H2O flux [TMAO]). Muscle samples were also collected from the dor- rate experiments were performed on lungfish during reim- solateral side of a subset of anesthetized animals that were mersion after 20 wk of air exposure. In these experiments, the terminally sampled, under aquatic conditions or after air ex- isotope was injected intraperitoneally (as previously described) posure for 4 or 20 wk, for determination of muscle water and and followed by reimmersion in 2.5 L of water 1 h later. An urea content. initial water sample (0 h; 10 mL) was then collected, followed To determine how the simultaneous stresses of starvation by additional samples at 4, 8, and 12 h. Care was taken to and air exposure affected body mass, lungfish were weighed at remove the cocoon from the water as it was shed by the lungfish. the beginning and end of 1, 4, or 20 wk of air exposure. Changes Nonterminal blood samples were collected from another group in body mass were also monitored in a subset of four animals of animals after 8 or 24 h of reimmersion for determination during reimmersion after 20 wk of air exposure to determine of plasma osmolality. how the return to completely aquatic conditions affected net water balance. In these experiments, mass was determined at Experiment 3: Unidirectional Naϩ,ClϪ, and Acid-Base Equivalent 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h of reimmersion. Movements during Air Exposure and Reimmersion. To determine routine rates of Naϩ and ClϪ net flux, influx, and efflux in 3 Experiment 2: Effects of Air Exposure on H-H2O Flux across the aquatic lungfish, dual-label experiments were performed using Ventral Body Surface. To examine water flux, we measured 3H- 22Naϩ and 36ClϪ as previously described (e.g., Wood 1988; Goss 3 H2O movements across the lungfish body surface (gills, skin, et al. 1992; Wilkie et al. 1998). Unlike the H-H2O efflux mea- and also renal routes) in water and in air (ventral body surface surements, ion influx measurement was based on decreases in Ϫ1 3 22 ϩ 36 Ϫ only) after IP injection of 0.75 mCi kg of H-H2O taken from water radioactivity due to uptake of Na or Cl across the 3 Ϫ1 a0.5mCi H-H2O mL stock dissolved in physiological saline. skin and/or gills (refer to “Analytical Techniques and Calcu- Before injection, body weights were determined in aquatic- lations” for additional details). Briefly, fish were held in cham- phase animals by covering them with a moistened cloth to bers containing 2.5 L water that was moderately aerated to prevent damage to their delicate skin, blotting them dry, and ensure adequate mixing of water and isotope. Fifteen minutes then recording mass to the nearest 0.1 g, using an analytical before initiating fluxes, 10 mCi of 22Naϩ or 20 mCi 36ClϪ were balance. The fish were then wrapped again with the moist cloth added to the water. Water samples (10 mL) were subsequently and positioned firmly on a large moistened sponge, and the taken at 0, 2, 4, and 8 h after isotope addition. Although pre- 3 3 H-H2O was injected. Care was taken to ensure that the H- viously published studies used smaller amounts of isotope, it 22 ϩ H2O solution did not leak out of the injection site. As an should be pointed out that the greater overall activities of Na 3 36 Ϫ additional precaution, the H-H2O-injected lungfish were left or Cl used in this experiment were needed to allow us to 1 h to allow the isotope to become equilibrated throughout resolve unidirectional ion fluxes against the 2-mmol-LϪ1 back- the extracellular and intracellular spaces (Evans 1967). Air- ground NaCl concentrations. The net effect was that the specific 102 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood activity of each isotope was approximately 2 mCi 22Naϩ/mmol of the lateral trunk muscle (∼100 mg) that had been dried to Naϩ and 4 mCi 36Cl/mmol ClϪ, which was in the same range constant weight at 80ЊC for 5 d and expressed as mL water gϪ1 used in similar unidirectional flux studies (e.g., Wood 1988; dry muscle. Goss et al. 1992; Wilkie et al. 1998). 3 Ion fluxes were also performed on air-exposed animals, but H-H2O Fluxes. Water efflux rates across the body surface were ϩ Ϫ in these experiments, 22Na (10 mCi) and 36Cl (20 mCi ) were determined by first calculating the decreases in whole body added to the bath water. Because the water was in direct contact radioactivity based on differences between water radioactivity with the ventral body surface, this allowed us to directly mea- at the beginning and end of the sampling period. This infor- 3 sure ion movements across this region of the lungfish body mation was then used to determine the H-H2O efflux rate 3 Ϫ Ϫ surface. After a 15-min mixing period, water samples were (J H-H2 O ) in counts per minute (CPM) kg 1 h 1, using the fol- collected at 0, 2, 4, and 8 h for later determination of radio- lowing formula: activity and ion concentrations. An empty chamber containing 22 ϩ 36 Ϫ Ϫ the same volume of water but spiked with Na and/or Cl 3 CPMifCPM J H-H2 O p ,(1) was used as a control. Because rehydration of the gills, a main T # M site of ion regulation in most fish (Perry 1997; Marshall 2002), could also alter ion movements after reimmersion, recovery where CPMi and CPMf represent the initial and final CPM for experiments in water that were similar to those described for a given flux period, T is the flux period duration (h), and M 3 H-H2O (above) were performed to track ion movements after is the mass of the fish (kg). The rates calculated in equation 4 wk of air exposure. In these experiments, water samples were (1) were then used to determine the water efflux (clearance) taken at 0, 2, 4, 8, 12, 16, and 24 h after reimmersion. rate as follows: To determine whether air exposure was associated with acid- 3 base disturbances and subsequent correction after reimmersion, J H-H2 O Hϩ water eff lux (clearance) rate p ,(2) net acid movements (Jnet ) were measured in five lungfish fol- Z Hϩ lowing reimmersion after 6 mo of air exposure. BecauseJnet is TA the sum of the titratable acid flux (J ) and ammonia excretion where Z equals the average CPM mLϪ1 in each fish during each (Jamm), the titratable alkalinity and ammonia concentration was flux period in question and water efflux rate is expressed as determined in water samples (20 mL) taken at 0, 4, 8, and 12 mL kgϪ1 hϪ1. Rate constants for exchangeable water efflux (K) h after reimmersion (cf. Wood 1988; Wilkie et al. 1998). Water were then determined as described by Evans (1967), where ion concentrations were also measured to determine whether differences in the net fluxes of Naϩ versus ClϪ could explain CPM possible acid-base equivalent movements during reimmersion K p 2.3logi . (3) 10 ()CPM (Wood 1988; Wilkie et al. 1998). f
where [ion]i and [ion]f represent the concentrations of “cold” parisons test was performed. Significance was determined at (nonradioactive) Naϩ or ClϪ in the water at the beginning and theP ! 0.05 level. end of a flux period, respectively; V is the volume of water (mL) in the container; and T and M are as previously stated. Results ϩ Na Ϫ Cl Rates of Na (JJin ) and Cl influx (in ) were based on re- ductions in water radioactivity during each flux period as de- Effects of Air Exposure on Osmolality, Urea, Ions, and scribed by Body Mass Air exposure was characterized by the formation of a cocoon (CPM Ϫ CPM ) # V ion p if that covered the dorsolateral body surface of Protopterus dolloi. Jin # # ,(5) MSA M T Under these conditions, most fish exhibited very little move- ment, but in a few instances it was clear that fish had shifted where CPM and CPM are the radioactivities for 22Naϩ and i f positions without damaging the cocoon. In addition, the fish 36ClϪ, respectively (CPM mLϪ1); MSA is the mean specific ac- sometimes responded to external stimuli (e.g., sudden noises, tivity of each isotope in the external water (CPM molϪ1); and m jarring of the container) with slight body movements and the V, M, and T are as previously stated. Back-flux correction occasional grunting sound. (Wood 1988) was not required because internal CPM never Plasma osmolality was unaffected by air exposure in the exceeded 10% of the total CPM in the water during any given Ϫ slender lungfish, fluctuating around 240–260 mOsm kg 1 under period. Because 22Naϩ emits both gamma and beta radiation, aquatic conditions and after 1, 4, and 20 wk of air exposure while 36ClϪ emits only beta radiation, water samples (2.5 mL) (Fig. 1A). This was despite a seven- to eightfold increase in were first counted on a Packard 5000 series gamma counter to mean plasma urea after 4 and 20 wk of air exposure (Fig. 1B), determine the radioactivity due to 22Naϩ. Thereafter, 5 mL of during which times individual values approached 100 mmol ACS scintillation fluor was added to the samples, which were Ϫ Ϫ urea-N L 1 in some fish (range p 12–104 mmol urea-N L 1). left overnight to minimize chemiluminescence, before total Despite the high plasma urea concentrations, the counterbal- CPM was determined the following morning via scintillation counting. Tests again demonstrated that quench was constant. The CPM due to 36ClϪ was based on the difference between the total scintillation CPM (22Naϩ plus 36ClϪ) and the gamma CPM (22Naϩ only) after correcting for differences in the count- ing efficiencies between the gamma counter and the scintillation counter.
Hϩ Net Acid Flux after Reimmersion. The measurement ofJnet is described by the following relationship:
HTAϩ p ϩ Jnet J Jamm,(6)
TA where J is the titratable acid flux and Jamm is the ammonia excretion rate. The J TA was based on the difference in titratable alkalinity between the beginning and end of a sample period, where titratable alkalinity was measured by titrating water sam- ples (10 mL; refrigerated for no more than 24 h) to an end point of pH 4.0, using analytical grade 0.02 mol LϪ1 HCl (Sigma). Differences in water ammonia concentrations between the beginning and end of a flux period were used to calculate
Jamm (see Wood 1988; Wilkie et al. 1998 for further details).
Statistical Analyses SEM. Where appro- Figure 1. Differences in plasma osmolality (A) and urea concentrations 1 ע All data are expressed as themean priate, data were analyzed using unpaired t-tests or either one- (B) in the slender African lungfish (Protopterus dolloi) under aquatic conditions (solid bar;N p 7 ), and after air exposure (hatched bars) way or repeated-measures ANOVA followed by a Tukey post- for 1 wk (N p 6 ), 4 wk (N p 11 ), or 20 wk (N p 15 ). Data presented test. In instances where the data were not normally distributed, as themean ϩ 1 SEM. Asterisks denote statistically significant differ- a nonparametric ANOVA followed by Dunn’s multiple com- ences from animals held under aquatic conditions (!0.05). 104 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood
Table 1: Plasma Naϩ and ClϪ concentrations and hematocrit measured in the slender African lungfish (Protopterus dolloi) during 20 wk of air exposure Air Exposure Aquatic 1 wk 4 wk 20 wk (15) 1.9 ע 103.6 (10) 2.8 ע 99.9 (5) 1.8 ע 105.0 (8) 3.4 ע Naϩ] (mmol LϪ1) 99.2] (15) 4.0 ע 84.4 (9) 3.1 ע 82.8 (5) 3.1 ע 98.5 (8) 5.0 ע ClϪ ] (mmol LϪ1) 88.2] (5) 1.9 ע 31.0 (5) 1.8 ע 29.2 … (5) 1.2 ע Hematocrit (%) 30.4 .SEM; sample sizes are in parentheses 1 ע Note. Data expressed as themean ancing solute TMAO and its precursor TMA were below limits did not significantly change over the first 4 h. In contrast, water of detection in the plasma in aquatic animals (N p 3 ) and in efflux was about 65% lower in animals that had been air ex- animals that were subject to 4 wk (N p 3 ) or 20 wk of air posed for 6 mo (Fig. 4). When rates of water influx were de- p 3 exposure (N 3 ). As a result, no further analysis for either termined by adding H-H2O to the water contacting the ventral TMAO or TMA was conducted. No significant changes in skin, water influx rates were similar to the water efflux rates plasma ammonia were observed; in both aquatic and air- measured in animals immediately after air exposure. However, exposed animals, ammonia fluctuated between 100 and 200 water influx was slightly lower than efflux in the group that mmol LϪ1 (data not shown). Plasma Naϩand ClϪ concentrations were stable under ter- restrial conditions compared with aquatic conditions, ranging from 100 to 105 mmol LϪ1 and 83 to 99 mmol LϪ1, respectively (Table 1). Similarly, blood hematocrit was also unaltered during air exposure, averaging approximately 30% under aquatic and terrestrial conditions (Table 1). In contrast to the plasma, muscle water content was 5.85 mL gϪ1 dry muscle after 20 wk of air exposure, which was 56% greater than that measured in lungfish held under aquatic con- ditions. Muscle water content was not significantly different from that of aquatic animals after 4 wk of air exposure, however (Fig. 2A). There was substantial urea accumulation in the mus- cle during air exposure, which had increased by fivefold after 4 wk. Most notable was that the eightfold greater muscle urea concentrations observed in lungfish that were exposed to air for 20 wk (Fig. 2B) coincided with the much greater water content that was observed in the muscle at this time (Fig. 2A). There was little change in body mass during 4 wk of air exposure, with the greatest differences occurring after 1 wk, during which time body mass significantly decreased by almost 4%. Although body mass was approximately 5% lower after 4 wk of air exposure, it was similar to original values after 20 wk (Fig. 3A). On reimmersion after 20 wk, body mass was stable for the first 4 h but decreased steadily thereafter. By 8 h, mass had significantly decreased by 5%, and by 24 h it was 20% lower than at the beginning of reimmersion (Fig. 3B). By 72 h, the body mass appeared to have stabilized (Fig. 3B). Figure 2. Differences in muscle water content (A) and urea concen- trations (B) in the slender African lungfish (Protopterus dolloi) under p 3 aquatic conditions (solid bar;N 5 ) and after air exposure (hatched H-H2O Fluxes bars) for 4 wk (N p 5 ) or 20 wk (N p 5 ). Water content expressed Ϫ1 3 as mL of H O g dry muscle . Data presented as themean ϩ 1 SEM. Following IP injection of H-H O, the water efflux rate across 2 2 Asterisks denote statistically significant differences from animals held the body surface of the lungfish was approximately 130 mL under aquatic conditions (P ! 0.05 ), while the dagger indicates water Ϫ1 Ϫ1 Ϫ1 kg h (Fig. 4), with a rate constant (K) of 17.6% h (Table contents significantly different from values measured after 4 wk of air 2). After acute transfer to terrestrial conditions, water efflux exposure. Osmoregulation and Ionoregulation in the African Lungfish 105
Cl Ϫ1 Ϫ1 Jin averaged 20 mmol kg h but in some instances was un- detectable, and the corresponding rate of ClϪ efflux averaged Ϫ75 mmol kgϪ1 hϪ1 (Fig. 7B). Acute air exposure for 8 h led to net Naϩ losses of approximately Ϫ50 mmol kgϪ1 hϪ1, but ClϪ balance was maintained (Fig. 7). The net Naϩ losses were mainly due to an increase in efflux, which increased 10-fold Na during the initial 8 h of air exposure, whileJin averaged ap- proximately 40 mmol kgϪ1 hϪ1 but was not significantly different from aquatic (pre-air-exposure) rates (Fig. 7A). Following 6 Na Cl mo of air exposure, neitherJJnet nor net was significantly different Na Cl Ϫ1 Ϫ1 from 0, andJJin and in averaged 30 and 10 mmol kg h , respectively (Fig. 7). On reimmersion after 4 wk of air exposure, when gill per- fusion and function were presumably resumed (see “Discus- Na sion”), there was an elevation ofJin , which increased by eight- Na fold over the first 4 h (Fig. 8A). AlthoughJin fluctuated between 30 and 60 mmol kgϪ1 hϪ1 between 4 and 24 h, these rates were not significantly different from air-exposed (and aquatic) values (Fig. 8A). Despite greater variability, no significant changes in Cl Jin were observed on reimmersion (Fig. 8B). Net ion losses and acidic equivalent movements were also examined after reimmersion. Although the first 4 h were char- acterized by a significant net loss of ClϪ in these fish (Table 3), Na ϩ Jnet was unaffected. This resulted in a predicted net H loss ϩ p ClϪ Na (predicted net H loss JnetJ net; Wood 1988) of approxi- Figure 3. Changes in the wet body mass (g) of Protopterus dolloi after mately Ϫ290 mmol kgϪ1 hϪ1 (Table 3). Similarly, actual net Hϩ 1, 4, or 20 wk of air exposure (A;N p 6–10 ) and after reimmersion after 20 wk of air exposure (B;N p 4 ). Data expressed as the excretion over this same 0–4 h reimmersion period was ap- Ϫ1 Ϫ1 ϩ -SEM. Asterisks indicate statistically significant differences proximately Ϫ180 mmol kg h (Table 3). This net H ex 1 ע mean between the initial and final masses measured in animals before and after 1, 4, or 20 wk of air exposure (A) or significant differences from mass measured at the beginning of the reimmersion period (B;0h; P ! 0.05). was chronically air exposed for 6 mo (Fig. 4). Since the gills were not immersed, both the water influx and efflux data con- firmed that water exchange was taking place across the ventral surface of the animals, the only region of the body in contact with the water. Although water efflux continued after air exposure, it was significantly reduced (by 55%) within 1 wk and remained de- pressed over 6 mo of air exposure, fluctuating between 45 and 60 mL kgϪ1 hϪ1 (Fig. 5), at which time K ranged between 5.0% and 8.0% hϪ1 (Table 2). When a subgroup of fish were re- immersed after 20 wk of air exposure, there was a three-and- one-half- to fourfold increase in water turnover during the first Figure 4. Water flux measured in Protopterus dolloi held under aquatic 12 h (Fig. 6A), but plasma osmolality was unaltered (Fig. 6B). conditions (N p 8 ), or after acute (4 h;N p 5 ) or chronic (6 mo; N p 4–5) air exposure. The rates of water efflux were measured in aquatic (solid bar) and air-exposed animals after intraperitoneal in- 3 ϩ Ϫ jection of H-H2O(hatched bars). For comparison, water influx was Unidirectional Na and Cl Fluxes also determined in air-exposed animals (open bars) after direct addition ϩ 3 of H-H2O to the water (see text for details). Data presented as the Under aquatic conditions, the lungfish maintained both Na ϩ Ϫ Na Cl mean 1 SEM. The asterisk denotes a statistically significant difference and Cl balance, as bothJJnet and net were not significantly from animals held under aquatic conditions, while the dagger denotes Na Ϫ1 Ϫ1 different from 0. TheJin averaged 15 mmol kg h , with a a significant difference between influx and efflux in the chronically (6 corresponding efflux rate of Ϫ10 mmol kgϪ1 hϪ1 (Fig. 7A). The mo) air-exposed lungfish (P ! 0.05 ). 106 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood
Table 2: Rate constants for water efflux (K) in aquatic and air-exposed Protopterus dolloi, Protopterus annectens, and some other freshwater fish K (% Body Water hϪ1 ) Reference Lungfish: Protopterus dolloi: This study (8) 06. ע Aquatic 17.6 Air-exposed: This study *(5) 1.1 ע h 11.8 4 This study *(6) 1.0 ע1wk 7.4 This study *(6) 9. ע4wk 4.9 This study *(6) 6. ע wk 7.7 20 This study *(5) 8. ע6mo 6.1 Protopterus annectens (aquatic) 44.1 Oduleye 1977 Teleosts: Yelloweel(Anguilla anguilla) 8.6 Evans 1969 Silver eel (Anguilla anguilla) 8.0 Evans 1969 Three-spine stickleback (Gasterosteus aculeatus) 11.0 Evans 1969 Roach (Rutilus rutilus) 13.0 Evans 1969 Brown trout (Salmo trutta) 27.0 Evans 1969 Atlantic salmon (Salmo salar) 47.5 Potts et al. 1970 Goldfish (Carassius auratus) 74.0 Maetz 1970 Killifish (Fundulus kansae) 138.0 Potts and Fleming 1970 Tilapia (Tilapia mossambica) 186.0 Potts et al. 1967 Note. Rate constants (K) for aquatic lungfish and teleosts are based on the combined efflux across the gills and skin, plus renal water losses; .SEM 1 ע data from air-exposed P. dolloi represent efflux across the ventral body surface only. Data from this study are expressed as themean Sample sizes in parentheses. * Statistically significant differences from aquatic values (P ! 0.05 ). cretion was mainly attributable to a lower uptake of titratable was in marked contrast to reports that other African lungfish acid across the body surface, as rates of ammonia excretion experienced pronounced increases in some or all of these pa- were unchanged. Beyond 4 h, there were no further significant rameters over similar or longer periods of estivation in the changes in net ion or net acid movements by the fish (Table laboratory (Smith 1931; Janssens 1964; Johansen et al. 1976b; 3). DeLaney et al. 1977). These differences can probably be ex- plained by the different air exposure methodologies used in the Discussion previous studies, in which the lungfish were held in jars or “estivation sacks” that permitted them to burrow into the mud, The Slender African Lungfish Maintains Osmotic and which was then gradually and completed dried out (Smith 1931; Electrolyte Balance during Air Exposure Janssens 1964; DeLaney et al. 1977). These previous findings The slender lungfish Protopterus dolloi has a remarkable ability led to a proposal that cocoon formation might be triggered by to withstand air exposure under humid conditions for up to internal desiccation (Fishman et al. 1986). Because the slender 6 mo, with no perturbation to osmotic and ion homeostasis. lungfish we examined formed cocoons while maintaining in- A key adaptation appears to be an ability to use the ventral ternal osmotic and ionic balance while exposed to air under body surface to take up water and ions from the thin layer of relatively humid conditions, it suggests that internal desiccation water lining the bottoms of their containers during air expo- may not in fact be a stimulus for cocoon formation and esti- sure. Under aquatic conditions, values of plasma osmolality, vation in the lungfish. Naϩ, and ClϪ were similar to values previously reported in P. Plasma urea concentrations in aquatic P. dolloi were com- dolloi (Ip et al. 2005) and its congener, Protopterus aethiopicus parable with concentrations in previous studies on this species (Delaney et al. 1977). The ability of P. dolloi to produce a cocoon (Lim et al. 2004; Ip et al. 2005; Wood et al. 2005) as well as P. during air exposure is also shared with other species of Pro- aethiopicus (Smith 1930; DeLaney et al. 1977; Loong et al. 2005) topterus (e.g., Smith 1931; Janssens 1964; DeLaney et al. 1977). and Protopterus annectens (Loong et al. 2005). The magnitude However, the absence of any change in osmolality, plasma ions of plasma urea elevation was comparable with increases pre- (Naϩ and Cl Ϫ), or hematocrit during air exposure in P. dolloi viously reported in this species during air exposure (Ip et al. Osmoregulation and Ionoregulation in the African Lungfish 107
Figure 5. Water efflux measured in Protopterus dolloi held under aquatic conditions (solid bar;N p 8 ) and after air exposure (hatched bars) for 4 h (N p 5 ), 1 wk (N p 6 ), 4 wk (N p 6 ), 20 wk (N p 8 ), or 6 mo (N p 5 ). Data presented as themean ϩ 1 SEM. Asterisks denote statistically significant differences from animals held under aquatic conditions (P ! 0.05 ). Note that the rates of efflux under aquatic conditions and after 4 h and 6 mo of air exposure were presented in Figure 4, but they were replotted here for reference.
2005; Wood et al. 2005) but less than in other species of es- tion, desiccation (e.g., Johansen et al. 1976b; DeLaney et al. tivating Protopterus (Smith 1930; Janssens 1964; DeLaney et al. 1977) probably leads to contraction of the extracellular and 1977; Ip et al. 2005). The accumulation of urea may not have intracellular spaces, thereby concentrating urea. However, the been as great in our study as in fully estivating lungfish due to extracellular and intracellular fluid volumes are probably ex- extrabranchial urea excretion. Indeed, recent divided-chamber panded by the above-described water uptake during air ex- experiments have revealed that extrabranchial urea excretion posure in P. dolloi, which would dilute urea in the plasma and sites such as the skin and/or renal routes made equal contri- other body compartments. This explanation is supported by butions to ammonia and urea excretion in water (Wood et al. the 56% increase in muscle water content (Fig. 2A) observed 2005). Although significant renal urea excretion is less likely in after 20 wk of air exposure and the high urea concentrations air, due to the possibility of oliguria (cessation of urination; in this compartment (Fig. 2B). If it is assumed that the lungfish Smith 1930; DeLaney et al. 1977), it is likely that significant body mass was 60% muscle, this would be equal to a net water cutaneous urea excretion did occur, as recently demonstrated gain of 32.3 mL in a 100-g animal. Such a large increase in in air-exposed P. dolloi by Wood et al. (2005). muscle water content would therefore mask a much larger in- Functioning as an osmolyte, urea retention would lower the crease in muscle urea content than the eightfold increase ob- vapor pressure of the body fluids (Kirschner 1991), leading to served when wet muscle mass was considered (Fig. 2B). Indeed, lower rates of evaporative water loss in the air-exposed lungfish. when expressed per gram dry muscle, urea concentration in- However, its accumulation in the muscle could also generate creased 13-fold from approximately 44 mmol gϪ1 dry muscle critical osmotic gradients to promote water entry into this com- in aquatic animals to an average of 570 mmol gϪ1 dry muscle partment during air exposure. Thus, the muscle could serve as after 20 wk air exposure. a “water reservoir” that could release water to the interstitial Urea accumulation and subsequent water uptake and storage space and plasma if the osmolality of the extracellular fluid in the muscle by the lungfish also explains the smaller than were to increase during prolonged air exposure or estivation. expected losses of body mass after 4 wk and the absence of Collectively, these strategies could delay the onset of hemo- change in body mass observed after 20 wk air exposure and concentration, that is, osmotic and ionic disturbances that are starvation in P. dolloi (Fig. 3). The approximately 20% decrease characteristic of estivation in lungfish (Delaney et al. 1976, (31.6 g; Fig. 3B) in body mass during the first 48–72 h of 1977; Johansen et al. 1976b). Indeed, P. dolloi live in marginal, reimmersion was probably due to increased water efflux, which swampy habitats where they may be subject to temporary would have been accompanied by very high rates of urea ex- periods of air exposure during which the gills would be in- cretion following submersion (Smith 1930; Wood et al. 2005). operative for osmo- or ionoregulation. Under such conditions, Indeed, the period of greatest water loss was from 6 to 24 h, water and ion uptake through the ventral body surface and which corresponds with the period of greatest urea excretion urea accumulation and water storage in the muscle could be in P. dolloi during reimmersion reported by Wood et al. (2005). essential for maintaining osmotic and ionic homeostasis. Further, the loss of body mass observed during reimmersion
In lungfish undergoing prolonged (several months) estiva- was equivalent to approximately 28 mL H2O for a 100-g lung- 108 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood
wk exposure period, thereby allowing the air-exposed lungfish to accumulate and store water in excess of 20 mL (20 g). Indeed, similar factors likely explain why P. annectens lost little mass (only approximately 6%) when estivated in the laboratory for approximately 6 mo (Janssens 1964). Although a cocoon was present in that study, weight loss was probably reduced because the mud into which the fish had burrowed was not dried out completely (Janssens 1964). To offset urea’s perturbing effects, the counterbalancing sol- ute TMAO is also retained in the plasma and tissues of elas- mobranchs (Ballantyne 1997; Yancey 2001). Although we sus- pected that TMAO could play a similar role in P. dolloi,we were unable to detect TMAO or its precursor TMA in the plasma. Perhaps there is little selective pressure to offset the possible inhibition of metabolic enzymes by urea because it might actually provide a mechanism of metabolic downregu- lation during air exposure and/or estivation (Smith 1930; Jans- sens 1964). Against this hypothesis is the work of Grundy and Storey (1994), who demonstrated that the kinetic properties of pyruvate kinase and phosphofructokinase in skeletal muscle homogenates of estivating spadefoot toads and nonestivating
Figure 6. Differences in water efflux (A) and plasma osmolality (B) measured in Protopterus dolloi held under terrestrial conditions (hatched bar) and during the first 12–24 h after reimmersion (open bars). For water efflux,N p 8 during air exposure andN p 4 when reimmersed. For plasma osmolality measurements,N p 15 for air- exposed lungfish (replotted from Fig. 1 and included for reference) andN p 8 after 8 h and 24 h of reimmersion. Data presented as the mean ϩ 1 SEM. Asterisks denote statistically significant differences from air-exposed animals (P ! 0.05 ).
fish, which is very close to the net gain in muscle H2O (32.3 mL) calculated above, and lends further support to this “water unloading” hypothesis. The three- to fourfold increase in 3H-
H2O efflux observed in reimmersed P. dolloi (Fig. 6A) also suggests that there was considerable water loss during re- immersion. It should also be noted that reimmersion was prob- ably accompanied by diuresis, which would also contribute to net water loss during reimmersion and should be investigated Figure 7. Unidirectional Naϩ and ClϪ fluxes measured in Protopterus in future studies. dolloi held under aquatic conditions (N p 4 ) and during acute air At first glance, it may be difficult to reconcile how the mass exposure for 8 h (N p 6 ) or chronic air exposure for 6 mo (N p 5 ). Na Cl Bars above the 0 baseline represent rates of ion influx (JJin , in ); bars gain by the air-exposed lungfish could exceed 20 g when the Na Cl below the 0 baseline depict ion efflux (JJout , out ), while solid bars rep- ע water volume lining the bottom of its chamber was only ap- ionp ionϩ ion resent the net flux (JnetJ inJ out ). Data presented as the mean proximately 20 mL. However, it should be noted that the water 1 SEM. Asterisks denote statistically significant differences from ani- in the chamber was regularly replenished (weekly) over the 20- mals held under aquatic conditions (P ! 0.05 ). Osmoregulation and Ionoregulation in the African Lungfish 109
water fluxes revealed appreciable water movement across the ventral body surface of P. dolloi during air exposure. Because water flux during initial air exposure (4 or 8 h) was not sig- nificantly different from the aquatic condition, our findings suggest that the majority of water exchange is ventral, even when the animals are submersed in water. We also measured unidirectional water influx by tracking decreases in external 3 H-H2O radioactivity that was added to the bath in acutely (4 h) and chronically (6 mo) air-exposed animals. Water influx approximately equaled water efflux measured in the acutely air- exposed animals but was slightly lower in the chronically air- exposed animals. Nevertheless, these findings not only validated our protocol but also confirmed our hypothesis of ventral water exchange (Fig. 4). Sturla and colleagues (2001) demonstrated that the dorsal and ventral skin of P. annectens contains mitochondria-rich (MR) cells similar to those found in the fish gill. This indicates that the skin in African lungfish probably has an ionoregulatory Figure 8. Rates of Naϩ influx (A) and ClϪ influx in (B) Protopterus role (see below), as has been well established in amphibian skin dolloi after 4 wk of air exposure (N p 9 ) and the first 24 h following (e.g., Koefoed-Johnsen and Ussing 1958; Ehrenfeld and Garcia- p Na p Cl reimmersion (N 15–16 forJNin ;11 forJin ). Data presented as Romeu 1977; Ehrenfeld et al. 1989). Further, water and ion ϩ themean 1 SEM. Asterisks denote statistically significant differences uptake are both known to take place in the ventral pelvic region from air-exposed animals (P ! 0.05 ). of amphibians (pelvic patch; Toledo and Jared 1993), which also contains aquaporins, as recently demonstrated in the tree leopard frogs (Rana pipiens) were virtually unaffected by urea Ϫ1 frog (Hyla japonica; Hasegawa et al. 2003). The possibility of (up to 600 mmol N L ) and TMAO. Studies on a greater an analogous ion and water transport region in lungfish offers number of amphibians and lungfish are clearly required to potentially exciting insight on the mechanisms and evolution determine whether enzyme inhibition by urea is an important of ion and water transport in vertebrates. aspect of metabolic downregulation in at least some of these A notable effect of air exposure was the persistent 40%–70% animals. decrease in overall water flux across the ventral body surface after approximately 1 wk (Fig. 5). Since plasma osmolality was stable during air exposure, the fish were more or less in an Extrabranchial Route(s) of Water Exchange osmotic steady state by this time. Thus, the reduction in water In water, the tritiated water flux constant (K) was approxi- flux might be a consequence of decreases in evaporative water mately 18% hϪ1. While low, this indicates that the overall water loss due to complete formation of the water resistant cocoon permeability of P. dolloi was merely at the low end of the range covering the dorsolateral body surface. In some Australian des- for freshwater fish (Table 2), somewhat surprising given the ert frogs, African ranids, and South American frogs, cocoon lungfish’s greatly reduced gill (Burggren and Johansen 1986). formation reduced water loss by 80%–90% during prolonged Anatomically, the gills of Protopterus lack filaments and sec- estivation (Toledo and Jared 1993). Although the cocoon’s role ondary lamellae on the anterior gill arches, and lamellar per- in reducing evaporative water loss in the lungfish is a frequent fusion is drastically reduced to the posterior arches during air subject of speculation, we are aware of no studies that have exposure and after lung breaths due to the opening of arterio- quantified it. Regardless, our findings support the supposition arterial shunts (Laurent et al. 1978). Based on this evidence, that lungfish efficiently extract available water from their ex- we had hypothesized that water turnover would be lower than ternal surroundings to stay hydrated during air exposure and values reported in exclusively aquatic fish. As our data did not probably also during the initial stages of estivation. support this hypothesis, they suggest that an additional site of water exchange was the skin. Ion Uptake Continues in Air Few studies have examined the skin of lungfish (e.g., Kitzan and Sweeney 1968; Sturla et al. 2001, 2002). Graham (1997) Inspection of the electron micrographs and immunohisto- reported that supradermal capillary density in P. annectens was chemistry of the skin and gills of P. annectens (Sturla et al. comparable with the density in many frogs, in which the critical 2001) suggests the MR cells are fewer in number and size com- role of the skin for water uptake is firmly established (for re- pared to teleosts (Perry 1997; Marshall 2002). These observa- views, see Toledo and Jared 1993; Jørgensen 1997). Tritiated tions, combined with the lungfish’s reduced gill (Laurent et al. 110 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood
Table 3: Predicted and actual net acid fluxes (mmol kgϪ1 hϪ1) across the body surface of Protopterus dolloi after 6 mo of air exposure and during reimmersion Reimmersion (N p 5) Terrestrial (N p 9) 0–4 h 4–8 h 8–12 h 115.3 ע Ϫ94.3 94.6 ע 320.8 *100.8 ע Ϫ281.9 4.4 ע Net ClϪ flux Ϫ28.1 154.0 ע Ϫ139.6 68.9 ע Ϫ60.7 112.9 ע 9.6 2.4 ע Net Naϩ flux Ϫ6.6 128.8 ע 45.2 89.6 ע 381.5 169.2 ע Ϫ291.4 2.9 ע Predicted net Hϩ flux Ϫ21.6 37.9 ע 155.0 27.1 ע 250.1 *38.6 ע Titratable acid flux … Ϫ8.3 41.8 ע Ϫ192.0 66.7 ע Ϫ168.6 30.6 ע Ammonia flux … Ϫ171.0 51.3 ע Ϫ37.0 80.4 ע 81.5 *45.7 ע Actual net Hϩ flux … Ϫ179.3 .SEM 1 ע Note. Data expressed as themean * Significant difference from values measured during the 4–8-h and 8–12-h flux periods following reimmersion (P ≤ 0.05 ).
1978; Burggren and Johansen 1986), suggested that P. dolloi osmoregulation and ionoregulation between lungfish and would have low basal rates of ion uptake. Indeed, rates of amphibians. unidirectional Naϩ and ClϪ influx were more than 90% lower The increase in Naϩ influx observed immediately after re- than values typically measured in comparably sized freshwater immersion was probably related to reperfusion of blood to the fish ranging from lampreys (Wilkie et al. 1998) to teleosts gills. Similar increases in urea excretion are also thought to be (Evans 1979; Wood 1988; Goss et al. 1992). Influx was more at least partially attributable to this factor in African lungfish or less balanced by similarly low rates of diffusive efflux (out- (Smith 1930; Wood et al. 2005). It is tempting to speculate that flux) for both Naϩ and Cl Ϫ. These data suggest that, compared the increase in Naϩ influx was related to the large surge of urea with gills in other freshwater fish, the lungfish gill has low ion excretion (2,000–4,000 mmol kgϪ1 hϪ1), which reportedly occurs permeability. Since lungfish are likely capable of surviving un- at this time and is proposed to involve facilitated and/or active der a variety of harsh conditions, including acidic, hypoxic/ urea transport (Wood et al. 2005), but more detailed exami- anoxic, and hypercapnic exposures, gills of low ion and gas nations are needed. permeability could be adaptive. In addition to preventing the The movements of Naϩ and ClϪ might also be manipulated diffusional loss of O2 across the gills to O2-depleted waters, for the purpose of acid-base regulation after reimmersion. Due ϩ Ϫ ϩ diffusional uptake of H (equals loss ofHCO3 ) or CO2 would to the need to maintain electroneutrality, loss of either Na or also be expected to be lower. Indeed, the nests used by P. dolloi ClϪ across an epithelial surface must be accompanied by re- Ϫ ϩ ϩ during the dry season and for breeding are characterized by spective losses ofHCO3 (or H uptake as a counterion) or H Ϫ low pH (4.7–6.5), high CO2, and low O2 (Brien et al. 1959, (orHCO3 uptake) according to the strong ion difference theory cited by Greenwood 1986). (Stewart 1983; Goss and Wood 1991). Although we did not Our data do differ from those of Oduleye (1977), who re- measure internal acid-base status, the relatively short-term, ϩ Hϩ ported that the unidirectional efflux of Na by P. annectens was slight stimulation ofJnet after reimmersion indicates that pH approximately 250–500 mmol kgϪ1 hϪ1 after injection of 22Naϩ. disturbances were probably minimal during air exposure. This Hϩ One possible explanation for this discrepancy is interspecific slight stimulation ofJnet appeared to result from greater net variation between P. dolloi and P. annectens. Indeed, Perry et ClϪ versus Naϩ losses (Table 3). Between 8 and 12 h, however, al. (2005) recently reported that unlike in P. annectens and P. the fish appeared to be in acid-base balance when titratable aethiopicus (McMahon 1970; Burggren and Johansen 1986), acid uptake was balanced by the stable, outward ammonia flux. most CO2 unloading in P. dolloi was via the lungs and not the gills. Other factors that might explain these discrepancies in Implications of Water and Ion Uptake during Estivation ion efflux rates include differences in body size, life stage, and methodology (isotope injection vs. addition to the water [this In many animals, torpor and hibernation are methods of last study]). resort in response to not only changes in water availability but Uptake of Naϩ and ClϪ clearly occurred through the ventral also temperature extremes, resource limitations, and/or de- skin during air exposure. The aforementioned presence of MR creases in oxygen availability. Recovery from such drastic sur- cells in both the dorsal and ventral skin of P. annectens (Sturla vival strategies can also be energetically expensive as animals et al. 2001) is in accord with these data. Because MR cells are attempt to reestablish homeostasis. In the African lungfish, es- also present in amphibian skin (Ehrenfeld et al. 1989), our data tivation is the most extreme response to reductions in water complement the morphological findings of Sturla et al. (2001, availability. Our study demonstrates that the amphibian-like 2002) and their prediction of a “convergence of strategies” of ability of P. dolloi to take up water and to exchange ions and Osmoregulation and Ionoregulation in the African Lungfish 111 acidic equivalents with its environment via the ventral body of the African lungfish Protopterus aethiopicus: cardiovascular surface enables this fish to withstand less extreme and tem- and respiratory functions. J Exp Biol 61:111–128. porary shortages of water without having to enter estivation. Delaney R.G., S. Lahiri, R. Hamilton, and A.P. Fishman. 1977. Moreover, by minimizing internal osmotic and ionic distur- Acid-base balance and plasma composition in the aestivating bances during air exposure, the animals probably recover more lungfish (Protopterus). Am J Physiol 23:R10–R17. rapidly after water restriction and therefore minimize energy Ehrenfeld J. and F. Garcia-Romeu. 1977. Active hydrogen ex- expenditures during recovery. We propose that the combination cretion and sodium absorption through isolated frog skin. of ventral skin water permeability and internal urea accumu- Am J Physiol 233:F46–F54. lation during air exposure allows P. dolloi to extract water from Ehrenfeld J., I. Lacoste, and B.J. Harvey. 1989. The key role of its surroundings and to store water in the muscle when water mitochondria-rich cell in Naϩ and Hϩ transport across the supply becomes limited. Since ammonia excretion continues frog skin epithelium. Pflu¨g Arch 414:59–67. during air exposure (Wood et al. 2005; Loong et al. 2005), our Evans D.H. 1967. Sodium, chloride, and water balance of the findings also suggest that the primary selective pressure for urea intertidal teleost, Xiphister atropurpureus. III. The roles of production and retention in estivating lungfish is water con- simple diffusion, exchange diffusion, osmosis and active servation rather than ammonia detoxification. transport. J Exp Biol 47:525–534. ———. 1969. Studies on the permeability of selected marine, freshwater and euryhaline teleosts. J Exp Biol 50:689–703. Acknowledgments ———. 1979. Fish. Pp. 305–391 in G.M.O. Maloiy, ed. Com- parative Physiology of Osmoregulation in Animals. Aca- We thank Drs. C. Glover, L. Diao, S. Nadella, and R. Kent, and demic Press, New York. M. Patel for their invaluable assistance with sample collection Fishman A.P., A.I. Pack, R.G. Delaney, and R.J. Gallante. 1986. and analysis, and M. Patel, C. Bucking, and the McMaster Estivation in Protopterus. J Morphol 1(suppl.):237–248. University Animal Care Staff for their assistance in the mon- Goss G.G., P. Laurent, and S.F. Perry. 1992. Evidence for a itoring and care of our colony of Protopterus dolloi.Wearealso morphological component in acid-base regulation during en- grateful to Dr. S. F. Perry, University of Ottawa; Dr. P. J. Walsh, vironmental hypercapnia in the brown bullhead (Ictalurus University of Ottawa/University of Miami; and Dr. M. Grosell, nebulosus). Cell Tissue Res 268:539–552. University of Miami; for their helpful insight and suggestions. Goss G.G. and C.M. Wood. 1991. Two-substrate kinetic anal- The constructive comments of two anonymous reviewers were ysis: a novel approach linking ion and acid-base transport also appreciated. This investigation was funded by a Natural at the gills of freshwater trout, Oncorhynchus mykiss. J Comp Sciences and Engineering Research Council Discovery grant to Physiol B 161:635–646. C.M.W., who is also supported by the Canada Research Chair Graham J.B. 1997. Air-BreathingFishes: Evolution, Diversity program. and Adaptation. Academic Press, San Diego, CA. Greenwood P.H. 1986. The natural of history of African lung- Literature Cited fishes. J Morphol 1(suppl.):163–179. Grundy J.E. and K.B. Storey. 1994. Urea and salt effects on Ballantyne J.S. 1997. Jaws: the inside story. The metabolism of enzymes from estivating and non-estivating amphibians. Mol elasmobranch fishes. Comp Biochem Physiol B 118:703–742. Cell Biochem 131:9–17. Burggren W.W. and K. Johansen. 1986. Circulation and res- Hasegawa T., H. Tanii, M. Suzuki, and S. Tanaka. 2003. Reg- piration in lungfishes (Dipnoi). J Morphol 1(suppl.):217– ulation of water absorption in the frog skins by two vaso- 236. tocin-dependent water-channel aquaporins, AQP-h2 and Chew S.F., N.K.Y. Chan, A.M. Loong, K.C. Hiong, W.L. Tam, AQP-h3. Endocrinology 144:4087–4096. and Y.K. Ip. 2004. Nitrogen metabolism in the African lung- Ip Y.K., P.J. Yeo, A.M. Loong, K.C. Hiong, W.P. Wong, and S.F. fish (Protopterus dolloi) aestivating in a mucus cocoon on Chew. 2005. The interplay of increased urea synthesis and land. J Exp Biol 207:777–786. reduced ammonia production in the African lungfish Pro- Chew S.F., T.F. Ong, L. Ho, W.L. Tam, A.M. Loong, K.C. Hiong, topterus aethiopicus during 46 days of aestivation in a mucus W.P. Wong, and Y.K. Ip. 2003. Urea synthesis in the African cocoon. J Exp Zool 303A:1054–1065. lungfish Protopterus dolloi: hepatic carbamoyl phosphate syn- Janssens P.A. 1964. The metabolism of the aestivating African thetase III and glutamine synthetase are upregulated by 6 lungfish. Comp Biochem Physiol 1:105–117. days of aerial exposure. J Exp Biol 206:3615–3624. Janssens P.A. and P.P. Cohen. 1968. Biosynthesis of urea in the Delaney R.G., C. Chub, and A.P. Fishman. 1976. Hematologic estivating African lungfish and Xenopus laevis under con- observations on the aquatic and estivating African lungfish ditions of water shortage. Comp Biochem Physiol 24:887– Protopterus aethiopicus. Copeia 3:423–434. 898. Delaney R.G., S. Lahiri, and A.P. Fishman. 1974. Aestivation Johansen K., J.P. Lomholt, and G.M.O. Maloiy. 1976a. Impor- 112 M. P. Wilkie, T. P. Morgan, F. Galvez, R. W. Smith, M. Kajimura, Y. K. Ip, and C. M. Wood
| https://docslib.org/doc/6204431/the-african-lungfish-protopterus-dolloi-ionoregulation-and-osmoregulation-in-a-fish-out-of-water |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Report
Themes
Assistive & Accessible Technology
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Vicki Austin,Dilisha Patel,Jamie Danemayer,Kate Mattick,Anna Landre,Marketa Smitova,Maryam Bandukda, Aoife Healy, Nachiappan Chockalingam,Diane Bell,Cathy Holloway
This report was prepared by Global Disability Innovation (GDI) Hub for the Disability Unit in the Cabinet Office His Majesty’s Government (HMG). The report presents findings from a Country Capacity Assessment (CCA) of AT access in England. Findings illustrate a complex state of AT in England. While delivery systems tend to provide quality products that have a strong, positive impact on people’s lives, processes are often slow and stressful for users and providers alike. Startlingly, there is also an AT access gap of 31% of disabled people not having the assistive products they need to flourish, thrive, or even participate in daily life.
The Cabinet Office; 2023
Abstract
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
The aim of this research was to undertake a Country Capacity Assessment (CCA) to inform a more integrated approach to Assistive Technology (AT) provision in England. The results aim to support policymakers in identifying actions to strengthen service delivery to better meet disabled people’s needs, improving outcomes for AT users and reducing inefficiencies in the current approach.
The research was undertaken from November 2022 to March 2023 and led by the Global Disability Innovation (GDI) Hub, which is the World Health Organization (WHO) Global Collaborating Centre on AT access, using WHO tools in the Assistive Technology Assessment (ATA) suite.
Cite
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Suggested Citation: Austin, V, Patel, D, Danemayer, J, Mattick, K, Landre, A, Smitova, M, Bandukda, M, Healy, A, Chockalingam, N, Bell D, and Holloway, C; Assistive Technology Changes Lives: an assessment of AT need and capacity in England; Cabinet Office, HMG; 2023
Assistive Technology Changes Lives: an assessment of AT need and capacity in England
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
Cite
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Cite
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Cite
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Assistive Technology (AT), for What?
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Chapal Khasnabis,Catherine Holloway, Malcolm MacLachlan
We are now in an era of assistive care and assistive living—whereby many people, of all ages, in good health, and those who are more frail, or with cognitive or functional impairments, are using a broad range of technologies to assist and enhance their daily living. Assistive living 1is becoming an important part of population health and rehabilitation, which can help to maximise an individual's abilities, regardless of age or functional capacity. This encouraging shift in ethos has been strengthened by the response to the COVID-19 pandemic, in which a plethora of digital and remote technologies have been used.
The Lancet; 2020
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Type
Editorial
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Social Justice
Critical Junctures in Assistive Technology and Disability Inclusion
Dr Maria Kett,Catherine Holloway,Vicki Austin,Dr Maria Kett
It is clear from the events of the last 18 months that while technology has a huge potential for transforming the way we live and work, the entire ecosystem—from manufacturing to the supply chain—is vulnerable to the vagaries of that ecosystem, as well as having the potential to exacerbate new and existing inequalities [1]. Nowhere has this been more apparent than in the lives of people with disabilities, who make up around 15% of the world’s population and already face barriers to accessing education, employment, healthcare and other services [2]. Some of these barriers are a result of unequal access and opportunities. However, there is a growing movement to better understand how assistive technology systems and services can be designed to enable more robust and equitable access for all. As part of this growing movement, the Paralympic Games in Tokyo this autumn saw the launch of a new global campaign to transform the lives of the world’s 1.2 bn persons with disabilities: the ‘WeThe15’ campaign reached more than 4.5 billion people through its marketing and stands ready to be the biggest of its kind in history. Next year, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), AT scale and GDI Hub will publish the first World Report on Access to Assistive Technology, which will include research from the £20 million, UK Aid funded, GDI Hub-led, programme, AT2030. Ahead of that, in this Special Issue, we focus on how some events and situations—as diverse as the coronavirus pandemic and the Paralympics—can act as ‘critical junctures’ that can enable a rethink of the status quo to facilitate and promote change.
Sustainability; 2021
Critical Junctures in Assistive Technology and Disability Inclusion
Kett, M.; Holloway, C.; Austin, V. Critical Junctures in Assistive Technology and Disability Inclusion. Sustainability2021, 13, 12744.https://doi.org/10.3390/su1322...
Critical Junctures in Assistive Technology and Disability Inclusion
| https://www.disabilityinnovation.com/publications?subject=design+prosthetics&type=toolkit+editorial+phd+report |
Nimbha Branch Post Office, Hinganghat 01, Wardha, Maharashtra
Get Nimbha post office address, pincode, phone number, Nimbha speed post tracking, saving scheme and location map.
Nimbha Post Office, Hinganghat
Nimbha Post Officeis located at Nimbha, Hinganghat, Wardhaof Maharashtra state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Nimbha POis 442301. This Postoffice falls under Wardha postal division of the Maharashtra postal circle. The related head P.O. for this branch office is Wardha head post office and the related sub-post office (S.O.) for this branch office is Hinganghat post office.
Nimbha dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Nimbha. The official website fo this PO is http://www.indiapost.gov.in.
Types of Post Offices
are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Nimbha P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Nimbha Post Office & Its Pin Code
Branch Office Information
Nimbha Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Nimbha Post Office Recruitment
Location Map
Contact Details
About India Post
Nimbha Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Nimbha Post Office has the Postal Index Number or Pin Code 442301. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Nimbha PO Pincode 442 301
The first digit of 442301 Pin Code '4' represents the region, to which this Post Office of Nimbha belongs to. The first two digits of the Pincode '44' represent the sub region, i.e, Maharashtra. The first 3 digits '442' represent the post-office revenue district, i.e, Wardha. The last 3 digits, i.e, '301' represent the Nimbha Delivery Branch Office.
Branch Office Information
The Nimbha Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Wardha, which falls under Nagpur region. The circle name for this PO is Maharashtra and it falls under Hinganghat Taluka and Wardha District. The state in which this Dakghar is situated or located is Maharashtra. The related head postoffice is Wardha post office and the related sub post office is Hinganghat post-office. The phone number of Nimbha post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Wardha Postal Region Nagpur Postal Circle Maharashtra Town / City / Tehsil / Taluka / Mandal Hinganghat District Wardha State Maharashtra Related Sub PO Hinganghat Sub Office Related Head PO Wardha Head Post Office
Nimbha Post Office Services
Traditionally the primary function of Nimbha post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Nimbha P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Nimbha and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Nimbha Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Nimbha can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Nimbha peoples and nearby living people. The premium services provided by Nimbha Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Nimbha customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Nimbha Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Nimbha postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Nimbha postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Nimbha people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Nimbha post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Nimbha customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Nimbha customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Nimbha postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Nimbha can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Nimbha area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Nimbha postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Nimbha postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/- and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 08:00 AM or 09:00 AM or 10:00 AM and the closing time is 04:00 PM or 05:00 PM or 06:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Nimbha Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Nimbha people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Nimbha Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Nimbha postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Nimbha Post Office Recruitment
For latest Nimbha post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Nimbha Branch Post Office is located in Nimbha, Hinganghat, Wardha.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc.services in Nimbha Post Office, can be resolved at Nimbha Branch Post Office. You can send letters to "Postmaster, Nimbha Branch Post Office, Nimbha, Hinganghat, Wardha, Maharashtra, India, Pincode: 442 301". The official website of the Berhampur University Sub Office is http://www.indiapost.gov.in.
Nimbha Branch Office
Address: Nimbha Branch Post Office, Nimbha, Hinganghat, Wardha , Maharashtra , India
Pin Code: 442301
Website: www.indiapost.gov.in
About India Post
India Postis a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the Indiawith over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Nimbha Post Office Summary
Dak Ghar Name Nimbha Branch Post Office Pincode 442301 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Wardha Postal Region Nagpur Postal Circle Maharashtra Location Nimbha Town / City / Tehsil / Taluka / Mandal Hinganghat District Wardha State Maharashtra Country India Related Sub Office Hinganghat Sub Office Related Head Office Wardha Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
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The Centre for Internet and Society
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<title>
Bangalore Meet-up for the Open Government Partnership Brasilia
<link>
https://cis-india.org/openness/open-government-partnership-brasilia-bangalore-meetup
<description>
<b>The international Open Government Partnership (OGP) is holding its first annual meeting on April 17 and 18, 2012. Representatives from over 50 member countries will gather in Brasilia to celebrate the progress that has been made to date, to exchange best practices, and to grow and strengthen the global collaborative network of open government leaders. Bangalore meet-up at CIS on April 17, 2012 from 5.30 p.m to 7.30 p.m.</b>
<p>Those who work on open government initiatives but unable to attend in person, can still participate remotely. OGP has tied-up with a number of external partners to make arrangements for people to participate in the event online. There will be live webcasts, interviews and chats. Viewers will be able to pose questions to those being interviewed and will be polled in real-time to see who is watching, where they are, what their interests are and what are their thoughts on the programme.</p>
<p>The two day meeting offers an opportunity for open government advocates throughout the world to connect with local civic activists and public officials as well as those working on similar problems in other countries.</p>
<p>The Centre for Internet & Society is hosting the Bangalore meet-up on April 17 and 18, 2012. Get together to watch the live video stream, engage in conversations via live chat, or on Twitter and Facebook for discussing plans to move open government forward in your region.</p>
<p><a class="external-link" href="http://www.opengovpartnership.org/civil-society-participation-april-2012-ogp-annual-meeting">Click</a> for the full list of countries participating in the event.</p>
<hr />
<p class="p7"><span class="s1"><strong>8:30-9:30 am</strong></span><span class="s2"><strong> </strong></span><span class="s4"><strong>Registration</strong></span><span class="s2"><strong> & Coffee</strong></span></p>
<p class="p8"><span class="s5"><strong>9:15-9:30 am</strong></span><span class="s2"><span class="Apple-tab-span"> </span><strong>Official photo </strong>of </span><span class="s1"><strong>OGP Member Government Heads of Delegation </strong></span><span class="s2">and </span><span class="s1"><strong>Steering Committee Members </strong></span></p>
<p class="p10"><span class="s5"><strong>9:30-10:15 am</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Opening Remarks and </strong></span><span class="s4"><strong>Welcome</strong></span></p>
<ul><li><span class="s1"><strong>The Honorable Dilma Rousseff, </strong></span><span class="s1">President of the Federative Republic of </span><span class="s4">Brazil</span></li><li><span class="s1"><strong>The Honorable Hillary Rodham Clinton, </strong></span><span class="s1">Secretary of State of the </span><span class="s4">United States of America</span></li><li><span class="s1"><strong>The Honorable</strong> <strong>Jakaya Kikwete, </strong></span><span class="s1">President of the United Republic of </span><span class="s4">Tanzania</span></li><li><strong>The Honorable</strong> <strong>Nika Gilauri, </strong><span class="s1">Prime Minister of </span><span class="s4">Georgia</span></li></ul>
<p class="p11"><span class="s5"><strong>10:15-10:45 am</strong></span><span class="s4"><strong> </strong></span><span class="s1"><strong>Setting the Stage for the Age of Open:</strong></span><span class="s4"><strong> OGP 2012</strong></span></p>
<ul><li><span class="s1">Minister <strong>Jorge Hage</strong>, </span><span class="s4">Brazil</span></li><li><span class="s1">Under Secretary of State <strong>María Otero</strong>, </span><span class="s4">United States</span></li><li><span class="s2"><strong>Warren Krafchik</strong>, </span><span class="s1">International Budget Partnership</span></li></ul>
<p class="p10"><span class="s5"><strong>10:45-11:15 am</strong></span><span class="s1"><strong> </strong></span><span class="s4"><strong>Coffee</strong></span><span class="s1"><strong> and Networking </strong></span></p>
<p class="p16"><span class="s5"><strong>11:15-12:30pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Plenary: Using </strong></span><span class="s4"><strong>Transparency</strong></span><span class="s1"><strong> to Transform </strong></span><span class="s4"><strong>Lives</strong></span><span class="s1"><strong> Online and Offline</strong></span></p>
<ul><li><strong>Secretary of the Interior Kenneth Salazar</strong>, United States</li><li><span class="s1"><strong>Gautam John</strong>, Akshara Foundation and TED Fellow,</span><span class="s6"> </span><span class="s1"> </span><span class="s4">India</span></li><li><span class="s1"><strong>Elisabeth Ungar Bleier</strong>, Transparency International, </span>Colombia</li><li><span class="s1"><strong>Juliana Rotich</strong>, Co-Founder of Ushahidi, </span><span class="s4">Kenya</span></li></ul>
<p class="p10"><em><span class="s1">Moderated by Samantha Power, The White House, </span><span class="s4">United States</span></em></p>
<p class="p20"><span class="s7"><strong>12:30-1:30 pm</strong></span><span class="s8"><strong> </strong></span><span class="s9"><strong>Innovation</strong></span><span class="s8"><strong> Village </strong></span><span class="s1">of Regional Government, Private Sector, and Civil Society organizations advancing Open Government </span></p>
<p class="p16"><span class="s5"><strong>1:30-2:45 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span></strong></span><span class="s2"><strong>Lunch and </strong></span><span class="s4"><strong>Networking.</strong></span></p>
<p class="p16">Lunch will be provided onsite at the conference center. </p>
<p class="p5"><span class="s5"><strong>2:45-5:30 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Open Government </strong></span><span class="s4"><strong>on the Move</strong></span><span class="s1"><strong>: The OGP Country </strong></span><span class="s4"><strong>Action</strong></span><span class="s1"><strong> Plans in Two Parts</strong></span></p>
<p class="p22"><em><span class="s1">In Part I and Part II of regional
breakout sessions, government ministers and leading civil society
activists will discuss country action plans and how to promote a race to
the top on open government in each region. Highlights from each panel
will be transcribed. Moderators will encourage discussion with the
audience following comments from panelists. </span></em><strong><em>Governments
not presenting in Part I will present in Part II of the regional
sessions, from 4:30 to 5:45pm. Participants presenting in Part II are
encouraged to attend the session of their choice during Part I and vice
versa.</em></strong></p>
<p class="p5"><span class="s5"><strong>2:45-4:00pm</strong></span><span class="s2"><strong><span class="Apple-tab-span"> </span><span class="Apple-tab-span"> </span></strong></span><span class="s1"><strong>Country Action Plans </strong></span><span class="s2"><strong>PART I </strong></span></p>
<p class="p5"><strong>South America, I</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Chile</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Colombia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Uruguay</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Brazil</strong></span></li><li>Maria Ferrari Fontecilla, Participa, Chile</li><li>Edison Lanza, CAInfo, Uruguay</li></ul>
<p class="p22"><em><span class="s1">Moderated by Juan Pardinas, IMCO, Mexico</span></em></p>
<p class="p26">C<strong>entral America and Caribbean</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Honduras</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Guatemala</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>El Salvador</strong></span></li><li><span class="s2">Government of </span><span class="s1"><strong>Dominican Republic</strong></span></li><li><span class="s1">Jose Ricardo Barrientos Quezada, ICEFI, Guatemala</span></li><li><span class="s1">Carlos Hernandez, Asociación para una Sociedad más Justa, Honduras</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Vonda Brown, Open Society Foundation, United States</span></em></p>
<p class="p22"><strong>Africa, I</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Liberia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Ghana</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>South Africa</strong></span></li><li><span class="s1">Alison Tilley, Open Democracy Advice Center, South Africa</span></li><li><span class="s1">Vitus Azeem, Ghana Integrity Initiative, Ghana</span></li></ul>
<p class="p22"><span class="s1">Moderated by Rakesh Rajani, Twaweza, Tanzania</span></p>
<p class="p26"><span class="s1"><strong>Asia </strong></span></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Mongolia</strong></span></li><li><span class="s1">Government of the </span><span class="s4"><strong>Republic of Korea</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Indonesia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Philippines</strong></span></li><li><span class="s1">Dorjdari Namkhaijantsan, Open Society Foundation, Mongolia</span></li><li><span class="s1">Vincent Lazatin, Transparency and Accountability Network, Philippines</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Suneeta Kaimal, Revenue Watch Institute</span></em></p>
<p class="p5"><strong>Central Europe</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Romania</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Bulgaria</strong></span></li><li><span class="s1">Government of the</span><span class="s4"><strong> Slovak Republic</strong></span></li><li>Government of <strong>Czech Republic</strong></li><li><span class="s1">Gergana Jouleva, Access to Information Program Foundation, Bulgaria</span></li><li><span class="s1">Andra Teodora, Fundatia Soros Romania</span></li></ul>
<p class="p22"><span class="s1">Moderated by Martin Tisne, Omidyar Network, United Kingdom</span></p>
<p class="p5"><strong>Western Europe, I</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Norway</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Sweden</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Denmark</strong></span></li><li><span class="s1">CSO Representative TBD</span></li><li><span class="s1">CSO Representative TBD</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Tim Kelsey, Cabinet Office, United Kingdom</span></em></p>
<p class="p26"><span class="s1"><strong>Southern Europe, I</strong></span></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Albania</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Montenegro</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Croatia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Macedonia</strong></span></li><li><span class="s1">Katarina Ott, Institute of Public Finance, Croatia</span></li><li><span class="s1">Vuk Maras, MANS, Montenegro</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Warren Krafchik, International Budget Partnership</span></em></p>
<p class="p5"><strong>Baltics</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Latvia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Lithuania</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Estonia</strong></span></li><li><span class="s1">Rura Mrazauskaite, Transparency International, Lithuania</span></li><li><span class="s1">Linda Austere, Center for Public Policy, Latvia</span></li></ul>
<p class="p23"><em>Moderated by Liia Hanni, E-Governance Academy, Estonia</em></p>
<p class="p5"><span class="s5"><strong>4:00-4:30 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Coffee </strong>and<strong> </strong></span><span class="s4"><strong>Networking</strong></span></p>
<p class="p5"><span class="s5"><strong>4:30-5:45 pm</strong></span><span class="s2"><strong> </strong></span><span class="s1"><strong>Country action plans </strong></span><span class="s2"><strong>PART II </strong></span></p>
<p class="p5"><strong>South America, II </strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Peru</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Paraguay</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Mexico</strong></span></li><li><span class="s1">Miguel Pulido, Fundar, Mexico</span></li><li><span class="s1">Samuel Rotta, Proetica, Peru</span></li></ul>
<p class="p22"><em><span class="s1">Moderator TBD</span></em></p>
<p class="p5"><strong>North America</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Canada</strong></span></li><li><span class="s1">Government of the </span><span class="s4"><strong>United States</strong></span><span class="s1"> </span></li><li><span class="s1">Patrice McDermott, Openthegovernment.org Coalition, United States<span class="Apple-tab-span"> </span></span></li><li><span class="s1">Toby Mendel, Center on Law and Democracy, Canada</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Tara Hidayat, Government of Indonesia</span></em></p>
<p class="p5"><strong>Africa, II</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Tanzania</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Kenya</strong></span></li><li><span class="s1">John Ulanga, The Foundation for Civil Society, Tanzania<span class="Apple-tab-span"> </span></span></li><li><span class="s1">George Kegoro, International Commission of Jurists, Kenya</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Zohra Dawood, Open Society Foundation South Africa</span></em></p>
<p class="p5"><strong>Middle East</strong></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Israel</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Jordan</strong></span></li><li><span class="s1">Professor Tamar Hermann, Israeli Democracy Institute, Israel</span></li><li><span class="s1">CSO representative TBD</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Anthony Richter, Transparency and Accountability Initiative</span></em></p>
<p class="p26"><span class="s1"><strong>Northeastern Europe</strong></span></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Ukraine</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Moldova</strong></span></li><li><span class="s1">Serghei Ostaf, National NGO Council, Moldova</span></li><li><span class="s1">Khmara Oleksii, Civic Partnership for Supporting OGP in Ukraine</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Tom Blanton, National Security Archive, United States</span></em></p>
<p class="p26"><span class="s1"><strong>Western Europe, II</strong></span></p>
<ul><li><span class="s1">Government of the </span><span class="s4"><strong>United Kingdom</strong></span></li><li><span class="s1">Government of the </span><span class="s4"><strong>Netherlands</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Spain</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Italy</strong></span></li><li><span class="s1">Rufus Pollock, Open Knowledge Foundation, United Kingdom</span></li><li><span class="s1">Marjan Besuijen, Hivos, Netherlands</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Alan Hudson, ONE Campaign</span></em></p>
<p class="p26"><span class="s1"><strong>Southern Europe, II </strong></span></p>
<ul><li><span class="s1">Government of</span><span class="s4"><strong> Greece</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Malta</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Turkey</strong></span></li><li><span class="s1">CSO representative TBD</span></li><li><span class="s1">CSO representative TBD</span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Håkon Arald Gulbrandsen, Government of Norway </span></em></p>
<p class="p26"><span class="s1"><strong>South Caucasus </strong></span></p>
<ul><li><span class="s1">Government of </span><span class="s4"><strong>Armenia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Georgia</strong></span></li><li><span class="s1">Government of </span><span class="s4"><strong>Azerbaijan</strong></span></li><li><span class="s1">Eka Gigauri, Transparency International Georgia<span class="Apple-tab-span"> </span></span></li><li><span class="s1">Galib Abbaszade, National Budget Group, Azerbaijan<span class="Apple-tab-span"> </span></span></li><li><span class="s1">Liana Doydoyan, FOI Centre, Armenia </span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Jonas Moberg, Extractive Industries Transparency Initiative, Norway</span></em></p>
<p class="p5"><span class="s5"><strong>5:45-6:30 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>First Day </strong></span><span class="s4"><strong>Closing</strong></span><span class="s1"><strong> Remarks</strong></span></p>
<p class="p5"><span class="s5"><strong>7:00-9:30 pm</strong></span><span class="s1"><strong> <span class="Apple-tab-span"> </span>Celebrating</strong> Open Government: A Reception hosted by the </span><span class="s4"><strong>Government of Brazil</strong></span><span class="s1"> and </span><span class="s4"><strong>Omidyar Network.</strong></span></p>
<p class="p5">The reception is onsite at the Convention Center.</p>
<hr /><strong>Wednesday, April 18, 2012</strong>
<p class="p16"><span class="s5"><strong>9:00-10:00 am</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>OPENING Plenary: </strong></span><span class="s4"><strong>Responsibility</strong></span><span class="s1"><strong> and </strong></span><span class="s4"><strong>Challenges</strong></span><span class="s1"><strong> that Come with </strong></span><span class="s4"><strong>Openness</strong></span></p>
<ul><li><span class="s1"><strong>Walid al-Saqaf</strong>, YemenPortal.net & Alkasir, </span><span class="s4">Yemen</span></li><li><span class="s1">Minister <strong>Francis Maude</strong>, </span><span class="s4">United Kingdom</span></li><li><span class="s1">Secretary of State <strong>Ben Abbes</strong>, </span><span class="s4">Tunisia</span></li><li><span class="s1"><strong>Fernando Rodrigues</strong>, Folha de São Paulo, </span><span class="s4">Brazil</span></li></ul>
<p class="p11"><em><span class="s1">Moderated by Alex Howard, O’Reilly Media, </span><span class="s4">United States</span></em></p>
<p class="p7"><span class="s1"><strong>10:00-10:30 am</strong></span><span class="s2"><strong><span class="Apple-tab-span"> </span>Coffee and </strong></span><span class="s4"><strong>Networking</strong></span></p>
<p class="p5"><span class="s5"><strong>10:30-12:30 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Thematic Breakout Sessions: </strong></span><span class="s4"><strong>Paths to Openness</strong></span></p>
<p class="p22"><em><span class="s1">Participants choose one of five breakout sessions to attend in the morning block of thematic discussions. </span>Follow
Sessions 1 or 2 in the morning and afternoon blocks for in-depth
discussions on one topic, explored from three perspectives: government,
civil society, and the private sector.</em></p>
<p class="p22"><strong>Access to Information: Government Perspectives</strong></p>
<ul><li>Vania Vieira, CGU, Government of <strong>Brazil</strong></li><li>Dr. Ali M. Abbasov, Minister of Communications and Information Technologies, Government of <strong>Azerbaijan</strong></li><li><span class="s1"><strong>Government of Liberia</strong></span></li><li><span class="s1">Pierre Boucher, Deputy Chief Information Officer, Government of <strong>Canada</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Laura Neuman, The Carter Center, <strong>United States</strong></span></em></p>
<p class="p22"><strong>Lessons Learned in Service Delivery: Government Perspectives</strong></p>
<ul><li><span class="s1">Minister Mathias Chikawe, Government of <strong>Tanzania</strong></span></li><li><span class="s1">Ms. Marie Munk, Deputy Permanent Secretary, Ministry of Economy and the Interior, Government of <strong>Denmark</strong></span></li><li><span class="s1">Government of <strong>Estonia</strong> (invited)</span></li><li><span class="s1">Permanent Secretary Dr. Bitange Ndemo, Government of <strong>Kenya</strong> </span></li></ul>
<p class="p23"><em>Moderated by Mark Robinson, DFID/Transparency and Accountability Initiative, UK</em></p>
<p class="p23"><strong>Networking Mechanism Affinity Group: Open Data Portals</strong></p>
<ul><li><span class="s1">Steve Davenport, AidDATA, <strong>United States</strong></span></li><li><span class="s1">Tim Kelsey, Director of Transparency & Open Data, Cabinet Office, <strong>United Kingdom</strong></span></li><li><span class="s1">Marko Rakar, Windmill, <strong>Croatia</strong></span></li><li><span class="s1">Eric Gunderson, Development Seed, <strong>United States</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Abhinav Bahl, Global Integrity/OGP Networking Mechanism</span></em></p>
<p class="p26"><span class="s1"><strong>Networking Mechanism Affinity Group: Public Finance Management and Fiscal Transparency </strong></span></p>
<ul><li><span class="s1">Iara Pietricovsky, INESC, <strong>Brazil</strong></span></li><li><span class="s1">Secretary Butch Abad, Government of <strong>Philippines</strong> </span></li><li><span class="s1">Dr. Brian Wrampler, Boise State University, <strong>United States</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Nicole Anand, Global Integrity/OGPNetworking Mechanism</span></em></p>
<p class="p5"><strong>Advancing Open Government through Knowledge Exchange</strong></p>
<ul><li>Roberto Perez, IACC, <strong>Latin America</strong>, invited</li><li><span class="s1">Ms. Stela Mocan, Director e- Government Center, Government of <strong>Moldova</strong> </span></li><li><span class="s1">Miguel Pulido, Fundar, <strong>Mexico</strong></span></li><li>Prayoga Wiradisuria, President's Delivery Unit, <strong>Government of Indonesia</strong></li><li>Eric Braverman, McKinsey, <strong>United States</strong></li></ul>
<p class="p22"><em><span class="s1">Moderated by Han Fraeters, World Bank Institute</span></em></p>
<p class="p33"><span class="s1"><strong>12:30-2:00 pm</strong></span><span class="s2"><strong><span class="Apple-tab-span"> </span>Lunch and </strong></span><span class="s4"><strong>Networking.</strong></span></p>
<p class="p33">Lunch will be provided onsite at the conference center. </p>
<p class="p10"><span class="s5"><strong>2:00-4:00 pm</strong></span><span class="s1"><strong><span class="Apple-tab-span"> </span>Thematic Breakout Sessions: </strong></span><span class="s4"><strong>More</strong></span><span class="s1"><strong> </strong></span><span class="s4"><strong>Paths to Openness</strong></span></p>
<p class="p22"><span class="s1">Participants choose one of five breakout sessions to attend in the afternoon block of thematic discussions. </span></p>
<p class="p26"><span class="s1"><strong>Access to Information: Civil Society and Private Sector Perspectives </strong></span></p>
<p class="p22"><span class="s1"><strong>Panel I: Civil Society Perspectives</strong></span></p>
<ul><li><span class="s1">Karin Lissakers, Revenue Watch Institute</span></li><li><span class="s1">Alison Tilley, Open Democracy Advice Center, <strong>South Africa</strong> </span></li><li><span class="s1">Ivan Pavlov, Freedom of Information Foundation, <strong>Russia</strong></span></li><li><span class="s1">Karina Banfi, Alianza Regional Por La Libre Expresion e Informacion, <strong>Latin America</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Helen Darbishire, AccessInfo Europe, <strong>Spain</strong></span></em></p>
<p class="p22"><span class="s1"><strong>Panel II: Private Sector Perspectives</strong></span></p>
<ul><li><span class="s1">Alexandre Gomes, SEA Technologia, <strong>Brazil</strong></span></li><li><span class="s1">Chris Taggart, Open Corporates, <strong>United Kingdom</strong></span></li><li><span class="s1">Jose Francisco Compagno, Ernst and Young </span></li><li><span class="s1">Ginny Hunt, Google, <strong>United States</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Rufus Pollock, Open Knowledge Foundation, United Kingdom </span></em></p>
<p class="p5"><strong>Lessons Learned in Service Delivery: Civil Society and Private Sector Perspectives</strong></p>
<p class="p22"><span class="s1"><strong>Part I: Civil Society Perspectives</strong></span></p>
<ul><li><span class="s1">Jose Ricardo Barrientos Quezada, ICEFI, <strong>Guatemala</strong></span></li><li><span class="s1">Felipe Heusser, Ciudadano Inteligente, <strong>Chile</strong></span></li><li><span class="s1">Nikhil Dey, MKSS, <strong>India</strong></span></li><li><span class="s1">Harvey Lowe, Canadian Council on Social Development, <strong>Canada</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Rakesh Rajani, Twaweza, <strong>Tanzania</strong></span></em></p>
<p class="p22"><span class="s1"><strong>Part II: Private Sector Perspectives</strong></span></p>
<ul><li><span class="s1">Philip Ashlock, OpenPlans/Open311, <strong>United States</strong></span></li><li><span class="s1">Jorge Soto, Citivox, <strong>Mexico</strong></span></li><li><span class="s1">Tom Steinberg, MySociety, <strong>United Kingdom, </strong>invited</span></li><li><span class="s1">Michael Gurstein, Center for Community Informatics Research, Development and Training, <strong>Canada</strong></span></li></ul>
<p class="p22"><em><span class="s1">Moderated by Rakesh Rajani, Twaweza, <strong>Tanzania</strong></span></em></p>
<p class="p26"><strong>Open Government and Legislatures</strong></p>
<p><strong><em>Part I: Legislative Perspectives</em></strong></p>
<ul><li>Representative Paulo Pimenta, <strong>Brazil</strong></li><li>Denis Russo,Votenaweb, <strong>Brazil</strong></li><li>Laura Alonso, Legislature of City of Buenos Aires, <strong>Argentina</strong></li><li>Cristiano Ferri Soares de Faria, e-Democracy Program Director, Brazilian House of Representatives, <strong>Brazil</strong></li></ul>
<p><em>Moderated by Gherardo Casini, Head of Global Center for ICT in Parliaments, <strong>United Nations</strong></em></p>
<p><strong><em>Part II: Civil Society Perspectives</em></strong></p>
<ul><li>Andrew Mandelbaum, National Democratic Institute, <strong>United States</strong></li><li>John Wonderlich, Sunlight Foundation, <strong>United States</strong></li><li>Danardono Siradjudin, Indonesian Parliamentary Center, <strong>Indonesia</strong></li><li>Melissa Ortiz Masso, Latin American Network on Legislative Transparency, <strong>Latin America</strong></li></ul>
<p><em>Moderated by Tiago Peixoto, World Bank Open Government Specialist</em></p>
<p class="p22"><strong>Measuring for Impact: How to build the case for Open Government </strong></p>
<ul><li><span class="s1">Rolf Alter, OECD, <strong>France</strong></span></li><li><span class="s1">Nikos Passas, Northeastern University, <strong>United States/Greece</strong></span></li><li><span class="s1">Jorge Garcia-Gonzalez, Director of Technical Secretariat of MESICIC, Organization of American States, <strong>Latin America</strong> </span></li><li>Harlan Yu, Princeton University, <strong>United States</strong></li></ul>
<p class="p23"><em>Moderated by Martin Tisne, Omidyar Network, <strong>United Kingdom</strong></em></p>
<p class="p26"><span class="s1"><strong>Learning from Country Consultations to Date: New Strategies for Public Engagement</strong></span></p>
<ul><li><span class="s1">Samuel Rotta, Proetica, <strong>Peru</strong></span></li><li><span class="s1">Chris Vein, The White House, <strong>United States</strong></span></li><li><span class="s1">Khmara Oleksii, Civic Partnership for Supporting OGP in <strong>Ukraine</strong> </span></li><li>Government of <strong>Philippines</strong>, invited</li></ul>
<p class="p22"><em><span class="s1">Moderated by Warren Krafchik, International Budget Partnership, <strong>United States</strong></span></em></p>
<p class="p10"><span class="s1"><strong>4:00-4:30 pm<span class="Apple-tab-span"> </span></strong></span><span class="s4"><strong>Coffee</strong></span><span class="s1"><strong> and Networking </strong></span></p>
<p class="p10"><span class="s1"><strong>4:30-5:00 pm<span class="Apple-tab-span"> </span>Report from Working Group on </strong></span><span class="s4"><strong>Meeting Outcomes</strong></span><span class="s1"><strong> </strong></span></p>
<p class="p10"><span class="s1"><strong>5:00-6:00 pm<span class="Apple-tab-span"> </span></strong></span><span class="s4"><strong>OGP at Home</strong></span><span class="s1"><strong>: Closing Remarks with OGP Leadership</strong></span></p>
<ul><li><span class="s1">Vice-Minister <strong>Luiz Navarro</strong>, </span><span class="s4">Brazil</span></li><li><span class="s1"><strong>Samantha Power</strong>, White House, United States</span></li><li><span class="s1"><strong>Warren Krafchik</strong>, International Budget Partnership</span></li><li><span class="s1"><strong>Tim Kelsey</strong>, Director of Transparency and Open Data, Cabinet Office </span><span class="s4">United Kingdom</span></li></ul>
<p><strong><br /></strong></p>
<p><strong>Note: Brazil's local time is approximately eight and half hours behind us. The welcome address on April 17th starts at 9:30 A.M (B.R.T) which is approximately 5:00 P.M (I.S.T).</strong></p>
<p>
For more details visit <a href='https://cis-india.org/openness/open-government-partnership-brasilia-bangalore-meetup'>https://cis-india.org/openness/open-government-partnership-brasilia-bangalore-meetup</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Event Type </dc:subject>
<dc:subject> Open Content </dc:subject>
<dc:date> 2012-04-12T13:18:28Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/design-public-delhi">
<title> Design!PubliC — Event in Delhi </title>
<link> https://cis-india.org/openness/design-public-delhi </link>
<description>
<b>Centre for Knowledge Societies in partnership with IBM, Bill & Melinda Gates Foundation, Google, HeadStart, India@75, LiveMint, and the Centre for Internet & Society is organizing the third edition of Design!PubliC event in Delhi on April 19 and 20, 2012. </b>
<p>Design Public is a high-level conversation among a select group of thinkers, decision-makers and opinion-leaders who seek to transform India into an innovation society. It brings together influential actors from all sectors of society to deliberate the best ways in which innovation can serve the public interest. The larger goal of the Conclave is to serve as an enabling platform for building the necessary partnerships and consortia that will bring this agenda to practical realization.</p>
<p>This third edition of the Design Public Conclave is focused on issues of trust and participation and how they relate to innovation. We will be addressing key questions like:</p>
<ul><li>How can we overcome deficiencies in trust and participation to better facilitate innovation?</li><li>How can we better imagine India as an innovation society?</li><li>How can we build smarter cities and ensure sustainable urban development?</li><li>What does rural innovation really mean and how do we do it?</li><li>What are the necessary consortia and cross-sectoral alignments for driving innovation?</li></ul>
<p> </p>
<hr />
<h2>
The Panelists</h2>
<table class="plain">
<thead></thead>
<tbody>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Aditya.jpg/image_preview" alt="Aditya Dev Sood" class="image-inline image-inline" title="Aditya Dev Sood" /></td>
<td><strong>Aditya Dev Sood</strong><br />Aditya Dev Sood is Founder and CEO of the Center for Knowledge Societies (CKS), an innovation consulting firm that provides design services of a kind that Indian industry never thought it would even need — User Research, User Experience Design, Design Strategy and Innovation Management. Through his consulting work, and also through his writings and his public presentations, Aditya offers a compelling vision of the central role of design and innovation for emerging economies such as India. The focus on his firm has remained on lower income and rural groups, and through contractual consulting engagements it has sought always to bring about market successes as well as the greater societal good.<br /><br />Dr. Sood is a Fulbright scholar with two doctorates from the University of Chicago and a wide range of disciplinary competencies, gained through a long and diverse education, including Architecture, Art History, Critical Theory, Comparative Literature, Sanskrit Philology, Philosophy of Language, Cultural Anthropology, Social Theory and Political Economy.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Arun.jpg/image_preview" title="Arun Maira" height="132" width="177" alt="Arun Maira" class="image-inline image-inline" /></td>
<td><strong>Arun Maira</strong><br />Arun Maira is a Member of the National Innovation Council, a part of the National Planning Commission of the Government of India. In addition to being a prolific author on leadership and organization transformation, as well as the future of India, he has worked as an experienced consultant for companies all over the world and for a diversity of industries, from automobiles and pharmaceuticals to international agencies for economic development. Prior to joining the National Planning Commission, Arun Maira worked with the TATA Group in India, the Boston Consulting Group, Save the Children in India, the Axis Bank Foundation, and CII’s National Councils, among many others. He received his M.Sc. and B.Sc. in Physics from St Stephen’s College, Delhi University.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/AdityaM.jpg/image_preview" title="Aditya Mishra" height="146" width="194" alt="Aditya Mishra" class="image-inline image-inline" /></td>
<td><strong>Aditya Mishra</strong><br />In addition to leading a sales team for Tata Consultancy Services (TCS) Ltd., Aditya Mishra began his own not-for-profit company to promote entrepreneurship in India called Headstart. Headstart is run by volunteers dedicated to creating space for and promoting innovation in India by fostering individual entrenpreneurs, research, and the adoption of new technology. Aditya advises early stage start-ups and incubators through Startup Saturdays events to aid in the development of products and service, busines planning, and sales and marketing. Headstart is headquarted in Bangalore, but through the Headstart Network of entrepreneurs, academics, and industry professionals, activities are carried out in Mumbai, Hyderabad, Pune, Delhi, Ahmedabad, Chennai, and Kolkata. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Sukumar.jpg/image_preview" alt="Sukumar Ranganathan" class="image-inline image-inline" title="Sukumar Ranganathan" /></td>
<td><strong>Sukumar Ranganathan</strong><br />Sukumar Ranganthan was a founding member of Mint, a business paper of the Hindustan Times in association with the Wall Street Journal. Launched in 2007, Mint brings “Clarity in Business News” to readers across the country. He has worked in several capacities in business news, from Marketing Editor at The Hindu Business Line to Managing Editor of India’s leading business magazine, Business Today. In addition to a Master’s degree in Business Administration, Sukumar holds a Bachelor’s in Chemical Engineering and another Master’s in Mathematics. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Bhairavi.jpg/image_preview" title="Bhairavi Jani" height="170" width="228" alt="Bhairavi Jani" class="image-inline image-inline" /></td>
<td><strong>Bhairavi Jani</strong><br />After graduating from Miami University, Ohio, USA, and working with KPMG Consulting in Washington D.C., Bhairavi Jani returned to India in 2001 and began her career in business. After setting up and scaling up a fourth party logistics company, Bhairavi accepted the role of Director for all companies under the SCA Group in 2005, which manages shipping, customs, warehousing, logistics, and IT. As Group Director, she works with different teams from the respective companies withing the Group, providing them strategic advice. In addition to being a successful businesswoman, Bhairavi has worked closely with the late C. K. Prahalad on India@75 of the Confederation of Indian Industry (CII), a grassroots initiative for realizing an inclusive, sustainable, and developed India by 2022. It works to accelerate India’s transformative into an economically vital, technologically innovative, and socially and ethically vibrant global leader. Having served as a National Chairman of Young Indians, CII, Bhairavi has since 2011 taken a five year hiatus from her own businesses to serve as Executive Director for India@75. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Ashwin.jpg/image_preview" title="Ashwin Mahesh" height="200" width="200" alt="Ashwin Mahesh" class="image-inline image-inline" /></td>
<td><strong>Ashwin Mahesh</strong><br />Ashwin Mahesh is a professor of Public Policy at IIM Bangalore, but his innovative ideas and dedication to service has brought him outside academia. In 1998, he co-founded India Together, an online magazine of public affairs, policy, and development in India. He has also started Mapunity, an independent R&D company designed around reversing the trend of government lagging behind technology. Ashwin Mahesh has a PhD in atmospheric remote sensing from the University of Washington, and he does research in exploring the expanding role of technology & IT in urban traffic management. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Yamini.jpg/image_preview" title="Yamini Aiyar" height="157" width="211" alt="Yamini Aiyar" class="image-inline image-inline" /></td>
<td><strong>Yamini Aiyar </strong><br />Yamini Aiyar is the founder and director of the Accountability Initiative, an organization working to strengthen accountability and engagement in Indian governance, which has received praise from Indian government officials and even President Obama. She is also presently a Senior Research Fellow at the Centre for Policy Research, focusing on understanding accountability tools in order to institutionalize accountability methods and strengthen public service delivery systems. Prior to the Accountability Initiative, Aiyar worked at the World Bank and the Ford Foundations in New Delhi. She holds a MSc in Development Studies from the London School of Economics, and M.A. in Social and Political Sciences from St. Edmund’s College, Cambridge University, and a B.A. in Philosophy from St. Stephens College, Delhi University. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Scott.jpg/image_preview" alt="Scott Burnham" class="image-inline image-inline" title="Scott Burnham" /></td>
<td><strong>Scott Burnham</strong><br />Scott Burnham is a creative director, writer, and designer who has worked on strategies for cities to use design to reprogram relationships. He has created several projects for European cities including Urban Play for Amsterdam with Droog Design and Bairro Criativo for Porto, Portugal. Currently, Burnham directs the Trust Design project for Premsela, the Netherlands Institute for Design, exploring the relationship between trust and design from products and shared urban spaces. He is the editor of a special 4-issue publication series with Volume Magazine, and a guest lecturer at Design Academy Eindhoven. In addition to writing and speaking, Burnham worked as the Creative Director for the UK’s Urbis Center for Urban Culture from 2003-2006. <br /></td>
</tr>
<tr>
<td><img src="https://cis-india.org/home-images/Samanth.jpg/image_preview" title="Samanth Subramanian" height="160" width="215" alt="Samanth Subramanian" class="image-inline image-inline" /></td>
<td><strong>Samanth Subramanian</strong><br />Samanth Subramanian is a journalist who has written pieces for The New York Times, Mint, Newsweek, the Wall Street Journal, the Boston Globe, Foreign Policy, Foreign Affairs, the Hindu, and many others. Though he prefers long-form narrative articles, he also has written several shorter pieces, as well as a non-fiction book Following Fish: Travels around the Indian Coast, which won the 2010 Shaki Bhatt First Book Prize. He currently writes for the New York Times’ India Ink blog. Subramanian completed his undergraduate degree from Pennsylvania State University in journalism and received his Master’s degree in International Relations from Columbia University’s School of International and Public Affairs. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/copy_of_Sunil.jpg/image_preview" title="Sunil Abraham" height="167" width="208" alt="Sunil Abraham" class="image-inline image-inline" /></td>
<td><strong>Sunil Abraham</strong><br />Sunil Abraham is the Executive Director of The Centre for Internet and Society, which aims to criticaly engage with the interaction between the internet and the public, including concerns of digital pluralism, public accountability, adn pedagogic practices. While serving on the board of directors for CIS, Sunil has worked on many projects exploring the internet and information. He has been elected an Ashoka fellow, where he explored the democratic potential of the internet, and was granted a Sarai FLOSS fellowship as well. For the United Nations, Sunil managed the International Open Source Network for the Asia-Pacific Development Information Program between 2004 and 2007. The next year, he managed ENRAP, Knowledge Networking for Rural Development in the Asia-Pacific region, which worked to share knowledge amongst the projects and stakeholders of the International Fund for Agricultural Development. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Shankar.jpg/image_preview" alt="Shanker Annaswamy" class="image-inline image-inline" title="Shanker Annaswamy" /></td>
<td><strong>Shanker Annaswamy</strong><br />Shanker Annaswamy is the Managing Director for IBM India Private Limited, and Regional General Manager of IBM in India and South Asia. He is responsible for all sales, marketing, services, and delivery in India, Bangladesh, Nepal, and Sri Lanka. In addition to holding a senior position in IBM, Annaswamy has been President and Chief Executive Officer for GE Medical Systems in South Asia, Managing Director of Wipro-GE Medical Systems, and Adviser with the Ministry of Health for the Sultanate of Oman. He currently serves as Chair of the Confederation of Indian Industry’s (CII) National Committee on Intellectual Property Owners, having previously co-chaired CII’s advisory committee on its National Innovation Mission. In 2009, BusinessWeek listed Annaswamy among India’s 50 Most Powerful People. He received his Bachelor of Engineering degree from Madras University and a Diploma in Business Management Education from the All India Management Association, New Delhi. <br /></td>
</tr>
<tr>
<td><img src="https://cis-india.org/home-images/Ashok.jpg/image_preview" title="Ashok Alexander" height="170" width="215" alt="Ashok Alexander" class="image-inline image-inline" /></td>
<td><strong>Ashok Alexander</strong><br />Ashok Alexander is Director of Avahan, the Global Health Program’s HIV prevention initiative in India, which was founded by the Bill and Melinda Gates Foundation in 2003. As Director, he works with India’s federal and state governments, NGOs, and corporate partners. Before joining Avahan, Alexander worked in Hong Kong, the United States, and India for 24 years. After joining McKinsey & Company in New York, he moved to India to become the head of its New Delhi office. In addition, he has extensive experience working with NGOs, being a leader in the creation of the American India Foundation (AIF) and serving on the Board of Advisors. Alexander holds graduate degrees in economics and management from Delhi University and the Indian Institute of Management, Ahmedabad.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Jeby.jpg/image_preview" alt="Jeby Cherian" class="image-inline image-inline" title="Jeby Cherian" /></td>
<td><strong>Jeby Cherian</strong><br />Jeby Cherian is the Strategy Leader of IBM in India and South Asia, and also serves on the India Leadership Team. He provides guidance to IBM’s Corporate Development team in India, leads and positions IBM’s Security solutions portfolio to the Government of India, and provides executive sponsorship for growing the High End Server business in India. Before this, Cherian worked in Bangalore with IBM’s Global Solutions Delivery Center and with PricewaterhouseCoopers (PwC) in Finance Transformation services. Cherian is a CPA with a Master’s degree in Accounting from the University of Illinois and an MBA from the University of Chicago. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Pankaj.jpg/image_preview" title="Pankaj Jhunja" height="158" width="211" alt="Pankaj Jhunja" class="image-inline image-inline" /></td>
<td><strong>Pankaj Jhunja</strong><br />Pankaj Jhunja, now General Manager of Design for Tata Motors, has had the opportunity to work in a diversity of businesses each with different responsibilities and complexities of products. Before Tata Motors, Jhunja worked for Dilip Chhabria Design (DC) specializing in Custom Built Cars, Homeflow Inc. in Pune as Product Manager, and with Renault Nissan India in Mumbai as General Manager Design. Jhunja holds a Bachelor’s degree from the National Institute of Technology, Silchar, and a Master’s degree in Design from IIT Mumbai.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Chakshu.jpg/image_preview" title="Chakshu Roy" height="164" width="215" alt="Chakshu Roy" class="image-inline image-inline" /></td>
<td><strong>Chakshu Roy</strong><br />Chakshu Roy is a lawyer who heads technology initiatives at PRS Legislative Research (PRS), New Delhi. PRS is a unique initiative that provides non-partisan analysis to all Members of Parliament in India. Chakshu is developing a comprehensive technology strategy to engage large sections of the population in the policy process. He has conceptualised and developed India’s only online database of all state laws. Chakshu has conducted capacity-building workshops for over 1000 journalists on tracking the work of legislators.<br /><br />He specialised in real estate law and commercial agreements before joining PRS. He has earlier worked in corporate law with the Chamber of Law, New Delhi. He holds bachelors degrees in Commerce and Law from Delhi University. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Ekta.jpg/image_preview" title="Ekta Ohri" height="170" width="227" alt="Ekta Ohri" class="image-inline image-inline" /></td>
<td><strong>Ekta Ohri</strong><br />Ekta Ohri is the Head of Project Operations at the Center for Knowledge Societies (CKS). She holds experience of applying ethnographic and user experience research methods as well as principles of design thinking for addressing a variety of innovation challenges in emerging economies – ranging from improving rural public health delivery systems, providing financial services to the poor and bridging their information and communication gaps through telecommunications to enhancing urban mobility and luxury experiences. As the head of innovation at CKS, she works with different teams providing them strategic advice around innovation approaches, developing context (urban or rural) specific research methodologies and analyzing research insights in ways that leads to concepts that create maximum value for the users, as well as disseminating some of these ideas in the public domain through publications. Ekta has multi-disciplinary background in Architecture (Sushant School of Art and Architecture), Visual and Critical Studies (California College of the Arts), and Anthropology (Northwestern University) and is particularly interested in exploring linkages between design, culture and lived experiences.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/James.jpg/image_preview" title="James" height="171" width="128" alt="James" class="image-inline image-inline" /></td>
<td><strong>James Crabtree</strong><br />James Crabtree is the Mumbai Correspondent for the Financial Times since November 2011. He covers Indian corporate news and social and political trends in the country’s financial capital. James joined the FT in 2010 and was previously the Comment Editor based in London.He was previously an editor and essayist at Prospect.<br /><br />Before returning to journalism, James worked as policy advisor in the Prime Minister’s Strategy Unit, and also for various think tanks. He has also spent a number of years living in the US, first as a Fulbright Scholar at the Kennedy School of Government at Harvard University, and then living in Washington, working as a senior policy advisor at the New Democrat Network, another think tank. James is a trustee of the charity mySociety.org, one of the UK’s most innovative technology organisations.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Theo.jpg/image_preview" alt="Theo" class="image-inline image-inline" title="Theo" /></td>
<td><strong>Theo JJ Groothuizen</strong><br />Theo JJ Groothuizen is currently the Counsellor for Science and Technology at the Embassy of the Kingdom of the Netherlands in New Delhi India. He is member of the steering committee of the Delhi Sustainable Development Summit 2008.<br /><br />Born in 1949 in the Netherlands, he graduated in industrial Design Engineering at the Delft University of Technology, and is since 1986 principle of Landmark Design Holding (Netherlands and Switzerland). Groothuizen served as executive board member of International Council of Societies of Industrial Design (ICSID) and the Association of Dutch Designers (BNO) and as advisor for the Bureau of European Design Associations (BEDA).<br /><br />He was active in several international advisory boards and was tutor in international design workshops, initiated international exhibitions and has been invited as speaker, guest lecturer and jury member all over the world. He is fellow of the Foundation Design for the World, advisor for the European Institute for Design and Disability (EIDD) and honorary member of the BNO. He taught at the Delft University of Technology and served as member of its External Research Advisory Board. He also taught at the Design Academy and functioned as international curator of the Gwangju Design Biennale 2005.<br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Sam.jpg/image_preview" alt="Sam Pitroda" class="image-inline image-inline" title="Sam Pitroda" /></td>
<td><strong>Sam Pitroda</strong><br />Sam Pitroda is an international figure known for his strong support in India’s communications revolution and redefining the role that technology can play in India by linking it to better delivery of services to the underprivileged. He has long worked in government, business, and innovation in India. He served as Technology Advisor to Prime Minister Rajiv Gandhi, is founder and CEO of C-SAM, Inc., with offices worldwide, and chaired the National Knowledge Commission from 2005-2008. Now, in addition to Advisor to the Prime Minister of India on Public Information, Infrastructure & Innovations, chairman of India’s National Innovation Council, charting the roadmap for India’s ‘Decade of Innovation.’ Pitrota completed his Master’s in Physics and Electronics from Maharaja Sayajirao University and subsequently received another Master’s in Electrical Engineering from the Illinois Institute of Technology in Chicago. In 2010, he also received and Honorary degree from the University of Illinois at Chicago. <br /></td>
</tr>
<tr>
<td align="center"><img src="https://cis-india.org/home-images/Darshana.jpg/image_preview" title="Darshana" height="177" width="237" alt="Darshana" class="image-inline image-inline" /></td>
<td><strong>Darshana Gothi Chauhan</strong><br />Darshana is an architect and urban designer. She has varied experience in designing new towns, regeneration of town centres, transport action plans and urban extension projects. She is passionate about participatory planning and the approach of empowering local people to create better cities.<br /><br />Darshana is currently working at Urban Initiatives in London as a Managing Consultant. Her recent works at UI include Southall Big Conversation, a public consultation process in a culturally diverse area in London .<br />Darshana is also the Chapter Development Manager of INTBAU India, a charitable organisation promoting traditional architecture and urbanism in India . As part of INTBAU India, she has been instrumental in organising public consultation events backed with intensive baseline and capacity building work for the regeneration of the inner city of Pune in India.<br /><br />Darshana has simultaneously worked on projects for other consultancies such as The Max Lock Centre, London . Her works at Max Lock include a Spatial Planning Framework for Kaduna , a city of 3 million people for the Central Government of Nigeria. She has previously worked with the Ministry of Works and Human Settlements in Bhutan to develop the master plan for a new administrative capital in East Bhutan as part of Christopher Charles Benninger Architects. <br /></td>
</tr>
</tbody>
</table>
<h2>Agenda</h2>
<h3>Day 1: Certificate in Innovation Management <br /></h3>
<p>Venue: CKS House, New Delhi: 19th April, 2012</p>
<p>09.30 a.m. <a class="external-link" href="http://www.designpublic.in/schedule/icebreaker-dialogue/"><strong>Icebreaker Dialogue</strong></a><br />Participants will introduce themselves briefly and talk about their perceptions of innovation and its application in their work. A CKS member will aggregate the thoughts that emerge from the audience in order to articulate the multiple definitions of innovation that emerge. This will be followed by a quick call out on the value of innovation. </p>
<p>10.30 a.m. <a class="external-link" href="http://www.designpublic.in/schedule/analysis-of-innovation-case-studies/"><strong>Analysis of Innovation Case Studies</strong></a><br />CKS Innovation Experts will present various case studies of innovation in order to present the different tools, approaches and stages of innovation.</p>
<p>12.40 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/ude-approach-to-innovation/"><strong>UDE Approach to Innovation</strong></a><br />CKS Innovation Experts to present the U-D-E approach to innovation and demonstrate different uses of the Innovation Cycle.</p>
<p>01.15 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/wrap-up-and-invitation-to-consulations/"><strong>Wrap Up and Invitation to Innovation Consultations</strong></a><br />CKS Innovation Trainers conclude the morning's session and invite participants to sign up for Innovation Consultations post lunch at the Chaia Innovation Campus.</p>
<p>02.15 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/innovation-consultations/"><strong>Innovation Consultations</strong></a><br />Participants meet mentors on a one to one basis to receive consultation on how they can apply this approach in the specific context of their work or a particular challenge? Where are the opportunities to apply the approach and what value can that have?</p>
<h3><a class="external-link" href="http://www.nationalmuseumindia.gov.in/">Day 2: Design Public Conclave</a></h3>
<p>Venue: National Museum, New Delhi: 20th April, 2012</p>
<p>09.45 a.m.<a class="external-link" href="http://www.designpublic.in/schedule/word-of-welcome/"><strong> Word of Welcome</strong></a><br />Aditya Dev Sood, Center for Knowledge Societies, gives a word of welcome and short introduction to the logic of the conclave.</p>
<p>10.00 a.m.<strong> <a class="external-link" href="http://www.designpublic.in/schedule/crises-of-trust-are-crises-of-innovation-2/">Crises of Trust are Crises of Creativity, Design, and ultimately of Innovation</a></strong><br />by Samanth Subramanian, Scott Burnham and Yamini Aiyar<br />This opening panel will address questions of trust and participation in the wake of the global spring. How can institutions respond creatively to include the networked public? What are the inter-relationships between trust, creativity, design and innovation and why are these important for our future? </p>
<p>11.00 a.m. <strong><a class="external-link" href="http://www.designpublic.in/schedule/participation-collaboration-innovation-2/">Participation, Collaboration, Innovation</a></strong><br />by James Crabtree Ekta Ohri, Sunil Abraham, Ashwin Mahesh and Aditya Mishra<br />Crises of trust are often linked to failures of participation and inclusion. How can activists and critics of institutions be more creative in their approaches so as to restore and repair the public trust? What channels for feedback and more substantive modes of participation must be created so as to promote innovation through dialogue and collaboration? </p>
<p>12.00 p.m. <strong><a class="external-link" href="http://www.designpublic.in/schedule/imagining-india-as-an-innovation-society-2/">Imagining India as an Innovation Society</a></strong><br />by Aditya Dev Sood, Ashok Alexander, Shanker Annaswamy, Sukumar Ranganthan and Arun Maira<br />This panel brings together industry and government experts to imagine the values, behaviors, ways of working, societal institutions and diverse other dimensions of society that would have to change in India to transform it into an innovation society. But first, what is an innovation society? Do we understand this correctly? </p>
<p>02.00 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/breakout-one-smarter-cities/"><strong>Breakout One: Smarter Cities</strong></a><br />by Darshana Gothi Chauhan, Ekta Ohri and Jeby Cherian<br />Jeby Cherian of IBM will lead this breakout session on smarter Urban Management and Civic Administration. </p>
<p>02.00 p.m. <strong><a class="external-link" href="http://www.designpublic.in/schedule/breakout-two-how-can-we-grow-knowledge-of-design-and-innovation-in-india/">Breakout Two: How can we do Rural Innovation better?</a></strong><br />What should or could we mean by Rural Innovation? Is this the same old thing as jugaad, indovation and tinkering? This panel brings together designers and innovation experts to talk with management thinkers to describe the specific steps and stages involved in innovation processes and how they could apply in rural areas. What do steps individuals and organizations need to take to reeducate or empower decision makers at all levels in different sectors in India to bring about an awareness, understanding and orientation towards innovation?</p>
<p>02.00 p.m. <strong><a class="external-link" href="http://www.designpublic.in/schedule/breakout-three-50-steps-to-an-innovation-society/">Breakout Three: 50 Steps to an Innovation Society</a></strong><br />by Theo JJ Groothuizen Bhairavi Jani<br />Bhairavi Jani will lead this thematic breakout session on specific steps governments, corporations, social agencies, academics and individual citizens can take to better imagine and then build an Innovation Society. </p>
<p>03.30 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/reports-from-breakout-sessions/"><strong>Mutual Presentations</strong></a><br />Breakout sessions will cross-report to one another. </p>
<p>04.00 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/concluding-plenary-what-do-we-need-to-do-to-build-an-innovation-society/"><strong>Concluding Plenary: What Do We Need to Do To Build an Innovation Society?</strong></a><br />by Chakshu Roy Aditya Dev Sood Bhairavi Jani<br />This plenary session will include leading thinkers from government and media along with sectoral experts to discuss specific steps we must now undertake in order to work towards innovation in different domain and activity areas. In some ways this is the most challenging and important session of the day, for it will lay out the next steps and future path of the Design Public process. </p>
<p>06.00 p.m. <strong><a class="external-link" href="http://www.designpublic.in/schedule/wrap-up-and-word-of-thanks/">Wrap-Up and Word of Thanks</a></strong><br />Aditya Dev Sood gives a few concluding remarks and concludes the day with a vote of thanks to all advisors, sponsors, partners, speakers and participants at the Design Public Conclave.</p>
<p>07.00 p.m. <a class="external-link" href="http://www.designpublic.in/schedule/dinner/"><strong>Dinner</strong></a><br />All participants are invited to a dinner and celebration of 10 years of CKS at the Chaia Innovation Campus in Chattarpur Enclave, New Delhi. Transportation will be provided.</p>
<p>For registration,<a class="external-link" href="http://www.designpublic.in/register/"> click here</a></p>
<p>
For more details visit <a href='https://cis-india.org/openness/design-public-delhi'>https://cis-india.org/openness/design-public-delhi</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Event Type </dc:subject>
<dc:date> 2012-04-11T11:45:04Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/international-space-apps-challenge">
<title> International Space Apps Challenge </title>
<link>
https://cis-india.org/openness/international-space-apps-challenge
</link>
<b>The International Space Apps Challenge is an international codeathon-style event that will take place over a 48 hour period in cities on all seven continents – and in space – on the weekend of April 21-22, 2012. The event embraces collaborative problem solving with a goal of producing solutions to global challenges. The Centre for Internet & Society is organising the event in Bangalore.</b>
<h3>Background</h3>
<p>On September 20, 2011, President Obama, together with other heads of state, endorsed the principles of the Open Government Partnership – a new multilateral initiative to promote transparency, participation and collaboration between governments and citizens. Since then, 52 countries have joined the global partnership.</p>
<p>NASA is working with organizations around the world on the International Space Apps Challenge as part of the United States’ domestic commitment to the <a class="external-link" href="http://www.opengovpartnership.org">Open Government Partnership</a>. </p>
<h3>How it Works?</h3>
<p>Participants such as concerned citizens, discipline experts, engineers, scientists, and software code developers attend events hosted in cities around the world. At these events, individuals collaborate with others by forming teams focused on solving a particular challenge. The teams compete with other teams around the world to utilize publicly available data to design innovative “solutions” to a pre-determined series of global “challenges.” The challenges are collected prior to the event from supporting organizations.</p>
<h3>Challenges <br /></h3>
<p>Challenges are grouped into four broad categories:</p>
<ol><li>Software Development</li><li>Open Hardware</li><li>Citizen Science Platforms! </li><li>Data Visualization!</li></ol>
<p>It’s <em>not</em> just about smart phone applications! The International Space Apps. </p>
<p>Challenge will provide solutions that:</p>
<ol><li>Address strategic exploration needs! </li><li>Address strategic social needs (life on Earth) <br /></li></ol>
<p>To date, 50+ challenges have been submitted. These challenges are being vetted with development communities such as the Yahoo! Developer Network to refine them prior to the event.</p>
<h3>Benefits</h3>
<p>Some benefits of the International Space Apps Challenge include: </p>
<ul><li>Visible demonstration of a government’s interest in using publicly available data, in partnership with others, to address global needs.</li><li>Opportunity for citizens in countries with little or no investment in space exploration to contribute to space exploration through open source, open data, and code development.</li><li>Promotion of Science, Technology, Engineering and Mathematics (STEM) education by encouraging students from around the world to utilize publicly available data for solutions to global challenges.</li><li>Encouragement of international partnership and mutual understanding.</li><li>Demonstration of commitment to the principles of the Open Government Partnership.<br /></li></ul>
<hr />
<h2>Sample Event Agenda</h2>
<table class="plain">
<tbody>
<tr>
<td><br /></td>
<td>
<h3>Saturday, April 21</h3>
</td>
</tr>
<tr>
<td> 09:00</td>
<td> Registration</td>
</tr>
<tr>
<td>10:00</td>
<td>Schedule and logistics announcements</td>
</tr>
<tr>
<td>10:30</td>
<td>Subject Matter Expert briefing</td>
</tr>
<tr>
<td>11:00</td>
<td>Begin developing</td>
</tr>
<tr>
<td>12:30</td>
<td>Lunch break
13:30 Developing continued</td>
</tr>
<tr>
<td>16:30</td>
<td>Optional progress briefing, more developing</td>
</tr>
<tr>
<td>18:30</td>
<td>Dinner break</td>
</tr>
<tr>
<td>20:00</td>
<td>More developing</td>
</tr>
<tr>
<td> </td>
<td>
<h3>Sunday, April 22</h3>
</td>
</tr>
<tr>
<td> 10:00</td>
<td> Logistics briefing & updates</td>
</tr>
<tr>
<td> 10:15</td>
<td> Begin developing</td>
</tr>
<tr>
<td> 12:00</td>
<td> Submission Deadline</td>
</tr>
<tr>
<td> 12:00</td>
<td> Lunch break</td>
</tr>
<tr>
<td> 13:30</td>
<td> Presentations</td>
</tr>
<tr>
<td> 15:00</td>
<td> Judges Voting</td>
</tr>
<tr>
<td> 15:30</td>
<td> Awards</td>
</tr>
<tr>
<td> 16:00</td>
<td> Post event social</td>
</tr>
</tbody>
</table>
<hr />
<h2>
Frequently Asked Questions</h2>
<ul><li> <strong>What is the International Space Apps Challenge?</strong><br />The International Space Apps Challenge is a 2 day technology development event during which citizens from around the world will work together to solve current challenges relevant to both space exploration and social need.<br /></li><li><strong>When will it take place?</strong><br />The International Space Apps Challenge will take place on all seven continents – and in space - on 21-22 April 2012.<br /></li><li><strong>Who is leading the Challenge?</strong><br />On September 20, 2011, President Obama, together with other heads of state, endorsed the principles of the Open Government Partnership – a new multilateral initiative to promote transparency, participation and collaboration between governments and citizens. Since then, 52 countries have joined the global partnership. NASA is working with other organizations around the world on the International Space Apps Challenge as part of the United States’ domestic commitments to the Open Government Partnership.<br /></li><li><strong>Who can participate in the Challenge?</strong><br />Anyone can participate in the International Space Apps Challenge. It requires individuals with a broad range of skills. We are looking for engineers, technologists, scientists, designers, artists, educators, students, entrepreneurs – anyone who has a passion for changing the world and is willing to contribute.<br /></li><li><strong>Why should I participate in the Challenge?</strong><br />You should participate in the Challenge because the toughest challenges of the world are not one nation’s alone, and this is a unique opportunity to develop technology to reach the human race and make the world a better place. Additionally, the Challenge is an opportunity to: <br />
<ol><li>Demonstrate a commitment to the principles of the Open Government Partnership.</li><li>Exercise a government’s interest in using open data and technology, in partnership with others, to address global needs.</li><li>Engage citizens in countries with little or no investments in space exploration to contribute to space exploration through open source, open data, and code development.</li><li>Promote Science, Technology, Engineering and Mathematics (STEM) education by encouraging students from around the world to utilize open technology for solutions to global challenges.</li><li>Encourage international partnership and mutual understanding.<br /></li></ol>
</li><li><strong>What challenges will be addressed at the event?</strong><br />Challenges are in development from a wide variety of sources inside and outside of NASA. An initial set has been posted on the site and the community is invited to help develop them collaboratively there. New challenges will continue to be added on a weekly basis in anticipation of the event. To discuss contributing additional challenges or datasets, contact <a class="external-link" href="mailto:[email protected]">[email protected]</a>.<br /></li><li><strong>Where will the Challenge take place?</strong><br />Locations in which events are currently planned to be held include San Francisco, US; Tokyo, Japan; Melbourne and Canberra, Australia; Jakarta, Indonesia; Exeter and Oxford, UK; Nairobi, Kenya; Sao Paulo, Brazil; Santo Domingo, Dominican Republic; and McMurdo Station, Antarctica. There will be additional events throughout the world and participation by astronauts on the International Space Station.<br /></li><li><strong>What is a codeathon?</strong><br />A codeathon is a unique event that brings together citizens interested in collaborating on the development solutions that address critical challenges. A codeathon celebrates software development in its most positive context—using minimal resources and maximum brainpower to create outside- the-box solutions in response to interesting problems. Codathons are technology development marathons, drawing on the talents and initiative of the best and the brightest software developers, engineers, designers and technologists from around the world, who volunteer their time to respond to real- world problems with solutions than can have immediate impact. The International Space Apps Challenge is a “codeathon-style” event.<br /></li><li><strong>Is the event limited to just software development?</strong><br />No! Participants in the event will collaborate to build software, open hardware, data visualization, and citizen science platform solutions that contribute to space exploration and solve global challenges that focus on improving life on earth.<br /></li><li><strong>What happens at the event?</strong><br />At the events, individuals collaborate with others by forming teams focused on solving a particular challenge. The teams compete with other teams around the world to utilize publicly available space and data to design innovative “solutions” to a pre- determined series of global “challenges.”<br /></li><li><strong>What about licensing and IP rights?</strong><br />All solutions built at the event must be submitted under a license that permits the free and open dissemination of the work. NASA and the other supporting organizations do not own the rights to nor are committed to utilize any solution developed during the event.<br /></li><li><strong>Who organizes the events in each city?</strong><br />Each event is led as a collaboration between organizations who work together to host an event, mobilize the developer community and contribute to the overall success of the International Space Apps Challenge.<br /></li><li>How can organizations get involved?<br />There is still an opportunity to participate in the International Space Apps Challenge and contribute to an event in your country. We are looking for organizations who are interested in supporting events in cities around the world, as well as for subject matter experts who can share their expertise at the event, either in person or remotely. To express interest in supporting an event in your country, contact <a class="external-link" href="mailto:[email protected]">[email protected]</a> or <a class="external-link" href="mailto:[email protected]">[email protected]<br /><br /></a></li></ul>
<ol><li><a class="external-link" href="http://spaceappschallenge.org/press/">Register for the event here</a></li><li><a class="external-link" href="http://spaceappschallenge.org/press/">Click here</a> for the press kit</li><li><a class="external-link" href="http://spaceappschallenge.org/locations/">See all the event locations here</a><br /></li></ol>
<p>
For more details visit <a href='https://cis-india.org/openness/international-space-apps-challenge'>https://cis-india.org/openness/international-space-apps-challenge</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Event Type </dc:subject>
<dc:date> 2012-04-10T05:18:14Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/open-data-camp">
<title> Open DataCamp — 2012 </title>
<link> https://cis-india.org/openness/open-data-camp </link>
<description>
<b>A one-day unconference for people working with data from various sectors to come together and share their projects and ideas was organised in Bangalore on March 24, 2012. It was organised by the DataMeet group. Pranesh Prakash participated in the event.</b>
<h2>Sessions</h2>
<table class="plain">
<tbody>
<tr>
<td>9:00am - 10:00am</td>
<td>Registration</td>
</tr>
<tr>
<td>10:00am - 10:10am</td>
<td>Introduction to OpenDataCamp<br />Team DataMeet <br /></td>
</tr>
<tr>
<td>10:15am - 10.55am</td>
<td><strong>Panel Discussion: State of Open Data in India</strong><br />Data in India in general is in a state for much improvement. What does that mean for open data? How can open data help improve the data situation? What are the drawbacks of opening up data?<br />Anand S (Gramener), Zainab Bawa (HasGeek), Nithya Raman (Transparent Chennai), Moderator Nisha Thompson</td>
</tr>
<tr>
<td>11:00am - 11.25am <br /></td>
<td><strong>Pictures through numbers</strong><br />Anand, Chief Data Scientist, Gramener</td>
</tr>
<tr>
<td>11.25am - 11.40pm <br /></td>
<td>Tea <br /></td>
</tr>
<tr>
<td>11:45pm - 12.10pm</td>
<td><strong>Karnataka Guarantee of Services to Citizens</strong><br />Sridhar Pabbisetty, COO, Centre for Public Policy</td>
</tr>
<tr>
<td>12:15pm - 12.40pm <br /></td>
<td><strong>Open Data & Free Maps</strong><br />Shekhar Krishnan <br /></td>
</tr>
<tr>
<td>12.45am - 1.10pm <br /></td>
<td><strong>Introduction Aadhaar(UID) Data</strong><br />Pramod Varma & Sanjay Jain</td>
</tr>
<tr>
<td>1.10am - 2.15pm</td>
<td>Lunch</td>
</tr>
</tbody>
</table>
<table class="plain">
<tbody>
<tr>
<td> </td>
<td>Main Hall</td>
<td>Meeting Room (small) <br /></td>
<td>Food Court <br /></td>
</tr>
<tr>
<td>2:15pm - 2:40pm <br /></td>
<td><strong>Drawing By Numbers by Tactical Technology Collective</strong><br />Kaustubh Srikanth</td>
<td><strong>Why Big data and why should you bother?</strong><br />Mohan S,CEO, TrendWise Analytics</td>
<td><strong>Karnataka Learning Partnership</strong>
<br /> Data Practices and a Call for collaboration.<br /> Megha Vishwanath</td>
</tr>
<tr>
<td>2:45pm - 3:10pm <br /></td>
<td><strong>ISB's visualisation of migration in India.</strong><br />ISB & Gramener</td>
<td><strong>The State of Climate Data in India - Open and Closed.</strong><br />Pavan Srinath</td>
<td><strong>Anatomy of NSSO Data</strong><br />sumandro <br /></td>
</tr>
<tr>
<td>3.15pm - 3:40pm <br /></td>
<td><strong>Water Data</strong><br />Nisha Thompson, India Water Portal <br /></td>
<td><strong>Mobile as a Data Collection Device</strong><br />Thejesh GN <br /></td>
<td><strong>Open data API and the challenges</strong><br />Karthik B. R</td>
</tr>
</tbody>
</table>
<table class="plain">
<tbody>
<tr>
<td>3.40pm - 4.15pm</td>
<td>Tea <br /></td>
</tr>
</tbody>
</table>
<table class="plain">
<tbody>
<tr>
<td>4.15pm - 4.40pm <br /></td>
<td><strong>Modelling car insurance pricing</strong><br />Gaurav Vohra, Jigsaw Academy</td>
<td>Free slot <br /></td>
<td><strong>What is Data?</strong><br />Mrinal Wadhwa</td>
</tr>
</tbody>
</table>
<table class="plain">
<tbody>
<tr>
<td>4.45pm - 6.00pm <br /></td>
<td>Feedback, etc</td>
</tr>
</tbody>
</table>
<p>The sponsors included Google, India Water Portal, Gramener, Microsoft Research, Akshara Foundation, DataMeet, HasGeek and the Centre for Internet & Society.</p>
<p><strong>Venue</strong>:Google, 3rd, 4th and 5th floors,RMZ infinity, Tower ENo.3, Old Madras Road, Bennigana Halli, Bengaluru, Karnataka 560 016</p>
<p>For more info, <a class="external-link" href="http://odc.datameet.org/#about">click here</a></p>
<p>
For more details visit <a href='https://cis-india.org/openness/open-data-camp'>https://cis-india.org/openness/open-data-camp</a>
</p>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Open Data </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-03-30T14:49:14Z </dc:date>
<dc:type> Blog Entry </dc:type>
</item>
<item rdf:about=" https://cis-india.org/news/open-access-to-govt-data">
<title> Open access to government data on the cards </title>
<link>
https://cis-india.org/news/open-access-to-govt-data
</link>
<description>
<b>The way has been cleared for public access to the data collected by Union government ministries and departments, with official approval being accorded to the National Data Sharing and Accessibility Policy (NDSAP). T Ramachandran's article was published in the Hindu on March 25, 2012. Pranesh Prakash is quoted in it.</b>
<p>Following its recent approval by the Union Cabinet, the policy has been notified and is in the process of being gazetted, said R. Siva Kumar, CEO of the National Spatial Data Infrastructure, and head of the Natural Resources Data Management System, Department of Science and Technology.<br /><br />The use of open data as a tool for promoting governmental transparency and efficiency has been gaining ground in some parts of the world. An Open Government Partnership was launched last year by the United States and seven other governments. Forty-three other governments have joined the partnership, which has endorsed an Open Government Declaration, expressing a commitment to better “efforts to systematically collect and publish data on government spending and performance for essential public services and activities.” It acknowledges the ‘right' of citizens to seek information on governmental activities.</p>
<p>India has not joined the partnership, but is collaborating with the U.S. in developing an open source version of software for a data portal.<br /><br />The NDSAP states that at least five ‘high value' data sets should be uploaded to a newly created portal, data.gov.in, in three months of the notification of the policy. Uploading of the remaining data sets should be completed within a year.<br /><br />The Department of Science and Technology will co-ordinate the effort and create the portal through the National Informatics Centre. The Department of Information Technology will work out the implementation guidelines, including those related to technology and data standards.<br /><br />Welcoming the approval for the NDSAP, Pranesh Prakash, programme manager at the Centre for Internet and Society (CIS), a Bangalore-based NGO, said the removal of “a few good aspects” in an earlier draft of the policy — such as linkage with Sections 8 and 9 of the Right to Information Act that specify the kinds of information exempt from disclosure by the authorities — had weakened it “even further.” “None of the criticisms the CIS had sent in as part of the feedback requested on the draft have been addressed,” he said.<br /><br />The NDSAP seeks “to provide an enabling provision and platform for providing proactive and open access to the data generated through public funds available with various departments/organisations of the government of India.”<br /><br />However, the Ministries and Departments can draw up, within six months of the notification of the policy, a negative list of data-sets that will not be shared, subject to periodic review by an ‘oversight committee.'<br /><br />The policy envisages three types of access to data: open, registered and restricted. Access to data in the open category will be “easy, timely, user-friendly and web-based without any process of registration/authorisation.” But data in the registered access category will be accessible “only through a prescribed process of registration/authorisation by respective departments/organisations” and available to “recognised institutions/organisations/public users, through defined procedures.” Data categorised as restricted will be made available only “through and under authorisation.”<br /><br />The policy also provides for pricing, with the Ministries and Departments being asked to formulate their norms for data in the registered and restricted access categories within three months of the notification of the policy.</p>
<p><a class="external-link" href="http://www.thehindu.com/sci-tech/technology/article3223645.ece">Read the original published in the Hindu </a></p>
<p>
For more details visit <a href='https://cis-india.org/news/open-access-to-govt-data'>https://cis-india.org/news/open-access-to-govt-data</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Open Data </dc:subject>
<dc:subject> Open Content </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-03-26T07:31:48Z </dc:date>
<dc:type> News Item </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/francis-wins-ept-award">
<title>
Francis Bags EPT Award for Open Access in Developing World
</title>
<link>
https://cis-india.org/openness/francis-wins-ept-award
</link>
<description>
<b>The Electronic Publishing Trust recently announced a new annual award to be made to individuals working in developed countries who have made significant contribution for the cause of open access and free exchange of research findings. There were 30 nominations from 17 countries around the world and Dr. Francis Jayakanth from the National Centre of Science Information, Indian Institute of Science, Bangalore was selected for the inaugural EPT Award for Open Access in the Developing World by a committee that went through all the nominations. </b>
<p style="text-align: justify; ">The award function organised by the Electronic Publishing Trust for Development and the Centre for Internet and Society (CIS), Bangalore was held at the Sambasivan Auditorium, M S Swaminathan Research Foundation (MSSRF) in Chennai on 14 February 2012. Leading luminaries such as Prof. M.S. Swaminathan, Prof. Subbiah Arunachalam, Prof. G Baskaran and Prof. K Mangala Sunder participated in the award felicitation ceremony.</p>
<p style="text-align: justify; ">Giving the welcome speech, Prof. Arunachalam, distinguished fellow at CIS said that Dr. Jayakanth works for the Indian Institute of Science, Bangalore, has trained many students and helped a number of institutes to set up open access repositories. Prof. Arunachalam added that the event is being celebrated in India as the winner is from India and specified that it is being held at the MS Swaminathan Foundation as this was the institution that hosted the first workshop to promote open access. Prof. Swaminathan had a vital role in arranging funds for the workshop. About 50 people had learnt what open access was, how to set up open access repositories, how to use the EPrints software, etc. For this very reason it was decided to hold the event in Chennai and not Bangalore where Dr. Jayakanth is based.</p>
<p align="center"><img src="https://cis-india.org/home-images/Francis7.jpg/image_preview" alt="Participants in the Award Function" class="image-inline image-inline" title="Participants in the Award Function" /></p>
<p style="text-align: justify; ">Felicitating Dr. Jayakanth, Prof. Swaminathan who presented the award added that it is important to highlight the contributions of those who really convert the concept of social inclusion to reality. He said that today every politician talks about inclusive growth. What is this inclusive growth, how do you convert exclusion to inclusion? Exclusion creates large problems, social problems, economic problems, etc. On a concluding note, Prof. Swaminathan said that the Prime Minister, Dr. Manmohan Singh has declared 2012-13 as the year of science and he hopes that there will be a new science policy and technology policy and that he hopes that a very important component of that should be methods of ensuring open access including open access to knowledge and open access to literature.</p>
<table class="plain">
<tbody>
<tr>
<td><img src="https://cis-india.org/home-images/Francis3.jpg/image_preview" title="Francis Jayakanth" height="166" width="174" alt="Francis Jayakanth" class="image-inline image-inline" /></td>
<td style="text-align: justify; ">In his award acceptance speech, Dr. Jayakanth said that the atmosphere was very overwhelming and never in his two-and-a-half decade old career he had the opportunity to speak amidst such luminaries and added that it was a privilege and prestige to have received the award from Prof. Swaminathan, the father of the Green Revolution in India. He also added that no event in India or elsewhere is complete without the active participation and mentioning of the name of Prof. Arunachalam, the greatest advocate of open access that India has seen so far, and that he wouldn’t have been here at the award ceremony but for the timely intervention of Prof. Arunachalam. <br /></td>
</tr>
</tbody>
</table>
<p style="text-align: justify; ">Dr. Jayakanth concluded by saying that he would like to thank Prof. NV Joshi, Prof. Derek Law, Prof. Alma Swan, Prof. Balaram, Prof. N Balakrishnan, Prof. Giridhar, and Prof. TB Rajashekar, and particularly the students of the information and knowledge management programme at the National Centre of Science Information, Indian Institute of Science, who were responsible for the growth of a repository granting more visibility to the 32,000 publications that are part of the repository.</p>
<table class="plain">
<tbody>
<tr>
<td><img src="https://cis-india.org/home-images/Mangala.jpg/image_preview" title="Mangala Sunder" height="130" width="177" alt="Mangala Sunder" class="image-inline image-inline" /><br /></td>
<td style="text-align: justify; ">Prof. Mangala Sunder of IIT Madras and Prof. G Baskaran of the Institute of Mathematical Sciences, Chennai, also participated in the event. Prof. Sunder said that it is for the kind of information that we talk about, which we want to make public for which champions like Dr. Jayakanth have been working on the sidelines but working so efficiently to get institution after institution to convert what is known as a rigid framework into a flexible more open policy of bringing their scientific content to their intellectual information content. He said that he works in the area of content development from the point of view of education and he understands the difficulty of bringing material to the public. <br /></td>
</tr>
</tbody>
</table>
<p style="text-align: justify; ">There are many issues, such as issues about copyright, issues about people owning the information, issues about people feeling very rigid on what they want to say in the public, etc. Dr. Jayakanth has gone through all these exercises for the last 30 years in slowly creating the “little after little” what are called the waterways to finally see that everyone benefits. The linking of science, knowledge and sustainable development to open access to information, open access to research and open access to content completes the whole cycle of knowledge.</p>
<table class="plain">
<tbody>
<tr>
<td><img src="https://cis-india.org/home-images/Baskaran.jpg/image_preview" title="Prof. Basakaran" height="177" width="117" alt="Prof. Basakaran" class="image-inline image-inline" /></td>
<td style="text-align: justify; ">Prof. Baskaran said that it is a very well deserved award and Dr. Jayakanth has definitely raised the bar for future awardees. Prof. Baskaran stressed upon the aspects of open access. He said that as a theoretical physicist he understands the need for open access very well. Physicists, when they have new research results place them in arXiv, the open access repository for preprints in physics. Some people wonder what if some physicists deposit all kinds of articles in the arXiv. Experience has shown that 99 per cent of the articles appear in good journals later. He added that once it is put in the arXiv, the whole world gets access and a bad paper will be noticed and commented upon by many. No one likes to be the author of such a paper! He urged that other sciences, especially the life sciences should have a repository similar to arXiv and requested Prof. Swaminathan to take the intiative at MSSRF. <br /></td>
</tr>
</tbody>
</table>
<hr />
<h2>Dr. Francis Jayakanth</h2>
<p align="left"><img src="https://cis-india.org/home-images/Francis1.jpg/image_preview" alt="Francis with the Award" class="image-inline image-inline" title="Francis with the Award" /></p>
<p style="text-align: justify; ">Dr. Francis Jayakanth is a library-trained scientific assistant based at the National Centre for Science Information (NCSI), the information centre of the Indian Institute of Science (IISc) in Bangalore. He has played a significant role in the establishment of India’s first institutional repository (IR) (<a class="external-link" href="http://eprints.iisc.ernet.in">http://eprints.iisc.ernet.in</a>). He now manages the IR and has provided technical support for establishing IRs in many other universities and institutes in India. He has been the key resource person at many events to train people in setting up IRs and open access journals. He has delivered presentations on IRs, open access journals, the OAI protocol, OAI compliance, and the benefits of open access to authors and institutions and the role of libraries. He has developed a free and open source software tool (CDSOAI), which is widely used. Dr. Jayakanth can indeed be considered an open access ‘renaissance man’, an advocate and technical expert in all aspect of open access development and an inspiration to all, both at the research and policy level.</p>
<p><a href="https://cis-india.org/openness/francis-jayakanth-presentation" class="internal-link" title="Francis Jayakanth's Presentation">See Francis's presentation on Who Benefits from Open Access to Scholarly Literature?</a> [Powerpoint, 1523 KB]</p>
<p><b>See the video of the award function below:</b><b> </b></p>
<hr />
<p><iframe frameborder="0" height="250" src="http://blip.tv/play/AYLtr00A.html?p=1" width="250"></iframe>
<object classid="clsid:d27cdb6e-ae6d-11cf-96b8-444553540000" codebase="http://download.macromedia.com/pub/shockwave/cabs/flash/swflash.cab#version=6,0,40,0" height="100" width="100">
<param name="src" value="http://a.blip.tv/api.swf#AYLtr00A"><embed height="100" width="100" src="http://a.blip.tv/api.swf#AYLtr00A" type="application/x-shockwave-flash"></embed>
</object>
</p>
<p>
For more details visit <a href='https://cis-india.org/openness/francis-wins-ept-award'>https://cis-india.org/openness/francis-wins-ept-award</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Award </dc:subject>
<dc:subject> Open Content </dc:subject>
<dc:subject> Video </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:date> 2013-08-03T05:36:54Z </dc:date>
<dc:type> Blog Entry </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/interoperability-framework-for-e-governance">
<title>
Comments on Technical Standards for Interoperability Framework for E-Governance in India (Phase II)
</title>
<link>
https://cis-india.org/openness/interoperability-framework-for-e-governance
</link>
<description>
<b>The e-Governance Standards Division has called for public comments on the draft of the Technical Standards IFEG Phase II. We from the Centre for Internet and Society have given our comments. </b>
<p>The present document is — as the draft IFEG Phase I document was — an excellent step in the right direction, following very ably the policy guidelines laid down in the National Policy on Open Standards for e-Governance.</p>
<p>The Expert Committee and other contributors have made excellent choices as to the 29 standards that have been laid down in this phase of the IFEG. It is praiseworthy that the majority of these (20) are designated as mandatory, and only nine are designated as interim standards. Furthermore, the system has been quite transparent with the selection of standards, providing concise descriptions for each.</p>
<p>That said, the document could be improved by providing greater detail for those standards which are said to violate the National Open Standards Policy. In the current document, every interim standard is said to violate “clause 2”, rather than providing the more specific details (sub-clause, one-line explanation) about the violation.</p>
<p>It is unfortunate that yet again accessibility-related standards have been passed over in the presentation and archival domain.</p>
<p>As we have mentioned in earlier feedback, many other governmental interoperability frameworks are going beyond merely listing technical standards. Some governments, such as Germany and the EU, go beyond technical interoperability, and also have documents dealing with organizational, informational, and legal interoperability. These are equally important components of an interoperability framework. Other governments also also lay down best practice guides, and other aids to implementation, sometimes even including application recommendations. Further, there are many which lay out standards for the the semantic layer, business services layer, etc.</p>
<p>We at the Centre for Internet and Society are currently advising the government of Iraq on development of their e-Governance Interoperability Framework, and would be glad to extend any support that the Department of IT may require of us, including comments on all further phases.</p>
<h2>Section-specific Comments</h2>
<h3>Section 5.2.8</h3>
<p>It is unclear whether by IEEE 802.11-2007, the base version is being referred to or the amended version, since IEEE 802.11-2007 has been amended by IEEE 802.11n-2009 to include the IEEE 802.11n standard. As IEEE 802.11n has also become an established standard, it is suggested that section 5.2.28 make it clear that the amended standard is being referred to.</p>
<h3>Section 5.2.13</h3>
<p>It is recommended that IMAP v4rev1 (IETF RFC 3501, updated by RFCs 4466, 4469, 4551, 5032, 5182, 5738, 6186, supplemented by RFCs 2177, 4550) be used instead of POP3 (IETF RFC 1939). It is critical that governmental messages be preserved on government servers, and should not simply be downloaded and then deleted as is the default with POP3 implementations. IMAP allows for downloading and offline access to mails as well. Any deletion on the server from the client would be recorded in the server logs, hence allowing for transparency. Given this, and the more advanced features available in IMAP, it should be preferred to POP3. In other government interoperability frameworks where an e-mail access protocol is specified, including those of Germany, Malaysia, and Hong Kong, IMAP is provided as a standard and never is POP3 provided as the sole standard.</p>
<h3>Section 5.2.15</h3>
<p>SAML 2.0 is a standard for exchanging authentication and authorization data between security domains, and is not a ‘Wireless LAN Authentication’ standard. Indeed, section 5.2.8 (IEEE 802.11-2007) talks about ‘Wireless LAN Security’.</p>
<h3>Section 5.2.23<br /></h3>
<p>WML v1.3, as noted, is a declining standard that is deprecated due to the recommendation by W3C of XHTML Basic v1.1. If it is at all included, it should be included not as “Mandatory – Watchlist”, but as “Additional Standard”, as it is a direct competitor to XHTML Basic v1.1.</p>
<p>
For more details visit <a href='https://cis-india.org/openness/interoperability-framework-for-e-governance'>https://cis-india.org/openness/interoperability-framework-for-e-governance</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> pranesh </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-02-29T09:44:07Z </dc:date>
<dc:type> Blog Entry </dc:type>
</item>
<item rdf:about=" https://cis-india.org/news/will-open-access-replace-costly-commercial-publishing-models">
<title>
Will open access replace costly commercial publishing models?
</title>
<link>
https://cis-india.org/news/will-open-access-replace-costly-commercial-publishing-models
</link>
<description>
<b>Cost of research journals going up while funds available are coming down, writes Vasudha Venugopal in an article published in the Hindu on February 19, 2012.</b>
<p>Technology has inherently changed the way science education is propagated. Digital libraries, wikis, webinars, videoconferences, open access and repositories — all seem to be excellent tools for sharing scientific knowledge.</p>
<p><a class="external-link" href="http://www.thehindu.com/multimedia/archive/00929/Open_Access_929199a.pdf">Download the PDF</a></p>
<p>But with the escalating cost of research journals and the economic and logistical challenges that often accompany attending a conference, the open access model is increasingly being recognised as an alternative to expensive commercial publishing models.</p>
<p>Consider the situation at, say, a biological sciences research firm in Chennai. At least 16 per cent of its total budget is spent on the subscription of journals; more than 50 per cent of that going to the two largest publishing companies. Experts say the cost of journals is increasing at an average of eight per cent a year. Further, many academics do not consider work to have been adequately shared if it has been merely published in over-priced journals. </p>
<h3>Boycott <br /></h3>
<p>Incidentally, last week, more than 5,700 researchers started boycotting Elsevier, a leading publisher of science journals, amid growing concerns at cost and accessibility. More than 3,000 academics have signed a petition that claims the publisher charges “exorbitantly high” prices for its journals and criticises its practice of selling journals in ‘bundles,' forcing libraries to buy a large set with many unwanted journals, or none at all. <br /><br />"Since 1950, the volume of research results started getting too large for the scientific societies, leading to the entry of commercial publishers into the field. The cost per journal and the number of such journals are proliferating, while the funds available are coming down,” says Francis Jayakanth, who has been instrumental in creating an institutional repository, ePrints@IISc, which has more than 32,000 publications by researchers. <br /><br />India has nearly 53 registered open access repositories that allow users to download and use documents free. <br /><br />Open access advocates say Indian papers appear in both Indian and foreign journals, roughly in equal proportions, but most Indian journals have a very poor circulation, many of them below 1,500; and most Indian papers appear in low-impact foreign journals. “Most scientists in India are forced to work in a situation of information poverty. Others are unable to access what Indian researchers are doing, leading to low visibility and low use of their work. Thus, Indian work is hardly cited. Both these handicaps can be overcome to a considerable extent if open access is adopted widely, both within and outside the country,” says Subbiah Arunachalam, an open access advocate. <br /><br />Experts say many U.S. universities, including Princeton, MIT and Harvard, have their own repositories. Institutions in India, too, need to set up open-access repositories to ensure their work is available to the public even if it ends up being published in an expensive journal. Even if these are made available in different repositories, one can still access them all if all the repositories are interoperable. </p>
<h3>Trustworthy</h3>
<p>The established method for an academic to circulate his work is to publish in a peer-reviewed journal of repute, and the reader, too, places some degree of trust in the quality of the work being presented. So will open access, with the huge volume of papers, change that? “Not at all, open access is not vanity publishing or self-publishing or about publications that scientists expect to be paid for. Since every paper is peer-reviewed, the quality is never compromised,” says Dr. Jayakanth.</p>
<p><a class="external-link" href="http://www.thehindu.com/sci-tech/technology/article2910344.ece">Read the article in Hindu</a>. Prof. Subbiah Arunachalam has been quoted in it.</p>
<p>
For more details visit <a href='https://cis-india.org/news/will-open-access-replace-costly-commercial-publishing-models'>https://cis-india.org/news/will-open-access-replace-costly-commercial-publishing-models</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:date> 2012-02-23T09:12:10Z </dc:date>
<dc:type> News Item </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/interview-with-francis-jayakanth">
<title> An Interview with Dr. Francis Jayakanth </title>
<link>
https://cis-india.org/openness/interview-with-francis-jayakanth
</link>
<description>
<b>India has been losing out its best talents to the West, however, this trend could be reversed if we create adequate number of world-class institutions and research facilities, and our scientific productivity and quality of research will improve significantly, says Dr. Francis Jayakanth in an email interview with the Centre for Internet and Society, Bangalore. </b>
<ol>
<li style="text-align: justify; "><b>First of all congratulations for winning the inaugural EPT Award for Open Access</b>.<br />Thank you very much.</li>
<li style="text-align: justify; "><b>When did you first take an interest in Open Access and what are your research interests?</b><br />I have always been impressed with the electronic pre-print servers like the <a class="external-link" href="http://arxiv.org/">arXiv</a>, <a class="external-link" href="http://cogprints.org/">Cogprints</a>, etc. I wanted to do something similar for IISc research publications.<br /><br />One of the important activities of the National Centre for Science (<a class="external-link" href="http://www.ncsi.iisc.ernet.in/">NCSI</a>), Indian Institute of Science (<a class="external-link" href="http://www.iisc.ernet.in/">IISc</a>) has been the training programme. Till recently, NCSI was conducting an 18-month training course called Information and Knowledge Management. This was targeted primarily at students graduating from Indian library schools, with a view to providing them with classroom and practical training in the application of ICT. Essentially, the aim was to train the students in how to provide state-of-the-art, computer-based information services. I have been closely associated with this training programme by offering courses and overseeing projects.<br /><br />As part of the training programme the students are expected do a project. Around the year 2001, one of our students, <a class="external-link" href="http://www.linkedin.com/in/madhureshsinghal">Mr. Madhuresh Singhal</a> carried out a project work in implementing GNU Eprints.org software developed by the University of Southampton. Incidentally, ePrints is the first professional <i>software</i> platform for building high quality OAI-compliant repositories. The student project successfully demonstrated the self-archiving concept through institutional repositories. The project work was later implemented to set up the country’s first institutional repository, <a class="external-link" href="http://eprints.iisc.ernet.in/41239/1/Modeling.pdf">eprints@IISc</a> . Ever since, I have been an OA practitioner and an OA advocate.<br /><br />I’m not a hard-core researcher. My work interests lies in using free and open source software for providing web-based information services.</li>
<li style="text-align: justify; "><b>Why Open Access is important to science and particularly India?</b><br />When researchers publish their works in journals and conference proceedings, they would want their works to be read, cited, and built upon by as wide an audience as possible. Much of the scientific publications are being published by commercial publishers. Subscription costs of such publications are very high, constantly increasing, and beyond the means of most of the libraries. The high subscription costs create an access barrier to the scientific literature because of which the publications do not get the kind of visibility that the researchers would like to. The lack of adequate visibility will reduce the potential impact of the publications. This in turn could affect the advancement of knowledge. It is therefore imperative that the access barrier to scientific literature created because of high subscription costs should be overcome and this could be achieved through OA publishing.<br /><br />The problems with respect to research literature that India and other developing countries have always faced are two-fold:<br />
<ul>
<li>Not being able to access high quality scientific literature because of the high subscriptions costs, and</li>
<li>Research reported in the national journals does not reach the global audience because most of the journals published from the country are not indexed by Web of Science (<a class="external-link" href="http://isiknowledge.com/">WoS</a>) and/or <a class="external-link" href="http://www.scopus.com/">Scopus</a> databases, which are leading <a class="external-link" href="http://en.wikipedia.org/wiki/Citation_indexing">citation indexing</a> databases.<br /><br /></li>
</ul>
If all the journals that are being published in the country could migrate to open access platform then the visibility of research works reported in the journals published from the country will automatically improve with time. This has been the experience of several of the OA journals published by <a class="external-link" href="http://www.medknow.com/">MedKnow</a> and others.</li>
<li style="text-align: justify; "><b>In terms of the number of papers published in refereed journals, the number of citations to these papers, citations per paper, and the number of international awards and recognitions won, India’s record is poor. What needs to be done to improve this?</b><br />For a long time now, our country has been losing out the best of the talents to mostly western and other countries. If this trend could be countered by the creation of adequate number of world-class institutions and research facilities, our country's scientific productivity and also quality of research done in the country will improve significantly. This may also trigger reverse brain-drain.</li>
<li style="text-align: justify; "><b>Indian scientists lack access and visibility. They find it tough to access what other scientists have done, due to the high costs of access and libraries in India can’t afford to subscribe to key journals needed by users. Also other researchers are not able to access what Indian researchers are doing leading to low visibility. How can we overcome these deficits? Will adoption of Open Access within and outside India overcome the aforesaid handicaps?</b><br />Access to scientific literature in the country has improved significantly during the last decade or so. This is largely because of the several library consortia that have emerged in the country during that period. However, the existing consortia and the ones that are likely to emerge in the coming years, is not the solution for the access barrier to scientific literature that exists today. There has to be a world-wide adaptation of OA to overcome the access barrier.</li>
<li style="text-align: justify; "><b>Do you support the movement towards making scientific publications as freely accessible as possible and create an institutional repository? What steps are being taken by the Indian Institute of Science to maintain an open access archive?</b><br />Yes. Open Access Journals and Open Access Archives or Institutional Repositories (IRs) are the two ways to facilitate OA to scholarly literature. As per the <a class="external-link" href="http://www.doaj.org/">DOAJ</a> statistics, today, there are close to 7500 peer reviewed OA journals and as per the Directory of Open Access Repositories (<a class="external-link" href="http://www.opendoar.org/">DOAR</a>) there are more than 2770 institutional repositories across the world.<br /><br />In a recent <a class="external-link" href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0011273">study</a>, <a class="external-link" href="http://www.hanken.fi/staff/bjork/">Bo-Christer Bjork</a> estimated that the overall percentage of scientific literature currently available OA is about 20 per cent. This includes both papers published in OA journals and those deposited in institutional repositories and directly on the Web. So, still a long way to go in achieving 100 per cent OA to scholarly literature! If all the research institutions set up their IRs and ensure that copies of post-prints are placed in the IRs then 100 per cent OA to scholarly literature could be achieved, at least, from now onwards.<a class="external-link" href="http://eprints.iisc.ernet.in/"><br /><br />ePrints@IISc</a>, the OA institutional repository of IISc was established by NCSI in 2002. The repository holds more than 32,400 publications of IISc making the century-old institute’s research far more globally visible than before. NCSI has also provided technical help and support to several other institutes and universities in setting up their repositories and OA journals.</li>
<li style="text-align: justify; "><b>What are the key challenges of the scholarly publications in India?</b><br />Poor visibility and readership of many of the journals published from the country affects the citations of the articles published in such journals. This in turn affects the impact factors (<a class="external-link" href="http://en.wikipedia.org/wiki/Impact_factor">IF</a>) of the journals. No author would like to publish in very low IF journals. </li>
<li style="text-align: justify; "><b>What message would you give to funding agencies, the government and policy makers particularly for implementing a nation-wide mandate for Open Access?</b><br />Most of the research projects in the country are being funded by the government agencies. It is therefore imperative that we should have a nation-wide OA mandate for research publications that emerge from research projects funded from tax payers’ money. Such a mandate will not only help in enhancing the visibility of research done in the country; it may also help in avoiding duplication of research projects carried out in the country. </li>
</ol>
<p>
For more details visit <a href='https://cis-india.org/openness/interview-with-francis-jayakanth'>https://cis-india.org/openness/interview-with-francis-jayakanth</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Interview </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:date> 2012-11-24T06:09:54Z </dc:date>
<dc:type> Blog Entry </dc:type>
</item>
<item rdf:about=" https://cis-india.org/news/research-papers-in-public-domain">
<title> Research papers will be available in public domain </title>
<link>
https://cis-india.org/news/research-papers-in-public-domain
</link>
<description>
<b>IIT-Madras intends to make circle of knowledge complete, writes Vasudha Venugopal in this article published in the Hindu on 15 February 2012. Prof. Subbiah Arunachalam is quoted in the article.</b>
<p>2012-13 was declared the year of science by Prime Minister Manmohan Singh last year, and there is a lot of effort being made all over the country to not only intensify the quantity and quality of research but also ensure greater access for all. For instance, IIT-Madras plans to make available its research papers in all disciplines online, in the public domain. The institute already provides e-learning through online web and video courses in engineering, science and humanities streams through NPTEL.</p>
<p>The attempt now is to convince faculty members to upload their research papers into the institution's repository, says Mangala Sunder Krishnan, Web Coordinator (NPTEL). The move will not only benefit students and faculty members but will also help the circle of knowledge to be complete, he says.</p>
<p>What IIT- Madras plans to do is follow an Open Access policy that would make the access of journals and scientific research public and many other educational organisations plan to follow suite. “Most research publications stay locked up in commercial journals and are inaccessible to many. Open Access is the best way to ensure that research produced in the developing world gets wider visibility,” says Francis Jayakanth, a library-trained scientific assistant based at the National Centre for Science Information, the information centre of the Indian Institute of Science, Bangalore. Mr. Jayakanth has been instrumental in creating an institutional repository ePrints@IISc that has over 32,000 publications by researchers.</p>
<p>Subbiah Arunachalam, distinguished fellow at the Centre for Internet and Society explains: “A research produced by the Tuberculosis Research Centre in Chennai which would be of great relevance to researchers, say in a university in Maharashtra, may not be even noticed by the scientists there. Both groups receive funds from the same source - Government of India - and yet what one does is not easily accessible to the other. “Open Access would bridge that gap and make information available to everyone,” he says.</p>
<p>Open Access repositories would help authors place their papers in an interoperable institutional open access archive and anyone with an Internet connection can access it. Researchers say that in most reputed journals, it takes almost six months to get a paper published, and most insist that the paper is removed from the internal repository of the author's institution once it is published. “But 70 per cent of the publishers are now fine with the authors taking the pre-print of their paper uploaded in the repository. And since in open access, every thing is peer reviewed, the quality is never compromised,” says Mr. Jayakanth.</p>
<p>While institutions such as IIT- Madras subscribe to over 2,000 journals, many colleges under Anna University and University of Madras have access to just about 1,500 journals. “There is almost Rs.10 -12 lakh that the institution spends on journal subscriptions so unless there is funding, many self-financed colleges prefer not to subscribe to journals and go for a few mandatory ones prescribed by AICTE. Students and researchers have no way to acquaint themselves with recent updates,” says D. Krishnan, professor, Anna University.</p>
<p>Even if you go through consortiums, you have to spend Rs.20 lakh which many smaller R&D organisations cannot afford to, adds P. Ramamoorthy, librarian at Sameer- Centre for Electromagnetics, a government-funded research agency. “The restrictions imposed by many commercial publishers do not allow one to legally share the published output of his result with his colleague. Open access will relive authors of such hassles,” he says. </p>
<p><a class="external-link" href="http://www.thehindu.com/news/cities/chennai/article2893901.ece">The original article was published in the Hindu</a></p>
<p>
For more details visit <a href='https://cis-india.org/news/research-papers-in-public-domain'>https://cis-india.org/news/research-papers-in-public-domain</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:date> 2012-02-17T05:38:36Z </dc:date>
<dc:type> News Item </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/free-arduino-workshop">
<title> Free Arduino Workshop (For Beginners) </title>
<link>
https://cis-india.org/openness/free-arduino-workshop
</link>
<description>
<b>The Centre for Internet & Society, Bangalore invites you to a hands-on-free Arduino workshop in its office on 3 March 2012. The workshop will be held from 11.00 a.m. to 3 p.m.</b>
<h2>What is Arduino?</h2>
<p>Arduino, an Italian name meaning "strong friend", is a popular "open-source electronics prototyping platform based around a microcontroller. It accepts inputs, such as signals from sensors (light, temperature, moisture, etc.) or data from the Internet or wireless devices, and sends output signals to devices, such as LEDS, motors, speakers, MIDI sequencers, computers, and so on."</p>
<p>In simpler terms: It is a ready-to-use creative platform, designed to provide interactivity between humans, smartphones, PCs, sensors and the physical world. It is especially a boon for creative people who don't have a technical background and want to translate their wildest techno-ideas to reality in a snap.</p>
<p> </p>
<p> </p>
<p> </p>
<p> </p>
<p> </p>
<p> </p>
<p> </p>
<p><a class="external-link" href="http://goo.gl/YrflS">A comic by Jody Culkin, introducing Arduino</a></p>
<h2>What can Arduino Do?</h2>
<p>Applications of Arduino could include anything under the sun, from making your LED lights glow in reaction to the weather to interactive punching bags: your imagination is the limit (besides the sensors).</p>
<p><a class="external-link" href="http://goo.gl/lF1s8">Check what some folk did with a bunch of cameras for an amazing music video all in one day</a></p>
<p>For other examples, <a class="external-link" href="http://goo.gl/tkvJz">check out the Boing Boing listing</a></p>
<h2>Who can Attend?</h2>
<p>The workshop is especially meant for interaction designers, artists or anyone else enthusiastic to get started with creative projects and don't have prior experience with electronics, interfacing and all that hack talk. It would help to have a general understanding of instructional programming languages, but this shouldn't be a problem for starts as you will pick it up as we go along. Besides, we are super-friendly and patient folk who will assist participants to demystify geek code.</p>
<h2>Apply Now</h2>
<p>We have only 20 seats for this free workshop. Participants will work in groups of two. The workshop will last 4 hours, over a lunch break. All materials will be provided, and it would be great if you could get your laptop. </p>
<p>To apply please send a brief intro about yourself and why you think you will benefit from this to [email protected]. Selected participants will be notified shortly.</p>
<p><a class="external-link" href="http://goo.gl/2DM2j">A map, showing the location of CIS</a></p>
<p> </p>
<p><a class="external-link" href="http://goo.gl/2DM2j"><strong>VIDEOS</strong><br /></a></p>
<p> </p>
<iframe src="http://blip.tv/play/AYLwqQUA.html?p=1" frameborder="0" height="250" width="250"></iframe><embed style="display:none" src="http://a.blip.tv/api.swf#AYLwqQUA" type="application/x-shockwave-flash"></embed>
<iframe src="http://blip.tv/play/AYLxohcA.html?p=1" frameborder="0" height="250" width="250"></iframe><embed style="display:none" src="http://a.blip.tv/api.swf#AYLxohcA" type="application/x-shockwave-flash"></embed>
<p>
For more details visit <a href='https://cis-india.org/openness/free-arduino-workshop'>https://cis-india.org/openness/free-arduino-workshop</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Event Type </dc:subject>
<dc:subject> Workshop </dc:subject>
<dc:subject> Video </dc:subject>
<dc:date> 2012-04-28T04:07:50Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/inaugural-ept-award-for-dr.-francis-jayakanth">
<title> Inaugural EPT Award for Dr. Francis Jayakanth </title>
<link>
https://cis-india.org/openness/inaugural-ept-award-for-dr.-francis-jayakanth
</link>
<description>
<b></b>
<h2>Programme</h2>
<table class="plain">
<tbody>
<tr>
<td>16.00</td>
<td>Welcome and introduction to the award<br /><strong>Subbiah Arunachalam</strong><br /></td>
</tr>
<tr>
<td>16.05</td>
<td>Presenting the award and felicitation<br /> <strong>Prof. M S Swaminathan</strong><br /></td>
</tr>
<tr>
<td>16.15</td>
<td>Acceptance speech<br /> <strong>Dr Francis Jayakanth</strong> <br /></td>
</tr>
<tr>
<td>16.25</td>
<td>Felicitation by eminent scientists<br /><strong>Prof. G Baskaran</strong><br /><strong>Prof. K Mangala Sunder</strong><br /></td>
</tr>
<tr>
<td>16.35</td>
<td>Vote of thanks</td>
</tr>
<tr>
<td>16.40</td>
<td>Tea</td>
</tr>
</tbody>
</table>
Video
<iframe src="http://blip.tv/play/AYLtr00A.html?p=1" frameborder="0" height="250" width="250"></iframe><embed style="display:none" src="http://a.blip.tv/api.swf#AYLtr00A" type="application/x-shockwave-flash"></embed>
<p>
For more details visit <a href='https://cis-india.org/openness/inaugural-ept-award-for-dr.-francis-jayakanth'>https://cis-india.org/openness/inaugural-ept-award-for-dr.-francis-jayakanth</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:subject> Open Access </dc:subject>
<dc:date> 2012-02-27T12:24:25Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/summary-of-the-minutes-of-the-workshop-on-biodiversity-informatics">
<title>
Summary of the Minutes of the Workshop on Biodiversity Informatics
</title>
<link>
https://cis-india.org/openness/summary-of-the-minutes-of-the-workshop-on-biodiversity-informatics
</link>
<description>
<b>The Western Ghats Portal team had organized a one-day workshop to explore the contemporary state of biodiversity informatics as expressed in three spheres: technology behind biodiversity informatics, scientific commons and policy and biodiversity portals in India. It hoped to provide an opportunity to interact and learn from similar endeavors in this emerging discipline. The workshop was held at Ashoka Trust for Research in Ecology and Environment (ATREE), Bangalore on 25 November 2011.</b>
<p>There were 5 speakers and 10 panelists representing as many portal
initiatives, participating at the venue or via WebEx, addressing an
audience of 75 comprising of students, researchers, representatives from
governmental bodies and technological platforms.The entire day’s
sessions were peppered with questions and discussions, directed to the
presenters as also within the members of the audience.</p>
<p>The technology session presented an Indian initiative, Bhuvan, a
geospatial data alternative to GoogleEarth that was pertinent to the
India centric audience. The second presentation was the Atlas of Living
Australia, an international endeavor that was able to give a broad
overview of how government funding for the sharing of government data on
a public platform was able to source large information and present it
for open access on a portal. The project aims to serve a variety of
users from scientists, citizen scientists to policy makers and activists
in biodiversity and conservation. The WGP was presented by a discussion
of architecture and design of participation interface for recording and
accumulating biodiversity observation data. The scientific commons and
policy session covered a wide range of topics: the interpretation of the
Indian laws for portal developments across disciplines, the
governmental policies that may hinder the development of Open source
platforms, the creative commons licenses and how they work for
scientific data, and whether developing a biodiversity commons would
help the community at large.</p>
<p>Global initiatives in the area of scientific commons were presented.
Views from the participants on various aspects and the practicality of a
legal framework were discussed. There are plans to discuss and evolve a
draft of a charter for scientific commons that would be relevant for
biodiversity and conservation. A clearly articulated and agreed data
policy is also one of the deliverables of the project.</p>
<p>The third session centred on the experience of India-centric
biodiversity portals. Two of the panelists presented their portals and
attended the session over WebEx from the United States. A spectrum of
portals was presented. Some of them were focused on single taxa, or a
theme focus from medicinal plants to thematic citizen science
initiatives. The IBP and WGP were presented as broad based with large
collections of spatial data and species data. Perspective plans of large
biodiversity portal initiatives, like the GBIF node for India, INBIF,
were outlines to showing the things that may come in the next few years.</p>
<p>The discussions revolved around scientific rigor versus citizen
participation, large-scale projects v/s small-scale focused portals, and
maintaining quality with crowd sourced data. Ideas about how peer
recognition and scientific status could be achieved were discussed.
Focused portals closely managed by experts to provide valuate
biodiversity and species data were discussed, with methods of
maintaining quality and curating data. The event concluded by
discussions of how each portal can maintain its identity and focus but
at the same time evolve mechanisms for interoperability and exchange of
information. There were open discussions on whether we can network and
provide easy toolkits for building focused participation sites.</p>
<h2>Minutes of the Workshop on Biodiversity Informatics</h2>
<h3>Objectives of the Workshop</h3>
<p>Over the last few years, Biodiversity Informatics has emerged as a
field to aggregate and consolidate biodiversity information across the
world. With the increased penetration of the Internet into developing
economies, and the widespread adoption of web technologies, biodiversity
informatics has spawned an impressive variety of initiatives. These
initiatives range from global knowledge bases and networks, national
initiatives, eco-region based initiatives, as well as sharply focused
initiatives which address a single species or event. There have been
tangible advantages for stakeholders from these initiatives which has
inspired many other endeavors. Success stories exist at both global and
local level, and learning from these experiences can help one understand
the multi-faceted nature of this discipline.</p>
<p>The Western Ghats Portal team organized a one-day workshop to explore
the contemporary state of biodiversity informatics as expressed in
three spheres: i) technology behind biodiversity informatics, ii)
scientific commons and policy and iii) biodiversity portals in India.
The workshop was intended to bring together technologists, open data
policy experts, leaders of portal initiatives and user groups and
stakeholders to meet and discuss experiences and approaches to
Biodiversity Informatics.</p>
<p>Seventy five participants attended the workshop covering governmental
agencies, NGO’s, academic institutes, student groups, CEPF grantees and
other relevant stakeholders. There were 5 speakers and 10 panelists
representing as many portal initiatives, participating at the venue or
via WebEx from the continents of Australia and North America.</p>
<h3>Plenary I: Technology behind biodiversity informatics - 0930 - 1115 hrs</h3>
<p>This session was introduced by Dr.B.Ramesh of the French Institute of
Pondicherry, who welcomed the participants of the workshop. He
highlighted the growth of Biodiversity Informatics leveraging the
Internet. In this emerging discipline, stressed the need to take stock
of the latest developments in the area.</p>
<p><strong>Development of Information System, Open Data standards, Archive and Geospatial solutions, Visualization in Bhuvan - M. Arulraj</strong>, National Remote Sensing Centre (NRSC), Indian Space Research Organization (ISRO).</p>
<p>Arulraj gave an overview of the Bhuvan project, ISRO’s geo-portal
serving as a rich geteway to Indian earth observations. The project was
launched in August 2009 and has made rapid strides since then to expose
earth observation images and thematic maps on the Indian sub-continent.
The Bhuvan project has multiple modules, which include 3-D and 2-D
visualizations; a data archive and data download; thematic land use and
land cover maps; a mobile application; and a discussion forum. The
project is in active development and in beta, but is adding many
features and data to the portal. In addition to data dissemination it
provides a webGIS platform with the ability to do analyses and create
geographical layers by users. The Bhuvan portal conforms to the national
map policy while exposing spatial information and imagery through its
evolving portal.</p>
<p>Arulraj explained the architecture of the portal and surveyed the
webGIS and open source technologies that were available. A demo terminal
of Bhuvan was exposed during the lunch session. During the discussions
on map policy, Arulraj quoted that as per Remote Sensing Data Policy
(RSDP)-2011, all satellite data of resolutions up to 1 m shall be
distributed on a nondiscriminatory basis and on “as requested basis” by
NRSC/ISRO.</p>
<p><strong>Architecture and design of participation interfaces - Anand Janakiraman</strong>, Western Ghats Portal</p>
<p>Anand Janakiram spoke about the design of participation interfaces
for the Western Ghats portal. The intent was to engage with user groups
on the user interfaces and usability of an observation interface, where
users will be able to upload a multi-media object; provide a location
for the observation; make a species call with a certain level of
confidence; and provide notes and comments on the observation. The
observation will be rated by the crowd. Species calls could be changed
if necessary and agreed or disagreed upon.</p>
<p>Various rating systems were discussed. These included a 5 or ten star
rating system, like movie rating systems; a multi-dimensional rating
system like in Wikipedia; a “like” rating system that is used in many
sites; and an expert based rating system. There was a lot of discussion
on rating systems among the participants concerning the necessity of an
expert based system; the wisdom of the public in identifications; a
simple and easy to use rating system on the portal.</p>
<p><strong>Challenges on the emerging discipline of Biodiversity Informatics - Donald Hobern</strong>, Atlas of Living Australia - Web participation.</p>
<p>Donald Hobern participated in the session from Australia over the
Internet. His talk and presentation was viewed by the participants via
two-way WebEx where he answered questions and interacted with the
audience.</p>
<p>Donald presented the Australian Government supported
multi-institutional project called the Atlas of Living Australia (ALA).
The ALA is a multi-institutional project with large funding to build a
comprehensive biodiversity site focused on Australia. The conceptual
model for the portal is to build a platform that will aggregate
biodiversity information resources from specimen records, field
observations, literature, images, experts and amateurs. The information
will be integrated as species pages, distributions, regional atlases,
and nomenclature. Through this, the portal aims to serve a whole range
of users ranging from researchers, taxonomists, land-use planners, and
conservation and park managers.</p>
<p>Donald explained the typical specimen, field occurrence and
occurrence data and how it is the data is presented via collections. He
also explained the services to manage sensitive data and name services
available to the public through APIs. The ALA also has rich mapping
tools that help relate biodiversity to spatial parameters like rainfall,
temperature and other abiotic and biotic factors.</p>
<p>ALA also develops user communities among various stakeholders that
include resource management groups, conservation groups, ecological
researchers, environmental agencies, field naturalists and taxonomy
researchers. They also develop specific use cases and applications for
each of these groups.</p>
<p>The questions and interaction session was animated, even though it
was on the Internet. One of the issues raised was that the ALA seems to
be building an all encompassing and comprehensive portal, without any
particular focus theme or focus group. How was the planning of features
and functions being done? Donald’s response was the portal team would
build functions that they thought would be useful and then engage with
user groups to better and fine-tune the application. They engage with
user groups about functions on the portal.</p>
<p>The Western Ghats Portal team would like to thank Donald Hobern for
his active participation in the workshop with a valued presentation on
the state-of-the-art of a comprehensive biodiversity portal.</p>
<h3>Plenary II: Scientific commons and policy - 1130 - 1300 hrs</h3>
<p>The session was chaired by Dr. Ravi Chellam of the Madras Crocodile
Bank Trust. Ravi introduced the session and the speakers. The idea was
to generate discussions on data sharing policy among the participants in
the context of the Indian legal framework of map policy, biodiversity
act, intellectual property, scientific creative commons, and the culture
and attitude of Indian scientists. Ravi suggested that the session
should lead to further discussions to evolve a policy for data sharing
among biodiversity and conservation researchers and to evolve a charter
for the best practices among the community.</p>
<p><strong>Commons in the context of Biodiversity Information - Danish Sheikh</strong>, Alternative Law Forum</p>
<p>Danish Sheikh from the Alternate Law Forum (ALF) discussed the
creative commons and stressed that it maintains the copyright of the
contributor. Creative Commons only specifies the terms of sharing the
information and in today’s Internet driven world open access to
information was essential. With a complex legal framework of creative
commons, map policy, biodiversity act, and research interests of
individuals, for sharing biodiversity data we must consider property
versus propriety. The sharing of information on the portal must be seen
from the non-commercial and academic nature of the information as well
as the use of data for social good of conservation. Government data in
the form of maps and reports should be sharable on an artistic license
and they could be deployed on the portal. In the sharing of biodiversity
information, there are no concrete cases of violations of laws and thus
there are no examples to learn from.</p>
<p>Danish Sheikh had prepared a draft of declaration to be discussed and
agreed upon by the community. This was to be circulated to the
participants, comments solicited and a broad consensus evolved on the
best practices for sharing biodiversity information. The discussions
centered on the map policy and the need to carefully study the map
policy and the biodiversity act from a legal perspective and arrive at a
policy for the portal that will conform to the laws and acts in India.</p>
<p><strong>Open data in the scientific realm - Sunil Abraham</strong>, Centre for Internet and Society</p>
<p>Sunil Abraham from the Center for Internet and Society (CIS) spoke on
various national and international initiatives on open data in the
scientific realm. National consultations and discussions have been going
on towards evolving a National Data Sharing and Accessibility Policy
(NDSAP) among scientists and researchers in the country. The principle
of the policy is based on openness, flexibility, transparency, legal
conformity, protection of intellectual property, formal responsibility,
and professionalism. Based on these principles, various definitions have
evolved. He stressed upon a clear articulation of non-sharable data in
the negative list based upon the legal framework and Right to
Information Act; restricted access data and open access data.</p>
<p>Sunil Abraham also discussed various international initiatives on
scientific data sharing especially in the ecology and biodiversity
realm. He spoke of the Eye on Earth initiative for evolving a sharing
policy, the framework of the Shared European Environment Information
System (SEIS) and various standards for data sharing.</p>
<p>Discussions were around the issues of motivations for data sharing
and building social networks and peer encouragement for data sharing. He
opined that there was no recipe for engaging the crowd towards building
and participating on social networks and sharing information.</p>
<p>Sunil also suggested that the community should evolve a best
practices policy document by discussions and debates among themselves.
CIS should be seen as a service provider and advocate for evolving a
shared policy and lobbying with government if necessary. But the
biodiversity community should provide the lead in this effort and the
CIS would only be advisory.</p>
<h3>Plenary III - Biodiversity portals in India - 1400 - 1700 hrs</h3>
<p>The session was moderated by MD Madhusudan of the Nature Conservation
Foundation, Mysore. Over the last few years there has been a multitude
of portals focused on aggregating and publishing biodiversity
information of the Indian sub-continent. Some of these portals are
focused upon a region or taxa or subject of interest and some portals
address a wider canvas of issues on biodiversity and conservation. The
session was focused on presentations by each of the portals, presenting
the key features and focus of their portals; the experience of building
and running the portals; key lessons learnt and future plans for the
portal.</p>
<p>The response for the sessions on biodiversity was enthusiastic. Over
12 portal initiatives were presented. Some of the presentations were by
participants in the United States, who run portals on India. The
presentations and participation was done over WebEx sessions overcoming
the challenge of different time zones.</p>
<p>Madhusudhan moderated the session, keeping focus, and allowing time for discussions and debates.</p>
<p><strong>V.B Mathur</strong>, Indian Biodiversity Information Facility (InBIF)</p>
<p>VB Mathur presented plans for a GBIF node to be set up in India at
the Wildlife Institute of India called Indian Biodiversity Facility
(InBIF). The project is just being initiated and is conceived as a broad
and participative initiative to address the challenges to conservation
in the 21st century India. With a growing economy, the objective is to
provide biodiversity information to build sustainable development for
larger and inclusive populations of India. The InBIF has developed a
vision and mission statement and will produce a concept paper by a
consultative process by next year 2012. InBIF recognizes that such an
inclusive biodiversity portal will require significant funding and the
involvement of already present biodiversity portals. InBIF proposes to
seek substantial funding based on the concept paper via the 12th
Five-Year-Plan period starting 2012-2013.</p>
<p><strong>Suhel Quader</strong>, Season Watch (<a class="external-link" href="http://www.seasonwatch.in/">http://www.seasonwatch.in</a>), Migrant Watch (<a class="external-link" href="http://www.migrantwatch.in/">http://www.migrantwatch.in</a>)</p>
<p>Suhel Quader presented two portals Seasons Watch and Migrant Watch
focused on citizen science initiatives. The Seasons Watch portal is
focused on the observation and recording of seasons as revealed by
trees, by their fruiting, flowering and leaf fall patterns. About 100
species are observed all over the country. Migrant Watch observes the
arrival and departure of migrant bird species across the sub-continent.
Both these large citizen science efforts are focused on the recording
and understanding of seasons to create a base-line of data on seasons
and their variations. These sites are driven by questions and
hypotheses. The sites have an active citizen participation. The portals
are planning to expand significantly into school networks. The data
generated by citizens are freely available on the portals and it
encourages others to download, explore, analyze and publish analysis on
the data accumulated on the portal.</p>
<p>Sanjay Molur, Pterocount (<a class="external-link" href="http://www.pterocount.org/">http://www.pterocount.org/</a>)</p>
<p>Sanjay Molur presented Pterocount a South Asian bat monitoring
program. The project is aimed at creating awareness about bat
conservation issues and developing data on the status of South Asian bat
populations. There are about 3500 species of bats and data on the bat
roosts and their populations is collected through online portals as well
as offline forms. The information from all these sites will be compiled
and analyzed for trends in the population of bats, to identify key
threats to roosts and to provide recommendations for their conservation.
The data collected is contributed to the IUCN and is shared with other
researchers under creative commons licenses. The study is currently
focused on a single bat species Pteropus giganteus, but plans to expand
to other bat species as well.</p>
<p><strong>Suma Tagadur</strong>, Foundation for Revitalisation of Local Health Traditions (<a class="external-link" href="http://envis.frlht.org/">http://envis.frlht.org</a>)</p>
<p>Sathya Sangeetha presented the medicinal plants’ envis site
maintained by the Foundation for Revitalisation of Local Health
Traditions. The site is focused on the development of a database for
medicinal plants with details of taxonomy, local names, status,
distribution and trade. The site undertakes a systematic update for 12
medicinal plants per year. They also study the conservation status of
medicinal plants and help in the identification of a plant red list.
They have plans to develop a children’s portal for increasing awareness
of medicinal plants among children. With a focused agenda, the site has a
specific and valuable role in biodiversity and conservation of India.</p>
<p><strong>Ramesh BR</strong> - Western Ghats Portal (<a class="external-link" href="http://www.thewesternghats.in/">http://www.thewesternghats.in/</a>)</p>
<p>BR Ramesh presented the Western Ghats Portal. This is a relatively
young initiative launched about six months ago building on the India
Biodiversity Portal. The focus of the portal is to collect biodiversity
and conservation information on the Western Ghats, a biodiversity
hotspot. The portal has a map module, a species pages module, a
collaborative module and integrative theme pages. The portal has
aggregated significant available data on the Western Ghats and deployed
it on the portal. The portal plans to add an observation recording
interface and campaign for large scale participation on the portal, and
species identification keys.</p>
<p><strong>Shwetank Verma</strong>, Biodiversity of India, formerly Project Brahma (<a class="external-link" href="http://www.biodiversityofindia.org/">http://www.biodiversityofindia.org</a>)</p>
<p>Shwetank Verma presented the Biodiversity of India Portal. The portal
is developed and managed completely by voluntary effort, and is aimed
at being a wiki resource on the biodiversity of India. The site
aggregates data on Indian biodiversity from various public sites and
presents it attractively on the portal. It has an effective search
engine LigerCat that helps index all information on the portal. It aims
to add and enrich information on the human and cultural aspects of
species and their uses. The portal is keen on networking and sharing
information with other biodiversity sites by building necessary APIs for
interactions between various biodiversity sites.</p>
<p><strong>Krushnamegh Kunte</strong>, ifoundbutterflies (<a class="external-link" href="http://ifoundbutterflies.org/">http://ifoundbutterflies.org/</a>) web participation</p>
<p>Krushnamegh Kunte presented the ifoundbutterfiles portal over a WebEx
session from the United States. ifoundbutterflies is a community site
on the butterflies of India. It contains information on species pages,
life cycle pages, photographs, and identification keys of over 600
species of butterflies in India. All information is carefully peer
review and curated a team of biologists studying and researching
butterflies. The data is assuredly authenticated and verified and will
form a reliable source of butterfly information on India. </p>
<p><strong>Vijay Barve</strong>, DiversityIndia (<a class="external-link" href="http://diversityindia.org/">http://diversityindia.org/</a>) web participation</p>
<p>Vijay Barve presented the DiversityIndia, a social network group over
a WebEx session from the United States. The effort started off as a
yahoo group and then moved to facebook as a more convenient platform to
share information on the biodiversity of India. It plans to aggregate
the information posted in these groups into a site that will maintain
and develop biodiversity databases. The group is open to sharing
information and resources with other portals working on the biodiversity
of India.</p>
<p><strong>Deepak Menon</strong>, India Water Portal (<a class="external-link" href="http://www.indiawaterportal.org/">http://www.indiawaterportal.org/</a>)</p>
<p>Samuel Rajkumar presented the India Water Portal. Their portal is
supported by campaigning for participation and awareness among various
fora on water resources. The features include a question bank and an
interaction with experts on water; a data repository on water; and a
children’s section. The portal is currently working on a data project
aimed at accumulating a large repository of water related data on the
portal for open access. The portal intends on expanding with a map
component and a data visualization module.</p>
<p><strong>Chitra Ravi</strong>, India Biodiversity Portal (<a class="external-link" href="http://indiabiodiversity.org/">http://indiabiodiversity.org/</a>)</p>
<p>Chitra Ravi presented the India Biodiversity Portal. The portal was
started in 2008 after the first phase of portal development. Over the
past year, the portal has been enriched with checklists and species
pages. The portal is closely integrated with the Western Ghats Portal
sharing the platform, its features and the data. A comparison of the
availability of data in EOL showed that for the lesser known flora and
fauna, there is very little information publicly available. The portal
expects to fill this gap, by generating rich species and distribution
content for Indian species.</p>
<p><strong>M.D. Madhusudhan</strong>, Status of Golden Jackals in India</p>
<p>MD Madhusudhan presented a focused and time-based project on the
Golden Jackals on India. The site campaigned and crowd sourced on the
current and historical occurrence of the golden jackal in India. The
enthusiasm for participation was evident with large data collection. The
data was analyzed and made available publicly and freely to whoever
wanted to use the data. There was a need felt for a generic portal to
support such focused time-based crowd sourcing and citizen science
efforts.</p>
<p><strong>K.Sankara Rao</strong>, Centre for Ecological Sciences, IISc</p>
<p>K Sankara Rao, presented the Center for Ecological Sciences’ creation
of a virtual herbarium database from the rich herbarium available at
the Institute. The herbarium is Father Saldhana’s collection on the
flora of Karnataka and has the best representation of plant specimens of
Karnataka. The effort to digitize the herbarium is a passionate project
that will make the herbarium resources to be more widely available.
Sankara Rao requested volunteers to come forward and work on the
project.</p>
<p><strong>Discussions and summary of the day:</strong></p>
<p>The discussions centered on a range of topics and concerns for
Biodiversity Informatics in India. They focused on the following themes:</p>
<p>Large and comprehensive portals versus narrow and focused portals.
While focused portals seem efficient in achieving their objectives,
large portals are trying to explore different mechanisms of harnessing
and disseminating information. While such large and comprehensive
portals are necessary, they will require larger efforts, longer periods
and significant funding to deliver useful content in biodiversity.</p>
<p>Participation and Quality. There were different views on crowd
sourcing information and validation mechanisms. The importance of
expert-driven efforts on ensuring quality was appreciated, while there
was recognition that amateur naturalists and hobbyists could be very
knowledgeable and reliable.</p>
<p>The scientific status of a portal can be enhanced with careful expert
driven peer review mechanism. Portals could also serve as repositories
for data papers publications and citations that would be valued by the
scientific community. Target users for the portal. Discussions on target
users for the portal covered the whole spectrum from specialists and
scientists to activists and concerned citizens. A biodiversity portal
was expected to provide information to a variety of users and
stakeholders, including managers and policy makers.</p>
<p>Data exchange between portals: There was a general consensus on the
interaction and exchange of data among portals. This was heartening to
note, but since all the portals are new and evolving, mechanisms of
exchange and building APIs for exchange was lower in priority for most
portals. However, all portals were open to sharing information. Many of
the citizen science portals have made their data public and
downloadable.</p>
<p>There were discussions on larger projects like the WGP to engage in
technology facilitation for various citizen science projects. This was
discussed and opportunities for such technology facilitation need to be
explored.</p>
<p>Various mechanisms, such as quiz competitions, interaction with
experts, bio-blitzes, campaigns and road shows; to involve and engage
citizens on the portal were discussed. There were open-ended discussions
on how each portal can maintain its identity and focus, but at the same
time evolve mechanisms for interoperability and exchange of
information, and on whether we can network and provide easy tool kits
for building focused participation sites.</p>
<p>Dr. Prabhakar, concluded the event with a thank you note and by
expressing hope that the biodiversity conservation community can build
together on the momentum the workshop has created.</p>
<h2>List of participants present at the Workshop on Biodiversity Informatics, 25th November, 2011, ATREE, Bangalore</h2>
<table class="plain">
<thead>
<tr>
<th>Sr.No</th>
<th>Name</th>
<th>Affiliation</th>
<th>Role</th>
</tr>
</thead>
<tbody>
<tr>
<td>1<br /></td>
<td>Abhisheka</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 2</td>
<td>Ajith Ashokan</td>
<td>Mar Athanasios College for Advanced Studies Tiruvalla<br />(MACFAST), Kerala</td>
<td>Audience</td>
</tr>
<tr>
<td> 3</td>
<td>Amruta</td>
<td>Research and Action in Natural Wealth<br />Administration (RANWA)</td>
<td>Audience</td>
</tr>
<tr>
<td> 4</td>
<td>Anand Janakiraman</td>
<td>Western Ghats Portal</td>
<td>Speaker</td>
</tr>
<tr>
<td> 5</td>
<td>Aneesh A</td>
<td>Ashoka Trust for Research<br />in Ecology and the<br />Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 6</td>
<td>Anup Prasad K S</td>
<td>TCS, Bangalore</td>
<td>Audience</td>
</tr>
<tr>
<td> 7</td>
<td>Anuradha S</td>
<td>University of Maryland,<br />College Park</td>
<td>Audience</td>
</tr>
<tr>
<td> 8</td>
<td>Aravind N A</td>
<td>Ashoka Trust for Research in Ecology and the<br />Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 9</td>
<td>Asha.A</td>
<td>Centre for Ecological<br />Sciences - Indian Institute of<br />Science (IISc)</td>
<td>Audience</td>
</tr>
<tr>
<td> 10</td>
<td>Ashwini H S</td>
<td>Kuvempu University</td>
<td>Audience</td>
</tr>
<tr>
<td> 11</td>
<td>Avinash K S</td>
<td>Kuvempu University</td>
<td>Audience</td>
</tr>
<tr>
<td> 12</td>
<td>Baiju Raj</td>
<td>Agra bear rescue facility</td>
<td>Audience</td>
</tr>
<tr>
<td> 13</td>
<td>Balasubramanian D</td>
<td>French Institute of Pondicherry</td>
<td>Audience</td>
</tr>
<tr>
<td> 14</td>
<td>Baranidharan.K</td>
<td>Forest College and<br />Research Institute</td>
<td>Audience</td>
</tr>
<tr>
<td> 15</td>
<td>Chitra Ravi</td>
<td>Ashoka Trust for Research in Ecology and the<br />Environment (ATREE)</td>
<td>Panelist</td>
</tr>
<tr>
<td> 16</td>
<td>Danish Sheikh</td>
<td>Alternate Law Forum</td>
<td>Speaker</td>
</tr>
<tr>
<td> 17</td>
<td>Deepak Menon<br /></td>
<td>ARGHYAM<br /></td>
<td>Panelist</td>
</tr>
<tr>
<td> 18</td>
<td>Devayani Khare</td>
<td>French Institute of Pondicherry</td>
<td>Audience</td>
</tr>
<tr>
<td> 19</td>
<td>Dharnidharan</td>
<td>French Institute of Pondicherry</td>
<td>Audience</td>
</tr>
<tr>
<td> 20</td>
<td>Dinesh T B</td>
<td>Servelots Infotech Pvt. ltd</td>
<td>Audience</td>
</tr>
<tr>
<td> 21</td>
<td>Dr. B R Ramesh</td>
<td>French Institute of Pondicherry</td>
<td>Panelist</td>
</tr>
<tr>
<td> 22</td>
<td>Dr. Bhaskar Acharya</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 23</td>
<td>Dr. Chikkaswamy</td>
<td>Om Bioscience Research</td>
<td>Audience</td>
</tr>
<tr>
<td> 24</td>
<td>Dr. Easa</td>
<td>Asia Biodiversity Conservation Trust (ABCT)</td>
<td>Audience</td>
</tr>
<tr>
<td> 25</td>
<td>Dr. Gautam Talukdar</td>
<td>Wildlife Institute of India</td>
<td>Audience</td>
</tr>
<tr>
<td> 26</td>
<td>Dr. Gladwin Joseph</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 27</td>
<td>Dr. Jagdish Krishnaswamy</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 28</td>
<td>Dr. K N Ganeshaiah</td>
<td>University of Agricultural Sciences, Bangalore</td>
<td>Panelist<br /></td>
</tr>
<tr>
<td> 29</td>
<td>Dr. Karthikeyan Vasudevan</td>
<td>Wildlife Institute of India</td>
<td>Audience</td>
</tr>
<tr>
<td> 30</td>
<td>Dr. L Shashikumar</td>
<td>Jnana Bharathi, Bangalore University</td>
<td>Audience</td>
</tr>
<tr>
<td> 31</td>
<td>Dr. M H Swaminath</td>
<td>Addl. Principal Chief Conservator of Forests (Wildife)</td>
<td>Audience</td>
</tr>
<tr>
<td> 32</td>
<td>Dr. M Sanjappa</td>
<td>Botanical Survey of India(BSI)</td>
<td>Audience</td>
</tr>
<tr>
<td> 33</td>
<td>Dr. N S Hallikhed</td>
<td>BISB</td>
<td>Audience</td>
</tr>
<tr>
<td> 34</td>
<td>Dr. R Sukumar</td>
<td>Centre for Ecological Sciences (CES), IISc</td>
<td>Audience</td>
</tr>
<tr>
<td> 35</td>
<td>Dr. Ravi Chellam</td>
<td>Madras Crocodile Bank Trust</td>
<td>Speaker</td>
</tr>
<tr>
<td> 36</td>
<td>Dr. V B Mathur</td>
<td>Wildlife Institute of India</td>
<td>Panelist</td>
</tr>
<tr>
<td> 37</td>
<td>G Areendran</td>
<td>Wildlife Institute of India</td>
<td>Audience</td>
</tr>
<tr>
<td> 38</td>
<td>G Muthu Sankar</td>
<td>French Institute of Pondicherry</td>
<td>Audience</td>
</tr>
<tr>
<td> 39</td>
<td>Harinandanan P V</td>
<td>Mar Athanasios College for Advanced Studies Tiruvalla (MACFAST), Kerala</td>
<td>Audience</td>
</tr>
<tr>
<td> 40</td>
<td>Jagadish</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience</td>
</tr>
<tr>
<td> 41</td>
<td> Jyotish M S</td>
<td>Mar Athanasios College for Advanced Studies Tiruvalla (MACFAST), Kerala</td>
<td> Audience</td>
</tr>
<tr>
<td> 42</td>
<td> Kavitha A</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 43</td>
<td> Kiran M C</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 44</td>
<td> Krushnamegh Kunte</td>
<td> Harvard University</td>
<td>Panelist <br /></td>
</tr>
<tr>
<td> 45</td>
<td> M Arulraj</td>
<td>National Remote Sensing Centre (NRSC), Hyderabad</td>
<td> Speaker</td>
</tr>
<tr>
<td> 46</td>
<td> M D Madhusudan</td>
<td> Nature Conservation Foundation</td>
<td> Audience</td>
</tr>
<tr>
<td> 47</td>
<td> M Sathya Sangeetha</td>
<td>Foundation for Revitalisation of Local Health Traditions</td>
<td> Audience</td>
</tr>
<tr>
<td> 48</td>
<td> Madhura Niphadkar</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 49</td>
<td> Meganath V</td>
<td>Mar Athanasios College for Advanced Studies Tiruvalla (MACFAST), Kerala</td>
<td> Audience</td>
</tr>
<tr>
<td> 50</td>
<td> Naveena N L</td>
<td>University of Agricultural Sciences, GKVK, Bangalore</td>
<td> Audience</td>
</tr>
<tr>
<td> 51</td>
<td> Nishadh</td>
<td>Salim Ali Centre for Ornithology and Natural History</td>
<td> Audience</td>
</tr>
<tr>
<td> 52</td>
<td> Prashanth M B</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 53</td>
<td> Priti Gururaj</td>
<td> Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 54</td>
<td> Prof. K Sankara Rao</td>
<td>Centre for Ecological Sciences - Indian Institute of Science (IISc)</td>
<td> Audience</td>
</tr>
<tr>
<td> 55</td>
<td> R C Prasad</td>
<td> Spatial Informatics Lab, IIITHyderabad</td>
<td> Audience</td>
</tr>
<tr>
<td> 56</td>
<td> Radhika Santhanam</td>
<td> Śramani</td>
<td> Audience</td>
</tr>
<tr>
<td> 57</td>
<td> Rahul Yadava</td>
<td>Strand Life Sciences<br /></td>
<td> Audience</td>
</tr>
<tr>
<td> 58</td>
<td> Rajan Pilakandy</td>
<td> Salim Ali Centre for Ornithology and Natural History</td>
<td> Audience</td>
</tr>
<tr>
<td>59</td>
<td> Rakesh K N</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 60</td>
<td> Ramesh Kannan</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 61</td>
<td> Ravikanth</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 62</td>
<td> Sabah Rubina</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 63</td>
<td> Samuel Rajkumar</td>
<td> Independent web-developer</td>
<td> Audience</td>
</tr>
<tr>
<td> 64</td>
<td> Sangeetha Sathya</td>
<td> FRLTH-IAIM</td>
<td> Audience</td>
</tr>
<tr>
<td> 65</td>
<td> Santosh S Gaikwad</td>
<td>Salim Ali Centre for Ornithology and Natural History</td>
<td> Audience</td>
</tr>
<tr>
<td> 66</td>
<td> Seena Narayanan K</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 67</td>
<td>Senthilkumar Umapathy</td>
<td> Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 68</td>
<td> Shashank P R</td>
<td> University of Agricultural Sciences, GKVK, Bangalore</td>
<td> Audience</td>
</tr>
<tr>
<td> 69</td>
<td> Shrinivas K R</td>
<td> Kuvempu University</td>
<td> Audience</td>
</tr>
<tr>
<td> 70</td>
<td> Shwetank Verma</td>
<td> Indian Institute of Science (IISc)</td>
<td> Panelist</td>
</tr>
<tr>
<td> 71</td>
<td> Sivarajan</td>
<td> French Institute of Pondicherry</td>
<td> Audience</td>
</tr>
<tr>
<td> 72</td>
<td> Sreerupa Sen</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td> Audience</td>
</tr>
<tr>
<td> 73</td>
<td> Suhel Quader</td>
<td> National Centre for Biological Sciences (NCBS)</td>
<td> </td>
</tr>
<tr>
<td> 74</td>
<td> Suma Tagadur</td>
<td> Foundation for Revitalisation of Local Health Traditions</td>
<td> Panelist</td>
</tr>
<tr>
<td> 75</td>
<td> Sunil Abraham</td>
<td> Centre for Internet and Society</td>
<td> Speaker</td>
</tr>
<tr>
<td> 76</td>
<td> Supriya K S</td>
<td>National Center for Biological Sciences</td>
<td> Audience</td>
</tr>
<tr>
<td> 77</td>
<td> T Bala</td>
<td> Keystone Foundation - Flora of Nilgiri</td>
<td> Audience</td>
</tr>
<tr>
<td> 78</td>
<td> Veeranagappa P</td>
<td>University of Agricultural Sciences, GKVK, Bangalore</td>
<td> Audience</td>
</tr>
<tr>
<td> 79</td>
<td> Vidyadhar Atkore</td>
<td>Ashoka Trust for Research in Ecology and the Environment (ATREE)</td>
<td>Audience <br /></td>
</tr>
<tr>
<td> 80</td>
<td> Vijay Barve</td>
<td> Diversity India</td>
<td> Panelist</td>
</tr>
</tbody>
</table>
Also see <a href="https://cis-india.org/news/bio-diversity-informatics-workshop" class="external-link">Western Ghats Portal: Workshop on Biodiversity Informatics </a>
<p> </p>
<p>
For more details visit <a href='https://cis-india.org/openness/summary-of-the-minutes-of-the-workshop-on-biodiversity-informatics'>https://cis-india.org/openness/summary-of-the-minutes-of-the-workshop-on-biodiversity-informatics</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Open Data </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-01-30T16:24:40Z </dc:date>
<dc:type> Blog Entry </dc:type>
</item>
<item rdf:about=" https://cis-india.org/openness/geekup-bangalore">
<title> Geekup on Open Data in Bangalore </title>
<link> https://cis-india.org/openness/geekup-bangalore </link>
<description>
<b>HasGeek in partnership with the Centre for Internet and Society invite you to a talk by Hapee de Groot on 25 January 2012 at CIS office in Bangalore.</b>
<h2>Hapee de Groot</h2>
<p>Hapee de Groot has worked on a wide range of issues around Open Source Data, ICT and Media Development, Access, Security, ICT for Development (ICT4D) and Localisation of Content, for a global stage towards greater transparency and accountability with the Dutch NGO Hivos since 2001. Before that, in the nineties, he was an advocate for free public internet access, working with xs4all and the <a class="external-link" href="http://www.nettime.org/Lists-Archives/nettime-l-0101/msg00085.html">digital city Amsterdam</a> (DDS). He has also served as an editor for OneWorld International and ran the Digital Divide Campaign which turned into a still ongoing digital channel at <a class="external-link" href="http://www.digitalopportunity.org/">DigitalOpportunity.org</a>.</p>
<p>Hapee is one of the earliest generations of hackers and is highly influential on the subjects of ICT and Technology, Open Source, Social Media, and Technology in Africa, according to the influence measures on Klout. This is his 5th visit to India where he has worked previously on Mission 2009 and setting up access for remote areas in India, in collaboration with Toxic Links and Sarai, Delhi. He was a participant at the InfoActivism Camp in Bangalore, 2008.</p>
<p>His current interest is in the field of Open Government Data and he partners with six international donor agencies to run the Transparency and Accountability Initiative. He brings together his technical skills, policy experience and development research to train people in understanding the politics, responsibilities and risks associated with open data platforms and helps NGOs and governments in producing secure and citizen friendly platforms of data collection, distribution and dissemination.</p>
<h2>Open Data</h2>
<p>From his background working for a development organisation (HIVOS) Hapee will talk about Open Data and its use for citizen engagement. This is a twofold process. On the one side there is the history of the traditional NGO and their limited impact on the system. On the other side there are the Open Government Data initiatives pushed from within administrations, including by the Obama administration. The question is of how both can benefit from each other.</p>
<p>Hapee has some examples of citizen driven projects in Africa that HIVOS supports. He will present on these projects, including on data visualization and technical platforms. He would like to hear from the audience (that's you!) on similar projects in India.</p>
<p>The other side of the coin is privacy which is a bigger issue in India than in Africa. How can we be open while still protecting privacy? Hapee will lead a discussion on this.</p>
<p><strong>Registrations are closed<br /></strong></p>
<p>Wednesday, 25 January 2012, Bangalore</p>
<table class="plain">
<tbody>
<tr>
<td>Welcome with tea, coffee and snacks</td>
<td>6.00 p.m. - 6.15 p.m.<br /></td>
</tr>
<tr>
<td>Lightning Talks</td>
<td>6.15 p.m - 7.00 p.m.<br /></td>
</tr>
<tr>
<td>Open Data<br /></td>
<td>7.00 p.m. - 8.00 p.m.<br /></td>
</tr>
</tbody>
</table>
<p>
For more details visit <a href='https://cis-india.org/openness/geekup-bangalore'>https://cis-india.org/openness/geekup-bangalore</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Open Data </dc:subject>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-01-31T03:38:25Z </dc:date>
<dc:type> Event </dc:type>
</item>
<item rdf:about=" https://cis-india.org/news/wikipedia-turns-11-today">
<title> Wikipedia turns 11 today </title>
<link>
https://cis-india.org/news/wikipedia-turns-11-today
</link>
<description>
<b>The world's largest free encyclopaedia turns 11 on Sunday. To mark the occasion, the Wikipedia community will host events in seven cities across the country. The community is also celebrating the first anniversary of the Wikimedia India chapter. </b>
<p>On this occasion, the India chapter will launch a new portal (www.wikimedia.in) for easy access to Wikimedia sites in the Indian languages. Wikipedia is currently available in 21 Indian languages.</p>
<p>The India chapter is focussed on creating greater awareness of Wikipedia in Indian languages and to increase the volunteer editor base and Indian content through its initiatives. “The portal will make it easier to locate Indian language Wikipedias and other projects,” said Arun Ram, executive committee member of Wikimedia India.</p>
<p>The Bangalore event, open to all Wikipedia users, contributors and enthusiasts, is being held at the Centre for Internet and Society at Domlur (Bangalore).</p>
<p>Besides Bangalore, events are being held in Ahmedabad, Cuttack, Delhi, Kolkata, Mumbai and Pune, all centres where Wikipedia editors or contributors are present in sizeable numbers.</p>
<p>‘Deepen engagement with students'</p>
<p>In order to address the complaint raised by the industry about students' “poor employability”, the Bangalore Chamber of Industry and Commerce organised a seminar in Bangalore on Wednesday.</p>
<p>A recent survey by the World Bank indicated that there was a “severe mismatch” between the skill sets required by the IT-ITES industry and what was available in graduates from Indian institutions.</p>
<p>S. Sadagopan, director, Indian Institute of Information Technology, said the level of engagement of the academic institutions with the students needed to be “reoriented and deepened”. “Equally important is the responsibility of the recruiters in changing their recruitment processes,” said Prof. Sadagopan. He added, “The question is, are you giving the recruits a challenging job?”</p>
<h3>Award for networking major</h3>
<p>Cisco announced that its Networking Academy has won the prestigious eINDIA 2011 jury choice award for the ‘Best ICT Enabled Skills Development Initiative'.</p>
<p>The award was conferred on Cisco Networking Academy in recognition of its efforts toward enabling students to develop valuable information, communications and technology skills for increased access to opportunities in the global economy, a release from the networking major said.</p>
<p>Speaking on the occasion, Bina Raj-Debur, regional head, Social Innovation Group, India and South Asia, said: “We are proud to receive this prestigious award. It is testimony to the continued efforts of the Networking Academy programme to make a positive difference to the skills-building efforts of the nation and the communities in which we live and operate. At Cisco, we aim to enhance the employability of youth through technology, enabling them to harness the enormous opportunities in the ICT domain. We are very pleased that our efforts have been recognised by industry and society alike.” </p>
<h3>Help with transition to IPv6 <br /></h3>
<p>Global IT major Hewlett Packard (HP) has signed a partnership agreement with the Government of Karnataka and the International Institute of Information Technology, Bangalore, to conduct a pilot project that will help organisations in Karnataka through a smooth transition to Internet Protocol version 6 (IPv6).</p>
<p>The current version of IP addressing, IPv4, is reaching its theoretical maximum of about four billion Internet addresses. IPv6 is the new Internet addressing protocol with the capacity to support 340 trillion addresses, a press release from HP said. This allows for the dramatic expansion of connected devices from computers and smart phones, to household electronics, industrial appliances, vehicles and commercial systems.</p>
<p>IPv6 also provides for improved quality and new applications like IP TV, telephony and ecommerce. The pilot project aims at identifying major challenges in IPV6 adoption, developing solutions to meet these challenges and actively promoting IPV6 adoption. </p>
<p><a class="external-link" href="http://www.thehindu.com/news/cities/bangalore/article2801684.ece">The news was published in the Hindu on 15 January 2012</a></p>
<p>
For more details visit <a href='https://cis-india.org/news/wikipedia-turns-11-today'>https://cis-india.org/news/wikipedia-turns-11-today</a>
</p>
</description>
<dc:publisher> No publisher </dc:publisher>
<dc:creator> praskrishna </dc:creator>
<dc:rights/>
<dc:subject> Openness </dc:subject>
<dc:date> 2012-01-16T09:41:30Z </dc:date>
<dc:type> News Item </dc:type>
</item>
| https://cis-india.org/search_rss?Subject%3Alist=Openness&b_start%3Aint=710&sort_order=ascending |
Republic Act No. 3482
Republic Acts - An Act Granting the Ormoc City Telephone Company, Inc. a Franchise to Install, Operate and Maintain a Telephone System in the City of Ormoc
REPUBLIC ACT No. 3482
An Act Granting the Ormoc City Telephone Company, Inc. a Franchise to Install, Operate and Maintain a Telephone System in the City of Ormoc
Be it enacted by the Senate and House of Representatives of the Philippine Congress Assembled:
Section 1.
Subject to the conditions established in this Act and the provisions of Commonwealth Act Numbered One hundred forty-six, as amended, and of the Constitution, applicable thereto, there is hereby granted to Ormoc City Telephone Company, Inc., hereinafter called the grantee, its successors and assigns for a period of fifty years from the approval of this Act, the right and privilege to construct, maintain and operate in the City of Ormoc, hereinafter referred to as the city, a telephone system to carry on the business of the electrical transmission of conversations and signals in the city. For this purpose, the grantee is hereby authorized to use all streets and public thoroughfares of the city for the construction, maintenance and operation of all apparatus, conductors, and appliances necessary for the electrical transmission of conversations and signals, to erect poles, string wires, build conduits, lay cables, and to construct, maintain, and use such other approved and generally accepted means of electrical conduction in, on, over or under the public roads, highways, lands, bridges, streets, lanes, and sidewalks of the city, and overhead or underground lines or on the surface of the ground as may be necessary and best adapted to said transmission.
Section 2.
All cables laid, all poles erected and all conduits constructed or used by the grantee shall be located in places designed by the grantee with the approval of the municipal board of the city:
Provided,
That all poles erected and used by the grantee or its successors or assigns shall be of such appearance as not to disfigure the roads or streets, and the wires and cables carried by said poles and the underground cables shall be strung and laid in accordance with professional standards approved by the Public Service Commission; and said poles shall be of such a height as to maintain the wires and cables stretched on the same at a height of at least fifteen feet above the level of the ground, and said wires and cables shall be so placed as not to imperil the public safety, in accordance with the plan approved by the Public Service Commission:
Provided, further,
That whenever twenty-five or more pairs of wires or other conductors are carried on one line of poles in any place of the city, said wires or conductors shall be placed in one cable, and whenever more than eight hundred pairs of wires or other conductors are carried on one line of poles, said wires or conductors shall be placed underground by the grantee, its successors or assigns, whenever ordered to do so by the Public Service Commission.
Section 3.
For the purpose of erecting and placing the poles or other supports of such wires or other conductors or of laying and maintaining underground said wires, cables or other conductors, it shall be lawful for the grantee, its successors or assigns, to make excavations or lay conduits in any of the public places, highways, streets, alleys, lanes, avenues, sidewalks or bridges in the city:
Provided,
That any public place, highway, street, alley, lane, avenue, sidewalk or bridge disturbed, altered or changed by reason of the erection of poles or other supports, or the laying underground of wires or other conductors, or of conduits, shall be repaired and restored to the satisfaction of the city engineer, and removing from the same all rubbish, dirt, refuse, or other material which may have been placed there or taken up in the erection of aid poles or the laying of said underground conduits, leaving them in as good condition as they were before the work was done.
Section 4.
Whenever any person has obtained permission to use any of the streets of the city for the purpose of removing any building or in the prosecution of any city work or for any other cause whatsoever, making it necessary to raise or remove any of said wires or conduits which may obstruct or hinder the prosecution of said work, the grantee, upon notice by the municipal board of the city, served upon said grantee, at least forty-eight hours in advance, shall raise or remove any of said wires or conduits which may hinder the prosecution of such work or obstruct the removal of said building, so as to allow the free and unobstructed passage of said building and the free and unobstructed prosecution of said work, and the person or entity at whose request the wires or poles or other structures have been removed, shall pay one-half of the actual cost of replacing the poles or raising the wires and other conductors or structures.
1awp++i1
The notice shall be in the form of a resolution duly adopted by the municipal board of the city and served upon the grantee or its duly authorized representative or agent by a person competent to testify as witness in a civil action, and in case of refusal or failure of the grantee to comply with such notice, the city mayor, with the approval of the municipal board of the city first had, shall order such wires or conduits to be raised or removed at the expense of the grantee, for the purpose aforesaid.
Section 5.
All apparatus and appurtenances used by the grantee, its successors or assigns, shall be modern and first class in every respect, and all telephone lines or installations used, maintained and operated in connection with this franchise by the grantee, its successors or assigns, shall be kept and maintained at all times in a satisfactory manner, so as to render an efficient and adequate telephone service, and it shall be the further duty of the grantee, its successors or assigns whenever required to do so by the Public Service Commission, to modify, improve and change such telephone system for the electrical transmissions of conversations and signals by means of electricity in such manner and to such extent as the progress of science and improvements in the method of electrical transmission of conversations and signals by means of electricity may make reasonable and proper.
Section 6.
The grantee, its successors or assigns, shall keep a separate account of the gross receipts of its telephone business, and shall furnish to the Auditor General and the Treasurer of the Philippines a copy of such account not later than the thirty-first day of January of each year for the twelve months preceding the first day of January.
Section 7.
The grantee, its successors or assigns shall be liable to pay the same taxes on their real estate, building, and personal property, exclusive of this franchise, as other persons or corporations are now or hereafter may be required by law to pay. In addition, the grantee, its successors or assigns, shall pay to the Treasurer of the Philippines each year, within ten days after the audit and approval of the accounts as prescribed in Section six of this Act, one per centum of all gross receipts of the telephone business transacted under this franchise, by the grantee, its successors or assigns, said percentage shall be in lieu of all taxes on this franchise or its earnings.
Section 8.
Within sixty days from the approval of this Act, the grantee shall file with the Public Service Commission its application for a certificate of public necessity and convenience. In case of failure to make said application within the period established, this franchise shall become null and void.
Section 9.
The grantee shall not commence any construction whatever pursuant to this franchise without first obtaining a certificate of public necessity and convenience from the Public Service Commission of the form and character provided for in Commonwealth Act Numbered One hundred forty-six, as amended, specifically authorizing such construction. The grantee shall not exercise any right or privilege under this franchise without first having obtained such certificate of public necessity and convenience from the Public Service Commission. The Public Service Commission shall have the power to issue such certificate of public necessity and convenience whenever it shall, after due hearing, determine that such construction or such exercise of the rights and privileges under his franchise is necessary and proper for the public convenience, and the Commission shall have the power in issuing such certificate to impose such conditions as to construction, equipment, maintenance, service or operation as the public convenience and interests may reasonably require, and such certificate shall estate the date on which the grantee shall commence construction and the period within which the work shall be completed. In order to avail itself of the rights granted by such certificate of public necessity and convenience, the grantee shall file with the Public Service Commission, within such period as said Commission shall fix, its written acceptance of the terms and conditions of this franchise and of the certificate, together with the document evidencing the fact that the deposit required in Section ten had been made. In the event that the grantee shall not commence the telephone service referred to in the certificate obtained and filed as herein provided within such period as the Public Service Commission shall have fixed, said Commission may declare said certificate null and void and the deposit pursuant to Section ten of this Act forfeited to the National Government unless the grantee shall have been prevented from doing so by fortuitous cause or force majuere, usurped or military power, martial law, riot, uprising, or other inevitable cause:
Provided,
That if the grantee shall have been prevented by any of said causes from commencing the telephone service within the period specified, the time during which he shall have been so prevented shall be added to said period:
Provided, further,
That failure on the part of the grantee to accept the conditions of this franchise and those imposed in the certificate of public necessity and convenience shall automatically void this franchise.
Section 10.
Upon the written acceptance of the terms and conditions of this franchise, the grantee shall deposit with the Treasurer of the Philippines one thousand pesos, or negotiable bonds of the Government of the Philippines or other securities approved by the Secretary of Public Works and Communications, of the face value of one thousand pesos as an earnest of good faith in accepting this franchise and a guaranty that, within six months from the date of the granting by the Public Service Commission of the certificate of public necessity and convenience authorizing the construction and operation by the grantee of a telephone service in the city, the grantee, its successors or assigns, will be completely provided with the necessary equipment and ready to begin operation in accordance with the terms of this franchise:
Provided,
That if the deposit is made in money, the same shall be deposited at interest in some interest-paying bank approved by the Secretary of Public Works and Communications, and all interest accruing and due on such deposit shall be collected by the Treasurer of the Philippines and paid to the grantee, its successors or assigns, on demand:
Provided, further,
That if the deposit made with the Treasurer of the Philippines be in negotiable bonds of the Government of the Philippines or other interest-bearing securities approved by the Secretary of Public Works and Communications, the interest on such bonds or securities shall be collected by the Treasurer of the Philippines and paid over to the grantee, its successors or assigns on demand.
Should the grantee, its successors or assigns, for any other cause than the act of God, the public enemy, usurped or military power, martial law, riot, civil commotion, or inevitable cause, fail, refuse, or neglect to begin within twelve months from the date of the granting of said certificate of public necessity and convenience, the business of transmitting messages by telephone, or fail, refuse, or neglect to be fully equipped and ready to operate, within twelve months from the date of the granting of said certificate of public necessity and convenience, the telephone service in the city applied for by the grantee according to the terms of this franchise, then the deposit prescribed by this section to be made with the Treasurer of the Philippines, whether in money, bonds, or other securities, shall become the property of the National Government as liquidated damages caused to such Government by such failure, refusal, or neglect, and thereafter no interest on said bonds or other securities deposited shall be paid to the grantee, its successors or assigns. Should the grantee, its successors or assigns, begin the business of transmitting messages by telephone and be ready to operate according to the terms of this franchise the telephone service in the city within twelve months from the date of the granting of said certificate of public necessity and convenience, then and in that event the deposit prescribed by this section shall be returned by the National Government to the grantee, its successors or assigns, upon recommendation of the Public Service Commission, as soon as the telephone service in the city applied for by the grantee has been installed in accordance with the terms of this franchise:
Provided,
That all the time during which the grantee, its successors or assigns, may be prevented from carrying out the terms and conditions of this franchise by any of said cause shall be added to the time allowed by this franchise for compliance with its provisions.
Section 11.
The books and accounts of the grantee, its successors or assigns, shall always be open to the inspection of the city auditor or his authorized representative, and it shall be the duty of the grantee, its successors or assigns, to submit to the Auditor General quarterly reports in duplicate showing the gross receipts and the net receipts for the quarter past and the general condition of the business.
Section 12.
The rights herein granted shall not be exclusive, and the right and power to grant to any corporation, association, or person other than the grantee, franchise for the telephone or electrical transmission of messages of signals shall not be impaired or affected by the granting of this franchise:
Provided,
That the poles erected, wires strung or cables or conduits laid by virtue of any franchise for telephone or other electrical transmission of messages and signals granted subsequent to this franchise shall be so placed as not to impair the efficient and effective transmission of conversations or signals under this franchise by means of poles erected, wires strung, or cables or conduits actually laid and in existence at the time of the granting of said subsequent franchise:
Provided, further,
That the Public Service Commission, after hearing both parties interest may compel the grantee of this franchise or its successors or assigns to remove, relocate, or replace its poles, wires or conduits; but in such case the reasonable cost of the removal, relocation, or replacement shall be paid by the grantee of the subsequent franchise or its successors or assigns to the grantee of this franchise of its successors or assigns.
Section 13.
The grantee, its successors or assigns, shall hold the national, provincial, city and municipal government harmless from all claims, accounts, demands or actions arising out of accidents or injuries, whether to property or to persons, caused by the construction or operation of the telephone or other electrical transmission system of the grantee, its successors or assigns.
Section 14.
The rates for the telephone service, flat rates as well as measured rates, shall be subject to the approval of the Public Service Commission.
The monthly rates for telephone having a metallic circuit within the limits of the city shall also be approved by the Public Service Commission.
Section 15.
The grantee shall not, without the previous and explicit approval of the Congress of the Philippines, directly or indirectly, transfer, sell or assign this franchise to any person, association, company, or corporation or other mercantile or legal entity. The successors or assigns of the grantee shall be firmly bound to comply with all the terms and conditions imposed upon the grantee by this franchise and by any and all certificates of public necessity and convenience issued to the grantee by the Public Service Commission or its legal successor, and to accept the same subject to all existing terms and conditions.
Section 16.
The grantee may install, maintain and operate an extension line within the same office or building, with a maximum of five telephone connections.
Section 17.
The grantee may install, maintain, operate, purchase or lease such telephone stations, lines, cables, or system, as is, or are, convenient or essential to efficiently carry out the purpose of this franchise:
Provided,
That the grantee, its successors or assigns, shall not, without the permission of the Public Service Commission first had, install, maintain, operate, purchase or lease such stations, lines, cables or systems.
Section 18.
The Philippine Government shall have the privilege, without compensation, of using the poles of the grantee to attach one ten-pin crossarm, and to install, maintain and operate wires of its telegraph system thereon:
Provided,
That the Bureau of Telecommunications shall have the right to place additional crossarms and wires on the poles of the grantee by paying a compensation the rate of which is to be agreed upon by the Director of Telecommunications and the grantee:
Provided, further,
That in case of disagreement as the rate of contract rental, the same shall be fixed by the Public Service Commission. The city also have the privilege, without compensation, of using the poles of the grantee, to attached one standard crossarm, and to install, maintain and operate wires of a local police and fire alarm system; but the wires of such telegraph lines, police or fire alarm system shall be placed and strung in such manner as to cause no interference with or damage to the wires of the telephone service of the grantee.
Section 19.
It is expressly provided that in the event the Government should desire to maintain and operate for itself the system and enterprise herein authorized, the grantee shall surrender its franchise and will turn over to the Government said system and all serviceable equipment therein, at cost, less reasonable depreciation.
Section 20.This Act shall take effect upon its approval.
Approved: June 16, 1962.
| https://www.lawphil.net/statutes/repacts/ra1962/ra_3482_1962.html |
Search Results | Failure Analysis | ASM Digital Library
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DOI: 10.31399/asm.fach.power.c0048845
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between the drum connector box and the junction valve. The
in question was 15 in. bore and had been in service for about 50 years...
During a hydraulic test on one of the boilers in a range, leakage occurred from the lower surface of a horizontal S bend in the main steam pipe between the drum connector box and the junction valve. The pipe in question was 15 in. bore and had been in service for about 50 years. Specimens were prepared for microscopical examination to include the defective zone and a section through a circumferential crack. The defective zone was found to contain numerous inclusions of slag and oxides of globular form. Regions surrounding the inclusions were decarburized, the indications being that this region of the plate had been heated to an excessively high temperature. A corrosion-fatigue fissure was at one location, this having originated at the internal surface of the pipe and run into an inclusion in the defective zone. The failure resulted from the development of corrosion-fatigue fissures which originated at a zone containing defects introduced at the time of manufacture. These may have had their origin in the ingot from which the plate was rolled or, alternatively, be indicative of a zone which suffered overheating and local burning at the time the forge weld was made.
Book Chapter
Feedwater Piping Erosion at a Waste-to-Energy Plant
By Wendy L. Weiss , Brian McClave
Book: Handbook of Case Histories in Failure Analysis
Series: ASM Failure Analysis Case Histories
Volume: 2
Publisher: ASM International
DOI: 10.31399/asm.fach.v02.c9001276
Turbulent flow Wall thickness Carbon steel Erosive wear Velocity-affected corrosion Erosion - corrosion Background Wall thinning and leaking were plaguing the feedwater
in a waste-to energy plant ( Fig. 1 ). Following the initial leaks, the
was analyzed by the
Abstract
Book Chapter
Cracking in a Boiler Steam Drum
By T.L. da Silveira , I. Le May
Book: ASM Failure Analysis Case Histories: Power Generating Equipment
Series: ASM Failure Analysis Case Histories
Publisher: ASM International
DOI: 10.31399/asm.fach.power.c9001002
... Abstract During the inspection of a
containing cracks at the superheater header connection, cracking also was detected within the main steam drum. This was fabricated from a Mn-Mo-V low-alloy steel. It operated with water and saturated steam at approximately 335 deg C. Cracking...
Abstract
During the inspection of a boiler containing cracks at the superheater header connection, cracking also was detected within the main steam drum. This was fabricated from a Mn-Mo-V low-alloy steel. It operated with water and saturated steam at approximately 335 deg C. Cracking was detected at the nozzles connecting the tubes for the entry of steam and hot water to the drum, at the downcomers, and at the connection to the safety valve. All cracks had a similar morphology, running in a longitudinal direction along the drum from the cutouts in the shell. All the cracks had developed under the influence of the hoop stress and were associated with the locally increased stress levels relating to the cutouts at nozzle and pipe connections. At their ends the cracks were filled with corrosion products, and their surfaces were seen to be very irregular. The process of crack growth was not due to fatigue only but can most probably be attributed to corrosion fatigue. The boiler steam drum design should be reviewed to reduce the local level of stress at the shell-nozzle connections.
Book Chapter
Stress Corrosion Cracking of Welded Butt Joints in Piping Handling Caustic Soda
Book: ASM Failure Analysis Case Histories: Chemical Processing Equipment
Series: ASM Failure Analysis Case Histories
Publisher: ASM International
DOI: 10.31399/asm.fach.chem.c9001407
... to a temperature of 130 deg C (266 deg F). Magnetic crack detection revealed circumferential crack-like indications situated a short distance from the butt weld. Cracking originated on the bore surfaces of the tube and was of an intergranular nature reminiscent of caustic cracking in steam
. The strength...
Abstract
The onset of leakage adjacent to two butt welds in a 2 in. bore pipe was traced to the development of fine cracks. The pipe carried 40% sodium hydroxide solution. The actual temperature was not known, but the pipeline was steam traced at a pressure of 30 psi, equivalent to a temperature of 130 deg C (266 deg F). Magnetic crack detection revealed circumferential crack-like indications situated a short distance from the butt weld. Cracking originated on the bore surfaces of the tube and was of an intergranular nature reminiscent of caustic cracking in steam boilers. The strength of the solution of caustic soda and possibly the temperature also were in the range known to produce stress-corrosion cracking of mild steels in the presence of stresses of sufficient magnitude. In this instance the location of the cracking suggested that residual stresses from welding, which approach yield point magnitude, were responsible. As all other welds were suspect, the remedy was to remove the joints and to reweld followed by local stress relief.
Book Chapter
Failure Analysis for a Carbon Steel Vaporizer Coil
Book: ASM Failure Analysis Case Histories: Chemical Processing Equipment
Series: ASM Failure Analysis Case Histories
... coil 5 following the second, most recent failure. The root cause failure analysis method was used in the current study. This method was implemented successfully by the Electric Power Research Institute in their
tubes failure correction, prevention, and control research project [ 1...
Abstract
A root cause failure analysis was performed on a vaporizer coil removed from a horizontal forced circulation vaporizer. The carbon steel coil was wound in a right-hand helix with a coil centerline diameter of about 2 m. The vaporizer was gas fired and used Dowtherm A as the heat transfer fluid. Design conditions are based on annular fluid flow to cool the coil wall. NDE, metallographic and fractographic examinations were performed. Numerous, circumferentially oriented, OD initiating cracks were found near the crown for two coils near the non-fired end of the vaporizer. The cracking was confined to the inner diameter of the vaporizer coil at positions from 4:00 to 7:00. The cracking was characterized as transgranular and the fracture surface had beach marks. The failure mechanism was thermal fatigue. The heat transfer calculation predicted that dryout of the coil would occur for coils at the non-fired end of the vaporizer during low flow transients. Dryout results in rapid increase in the tube wall temperature. Thermal cycling of the coil is completed by liquid quenching resulting from resumption of normal flow rates and the return to annular flow. The probable root cause of failure was low flow transient operation.
Book Chapter
Stress-Corrosion Cracking of Type 316 Stainless Steel Piping
Book: ASM Failure Analysis Case Histories: Chemical Processing Equipment
Series: ASM Failure Analysis Case Histories
| https://dl.asminternational.org/failure-analysis/search-results?q=Boiler%20pipes |
Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives | Request PDF
Request PDF | Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives | We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar... | Find, read and cite all the research you need on ResearchGate
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References (82)
Abstract
We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar patients and 35 of their relatives, and 113 nonpsychiatric subjects and 42 of their relatives. The frequency characteristics of the EEG showed moderate stability for a subgroup of these subjects (n = 106) who were tested twice, approximately 9 months apart. Both the schizophrenia and bipolar patients showed a generalized pattern of increased delta and theta and decreased alpha activity. The bipolar patients demonstrated additional right hemisphere activity that was not present among the schizophrenia patients and nonpsychiatric subjects, a finding consistent with hypotheses concerning nondominant hemisphere involvement in the regulation of elated mood. The schizophrenia patients' female relatives and/or relatives with affective disorders and the bipolar patients had significantly reduced peak alpha frequencies. This finding may be related to reduced information processing capacity among these subjects.
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... Resting-state EEG evaluations are designed to determine intrinsic brain activity not induced by a task. In an attempt to use EEG to diagnose BD, studies have been carried out [14] [15]
[16][17]. ...
... During this project, the authors aimed to discover if individuals with BD have different synchronization or network characteristics in their resting EEG. In another study, resting EEG was once again utilized to distinguish between individuals with first-episode SCH, bipolar psychosis, and their first-degree relatives [15]
. The researchers also employed resting EEG methods to investigate whether SCH and bipolar patients suffer from altered cortical functional networks [16]. ...
... • For alpha, BD patients exhibited a decrease in mean synchronization [13]. Also, in another study, there was a reduction in alpha activity in BD patients and reduced peak alpha frequencies [15]
. ...
Bipolar disorder traits: An electroencephalogram systematic review Article Full-text available
Dec 2022
Tien Dat Nguyen Toi Van Vo Thi Thanh Huong Ha
Bipolar disorder (BD) is a serious mental disorder that globally affected 40 million people in 2019. According to the National Alliance on Mental Illness (NAMI), the present state of scientific knowledge only permits psychiatrists to diagnose BD using subjective and imprecise questionnaires. Therefore, developing a diagnostic tool with objective and precise biomarkers should be a major focus of research in this field. Among the potential biomarkers for BD, electroencephalogram (EEG)-based signatures of BD are considered to be the most optimal marker due to their strong links with behavioural symptoms and also their non-invasiveness. The goal of this review is to give a detailed summary of current techniques for investigating the traces of BD through EEG abnormalities. In this review, 13 studies from databases such as ScienceDirect and PubMed seeking to utilize EEG characteristics to diagnose BD were selected. The search keywords were “EEG in BD diagnosis”, “EEG microstates in BD”, and “EEG features for BD patients”. The publication date was set from 2007 to 2021. From these studies, we synthesize the effects of BD on each EEG feature, as well as detail the pros and cons when using each feature as a biomarker for BD. Results showed that EEG microstates demonstrate their potential among the seven EEG properties discussed in this article, as shown by several studies. By definition, EEG microstates are a dynamic representation of the spatial distribution of the scalp's electric potential as it varies over time. Specifically, four microstate classes recorded in different brain regions are classified into A (right-frontal left-posterior), B (left-frontal right-posterior), C (midline frontal-occipital), and D (midline frontal topographies). Greater presence of microstate class B in BD patients during task-free resting states are a distinctive characteristic of BD patients from which BD can be differentiated from other psychiatric illnesses. Besides microstates, EEG resting states are also considered to have a bright future in BD diagnosis. Specifically, by investigating brain frequency bands, researchers have discovered that BD patients exhibit abnormal delta and alpha signals as compared to healthy controls (HCs). The abnormalities of microstate B in EEG microstate characteristics would be the most promising biomarker for detecting BD. In addition, anomalies in delta and alpha signals during resting EEG states are possible BD diagnostic indicators.
View Show abstract
... Another study (Hong et al., 2012), identified abnormal low-frequency theta-alpha as a specific SCZ risk marker. An increase in first-episode and chronic SCZ patients in theta frequency band is one of the most consistent observations in schizophrenia EEG/ERP studies, which can occur both locally and globally (Ciprian et al., 2021; Clementz et al., 1994)
. SCZ patients had theta/alpha band desynchronization, which started about 0.2 s after stimulus initiation, according to the results of a timefrequency study. ...
... The results of the present study concerning differences between SCZ patients and HCs in these two bands might be related to long range connectivity deviances, that if detected in future studies, could serve as a biomarker for schizophrenia. Moreover, the differentiation between first-degree relatives of patients from controls in the alpha and theta bands
(Clementz et al., 1994;
Hong et al., 2012), provide an indication for future investigation of whether such dissociation corresponds also to a connectivity differentiation between first-degree relatives of patients from controls, further suggesting that such functional deviances might be heritable. Few studies have explicitly evaluated whether those who are genetically predisposed to schizophrenia show schizophrenic symptoms (i.e., first-degree relatives) and irregularities in the resting state, implying that the delta and theta bands are amplified (Alfimova and Uvarova, 2003), specifically showing reduced frequency of the peak alpha (Clementz et al., 1994) and augmented beta (Winterer et al., 2001). ...
... Moreover, the differentiation between first-degree relatives of patients from controls in the alpha and theta bands (Clementz et al., 1994;Hong et al., 2012), provide an indication for future investigation of whether such dissociation corresponds also to a connectivity differentiation between first-degree relatives of patients from controls, further suggesting that such functional deviances might be heritable. Few studies have explicitly evaluated whether those who are genetically predisposed to schizophrenia show schizophrenic symptoms (i.e., first-degree relatives) and irregularities in the resting state, implying that the delta and theta bands are amplified (Alfimova and Uvarova, 2003), specifically showing reduced frequency of the peak alpha
(Clementz et al., 1994)
and augmented beta (Winterer et al., 2001). ...
Convolutional neural network propagation on electroencephalographic scalograms for detection of schizophrenia Article
Apr 2022 CLIN NEUROPHYSIOL
Alexandra Korda Errikos Ventouras
Pantelis Asvestas Nikolaos Smyrnis
Objective
Electroencephalographic analysis (EEG) has emerged as a powerful tool for brain state interpretation. Studies have shown distinct deviances of patients with schizophrenia in EEG activation at specific frequency bands.
Methods
We present evidence for the validation of a Convolutional Neural Network (CNN) model using transfer learning for scalp EEGs of patients and controls during the performance of a speeded sensorimotor task and a working memory task. First, we trained a CNN on EEG data of 41 schizophrenia patients (SCZ) and 31 healthy controls (HC). Secondly, we used a pretrained model for training. Both models were tested in an external validation set of 15 SCZ, 16 HC, and 12 first-degree relatives.
Results
Using the layer-wise relevance propagation on the classification decision, a heatmap was produced for each subject, specifying the pixel-wise relevance. The CNN model resulted in the first case in a balanced accuracy of 63.7% and 81.5% in the second case, on the external validation test 64.5% and 83.2%, respectively.
Conclusions
The theta and alpha frequency bands of the EEG signals had significant relevance to the CNN classification decision and predict the first-degree relatives indicating potential heritable functional deviances.
Significance
The proposed methodology results in important advancements for the identification of biomarkers in schizophrenia heritability.
View Show abstract
... Findings concerning delta band during resting-state in the early phases of schizophrenia are controversial, with some studies Frontiers in Psychiatry | www.frontiersin.org reporting no abnormality in delta power (73) or synchrony (74), while others finding differences between these subjects and HCs in power (75)
(76)(77)(78)(79) or functional connectivity (80) within this band activity. ...
... Specifically, studies during a resting-state condition that found abnormalities in delta band in FES compared to HCs, have reported a higher power (75)
(76)(77). Furthermore, additional studies and analyses also showed a lower delta amplitude peak (77), an excess of delta activity in prefrontal areas (78), and a distributed hypo-synchronization of delta activity between cerebral regions, mostly observed in parietal areas as suggested through LORETA analysis (78,80). ...
... In particular, some studies reported no significant difference in the theta band activity between HCs and FEP (87), FES (73,76,77), or HR (87) subjects. Other studies reported an increase in theta band activity in FES subjects compared to HCs (75,
88) during resting conditions. The increase in theta activity in FES was associated with the severity of negative symptoms (88) and this alteration was observed also in HR-T if compared to HR-NT and HCs (79). ...
EEG-Based Measures in At-Risk Mental State and Early Stages of Schizophrenia: A Systematic Review Article Full-text available
May 2021
Andrea Perrottelli Giulia Giordano
Francesco Brando Armida Mucci
Introduction: Electrophysiological (EEG) abnormalities in subjects with schizophrenia have been largely reported. In the last decades, research has shifted to the identification of electrophysiological alterations in the prodromal and early phases of the disorder, focusing on the prediction of clinical and functional outcome. The identification of neuronal aberrations in subjects with a first episode of psychosis (FEP) and in those at ultra high-risk (UHR) or clinical high-risk (CHR) to develop a psychosis is crucial to implement adequate interventions, reduce the rate of transition to psychosis, as well as the risk of irreversible functioning impairment. The aim of the review is to provide an up-to-date synthesis of the electrophysiological findings in the at-risk mental state and early stages of schizophrenia.
Methods: A systematic review of English articles using Pubmed, Scopus, and PsychINFO was undertaken in July 2020. Additional studies were identified by hand-search. Electrophysiological studies that included at least one group of FEP or subjects at risk to develop psychosis, compared to healthy controls (HCs), were considered. The heterogeneity of the studies prevented a quantitative synthesis.
Results: Out of 319 records screened, 133 studies were included in a final qualitative synthesis. Included studies were mainly carried out using frequency analysis, microstates and event-related potentials. The most common findings included an increase in delta and gamma power, an impairment in sensory gating assessed through P50 and N100 and a reduction of Mismatch Negativity and P300 amplitude in at-risk mental state and early stages of schizophrenia. Progressive changes in some of these electrophysiological measures were associated with transition to psychosis and disease course. Heterogeneous data have been reported for indices evaluating synchrony, connectivity, and evoked-responses in different frequency bands.
Conclusions: Multiple EEG-indices were altered during at-risk mental state and early stages of schizophrenia, supporting the hypothesis that cerebral network dysfunctions appear already before the onset of the disorder. Some of these alterations demonstrated association with transition to psychosis or poor functional outcome. However, heterogeneity in subjects' inclusion criteria, clinical measures and electrophysiological methods prevents drawing solid conclusions. Large prospective studies are needed to consolidate findings concerning electrophysiological markers of clinical and functional outcome.
View Show abstract
... Schizophrenia has shown increased low frequency power and coherence. Although findings for bipolar disorder have been less well characterized than schizophrenia, bipolar disorder has shown increased low frequency power and decreased alpha frequency power
(11)
(12)(13)(14). In addition, Kam et al. (14) reported that bipolar disorder showed increased high frequency power and coherence while schizophrenia showed increased low frequency connectivity within and across hemispheres. ...
... After dividing pre-processed EEG data into 2 s (2,048 points) epochs, all the epochs including significant physiological artifacts (amplitude exceeding ± 75 mV) at any of the 62 electrodes were rejected. In order to exclude any epochs with drowsiness, we calculated the relative power of theta (4-8 Hz) and alpha (8)(9)(10) (11)
(12) bands. Then, we rejected any epochs with ratios of the theta band power to the alpha band power exceeding 1, since these epochs were regarded as drowsiness or sleep stage 1 (38)(39)(40). ...
... Altered theta-band activities have repeatedly been reported in patients with schizophrenia and bipolar disorder. Resting-state EEG studies consistently reported that patients with schizophrenia show augmented theta-band power (9, 11)
. A study investigating source functional connectivity during resting-state EEG reported that schizophrenia patients had greater functional connectivity than healthy controls in theta band. ...
Altered Cortical Functional Networks in Patients With Schizophrenia and Bipolar Disorder: A Resting-State Electroencephalographic Study Article Full-text available
Jul 2020
Sungkean Kim Yong-Wook Kim
Miseon Shim Seung-Hwan Lee
Background
Pathologies of schizophrenia and bipolar disorder have been poorly understood. Brain network analysis could help understand brain mechanisms of schizophrenia and bipolar disorder. This study investigates the source-level brain cortical networks using resting-state electroencephalography (EEG) in patients with schizophrenia and bipolar disorder.Methods
Resting-state EEG was measured in 38 patients with schizophrenia, 34 patients with bipolar disorder type I, and 30 healthy controls. Graph theory based source-level weighted functional networks were evaluated: strength, clustering coefficient (CC), path length (PL), and efficiency in six frequency bands.ResultsAt the global level, patients with schizophrenia or bipolar disorder showed higher strength, CC, and efficiency, and lower PL in the theta band, compared to healthy controls. At the nodal level, patients with schizophrenia or bipolar disorder showed higher CCs, mostly in the frontal lobe for the theta band. Particularly, patients with schizophrenia showed higher nodal CCs in the left inferior frontal cortex and the left ascending ramus of the lateral sulcus compared to patients with bipolar disorder. In addition, the nodal-level theta band CC of the superior frontal gyrus and sulcus (cognition-related region) correlated with positive symptoms and social and occupational functioning scale (SOFAS) scores in the schizophrenia group, while that of the middle frontal gyrus (emotion-related region) correlated with SOFAS scores in the bipolar disorder group.Conclusions
Altered cortical networks were revealed and these alterations were significantly correlated with core pathological symptoms of schizophrenia and bipolar disorder. These source-level cortical network indices could be promising biomarkers to evaluate patients with schizophrenia and bipolar disorder.
View Show abstract
... Given rhythm, it is perhaps not surprising that these systems are disrupted in patients with psychotic disorders. Multiple studies have reported that patients with schizophrenia have decreased resting state alpha power, but there are also reports of increased alpha power
(Clementz et al., 1994;
Karson et al., 1988;Goldstein et al., 2015;Harris et al., 2006;Boutros et al., 2008;Narayanan et al., 2014). Decreased alpha power has been reported in a variety of psychiatric and neurological illnesses as well as in healthy relatives of individuals with psychotic disorders (Clementz et al., 1994;Boutros et al., 2008;Narayanan et al., 2014;Basar et al., 2012;Karadaǧ et al., 2003;Prinz and Vitiello, 1989;Llinas et al., 1999). ...
... Multiple studies have reported that patients with schizophrenia have decreased resting state alpha power, but there are also reports of increased alpha power (Clementz et al., 1994;Karson et al., 1988;Goldstein et al., 2015;Harris et al., 2006;Boutros et al., 2008;Narayanan et al., 2014). Decreased alpha power has been reported in a variety of psychiatric and neurological illnesses as well as in healthy relatives of individuals with psychotic disorders
(Clementz et al., 1994;
Boutros et al., 2008;Narayanan et al., 2014;Basar et al., 2012;Karadaǧ et al., 2003;Prinz and Vitiello, 1989;Llinas et al., 1999). Alpha power is decreased in medication-naïve first episode schizophrenia patients as well as in chronic, medicated patients and euthymic bipolar patients without psychotic symptoms (Clementz et al., 1994;Goldstein et al., 2015;Basar et al., 2012). ...
... Decreased alpha power has been reported in a variety of psychiatric and neurological illnesses as well as in healthy relatives of individuals with psychotic disorders (Clementz et al., 1994;Boutros et al., 2008;Narayanan et al., 2014;Basar et al., 2012;Karadaǧ et al., 2003;Prinz and Vitiello, 1989;Llinas et al., 1999). Alpha power is decreased in medication-naïve first episode schizophrenia patients as well as in chronic, medicated patients and euthymic bipolar patients without psychotic symptoms
(Clementz et al., 1994;
Goldstein et al., 2015;Basar et al., 2012). It is unlikely to be a medication effect given that patients with affective disorders who use antipsychotic medication appear to be indistinguishable from controls (Goldstein et al., 2015). ...
Decreased peak alpha frequency and impaired visual evoked potentials in first episode psychosis Article Full-text available
Feb 2019
Michael Murphy Dost Öngür
Abnormal spontaneous and evoked oscillations have been reported in several studies of patients with psychotic disorders. Resting alpha power and peak alpha frequency may be decreased in patients with psychosis. We used high-density EEG (hd-EEG) to record resting-state data and steady-state visual evoked potentials (SSVEPs) in patients with first episode psychosis (FEP) and healthy controls to compare brain resonances across multiple frequencies. We recorded hd-EEG (128 channels) from 22 FEP patients and 22 healthy controls during eyes-closed resting state and eyes-closed photic stimulation at 1 Hz, 4 Hz, 10 Hz, 20 Hz, and 40 Hz. Alpha power, peak alpha frequency, and SSVEP amplitude were analyzed using ANOVA and statistical non-parametric mapping. We found that FEP patients had lower peak alpha frequencies (9.72 Hz vs 10.40 Hz, p = .02, Cohen's d = 0.73) and this decrease was driven by slowing over the central and posterior scalp. There was no difference in alpha power. Alpha waves propagated primarily from anterior to posterior and that propagation was slowed in patients. During SSVEP, patients had smaller increases in EEG power in the stimulation band (F (1,184) = 5.3, p = .02). Patients had attenuated responses to SSVEP stimulation at alpha, beta and gamma frequencies. The gamma response was partially preserved in patients who also had depressive symptoms. We conclude that even in early stages of illness, psychotic disorders are associated with decreased alpha peak frequency and impaired evoked resonances. These findings implicate multiple patterns of dysconnectivity in cortico-cortico and cortico-thalamic networks in FEP.
View Show abstract
... Several studies of patients at different stages of schizophrenia, including the prodromal phases preceding the onset of the disorder, have recently reported abnormal spontaneous alpha oscillations and altered resting-state functional connectivity of the alpha rhythm [20][21] [22]
[23] . Crucially, alpha rhythm is generated by a complex interplay between thalamic and cortical pacemakers and propagates via short and long range cortico-cortical, www.nature.com/scientificreports/ ...
... At the same time, we looked separately at frontal and posterior features with particular focus on posterior alpha activity and intrahemispheric connectivity. This was determined by the fact that literature on schizophrenia has shown an important discrepancy between studies supporting a general alteration of these features 22,
23,50 , other pointing to a more specific hemispheric alteration 20,38,51,52 and finally findings revealing altered alpha indices specifically at posterior sites and excluding frontal regions in patients with first episode psychosis 27 . Using a tenfold nested cross-validation (CV) procedure, repeated 1000 times, in the test sets of the outer CV, we observed a sensitivity of 78.8% (4.9%) [mean (standard deviation)], specificity of 69.7% (5.2%), balanced accuracy of 74.3% (3.8%) and area under the receiver operating characteristic -curve (AUC) of 0.83 (0.04). ...
Resting state alpha oscillatory activity is a valid and reliable marker of schizotypy
Article Full-text available
May 2021
Jelena Trajkovic Francesco Di Gregorio Francesca Ferri Vincenzo Romei
Schizophrenia is among the most debilitating neuropsychiatric disorders. However, clear neurophysiological markers that would identify at-risk individuals represent still an unknown. The aim of this study was to investigate possible alterations in the resting alpha oscillatory activity in normal population high on schizotypy trait, a physiological condition known to be severely altered in patients with schizophrenia. Direct comparison of resting-state EEG oscillatory activity between Low and High Schizotypy Group (LSG and HSG) has revealed a clear right hemisphere alteration in alpha activity of the HSG. Specifically, HSG shows a significant slowing down of right hemisphere posterior alpha frequency and an altered distribution of its amplitude, with a tendency towards a reduction in the right hemisphere in comparison to LSG. Furthermore, altered and reduced connectivity in the right fronto-parietal network within the alpha range was found in the HSG. Crucially, a trained pattern classifier based on these indices of alpha activity was able to successfully differentiate HSG from LSG on tested participants further confirming the specific importance of right hemispheric alpha activity and intrahemispheric functional connectivity. By combining alpha activity and connectivity measures with a machine learning predictive model optimized in a nested stratified cross-validation loop, current research offers a promising clinical tool able to identify individuals at-risk of developing psychosis (i.e., high schizotypy individuals).
View Show abstract
... It has been revealed that BD is associated with abnormalities of resting-state and task-related alpha activity [164]. Inconsistent results related to alpha asymmetry and alpha power alterations have been found by several resting-state studies among bipolar patients with different clinical characteristics and different phases compared to healthy controls including decreased [165, 166]
and increased alpha power [167]. In addition, BD individuals showed higher right relative to left frontal alpha power during task performance [168] that is opposite to alpha asymmetry with greater left relative to right alpha reported by some resting-state studies [169] but not others [165]. ...
... On the other hand, individuals with bipolar depression showed increased relative right frontal activity [169], whereas patients with mania displayed increased relative left frontal activity [170]. In addition, decreased alpha and increased theta power in frontocentral regions were observed in BD patients
[166,
171]. Regarding coherence as an EEG index for brain connectivity, BD patients showed decreased interhemispheric synchronization [172]. An EEG study found a global decrease in alpha synchronization, most prominently in the right fronto-central and centro-parietal connections, in BD patients compared to healthy participants [173]. ...
EEG Correlates of Cognitive Functions and Neuropsychiatric Disorders: A Review of Oscillatory Activity and Neural Synchrony Abnormalities Article
Dec 2020
Meysam Amidfar Yong-Ku Kim
Background
A large body of evidence suggested that disruption of neural rhythms and synchronization of brain oscillations are correlated with variety of cognitive and perceptual processes. Cognitive deficits are common features of psychiatric disorders that complicate treatment of the motivational, affective and emotional symptoms.
Objective
Electrophysiological correlates of cognitive functions will contribute to understanding of neural circuits controlling cognition, the causes of their perturbation in psychiatric disorders and developing novel targets for treatment of cognitive impairments.
Methods
This review includes description of brain oscillations in Alzheimer’s disease, bipolar disorder, attentiondeficit/hyperactivity disorder, major depression, obsessive compulsive disorders, anxiety disorders, schizophrenia and autism.
Results
The review clearly shows that the reviewed neuropsychiatric diseases are associated with fundamental changes in both spectral power and coherence of EEG oscillations.
Conclusion
In this article we examined nature of brain oscillations, association of brain rhythms with cognitive functions and relationship between EEG oscillations and neuropsychiatric diseases. Accordingly, EEG oscillations can most likely be used as biomarkers in psychiatric disorders.
View Show abstract
... Generally, alpha oscillations are inhibited in bipolar patients in many aspects: both resting and evoked alpha waves, with eyes closed or open, and in euthymic or manic participants [170]
[171][172]. In contrast, theta and delta oscillatory activity is enhanced [170,[173][174][175]. ...
... Generally, alpha oscillations are inhibited in bipolar patients in many aspects: both resting and evoked alpha waves, with eyes closed or open, and in euthymic or manic participants [170][171][172]. In contrast, theta and delta oscillatory activity is enhanced [170,
[173][174][175]. Likewise, an enhancement in the beta power response to different stimuli was recorded, which differentiated bipolar disorder from schizophrenia [171,[176][177][178]. Nonetheless, the beta synchronization was decreased at rest and in response to an auditory stimulation [179,180]. ...
Transcranial alternating current stimulation (tACS): from basic mechanisms towards first applications in psychiatry Article Full-text available
Feb 2021 EUR ARCH PSY CLIN N
Osama Elyamany Gregor Leicht
Christoph S Herrmann Christoph Mulert
Transcranial alternating current stimulation (tACS) is a unique form of non-invasive brain stimulation. Sinusoidal alternating electric currents are delivered to the scalp to affect mostly cortical neurons. tACS is supposed to modulate brain function and, in turn, cognitive processes by entraining brain oscillations and inducing long-term synaptic plasticity. Therefore, tACS has been investigated in cognitive neuroscience, but only recently, it has been also introduced in psychiatric clinical trials. This review describes current concepts and first findings of applying tACS as a potential therapeutic tool in the field of psychiatry. The current understanding of its mechanisms of action is explained, bridging cellular neuronal activity and the brain network mechanism. Revisiting the relevance of altered brain oscillations found in six major psychiatric disorders, putative targets for the management of mental disorders using tACS are discussed. A systematic literature search on PubMed was conducted to report findings of the clinical studies applying tACS in patients with psychiatric conditions. In conclusion, the initial results may support the feasibility of tACS in clinical psychiatric populations without serious adverse events. Moreover, these results showed the ability of tACS to reset disturbed brain oscillations, and thus to improve behavioural outcomes. In addition to its potential therapeutic role, the reactivity of the brain circuits to tACS could serve as a possible tool to determine the diagnosis, classification or prognosis of psychiatric disorders. Future double-blind randomised controlled trials are necessary to answer currently unresolved questions. They may aim to detect response predictors and control for various confounding factors.
View Show abstract
... In connection to these findings, Itil et al. (1974) claims that abnormalities in case of untreated patients are a permanent feature of schizophrenic disorder. Clementz et al. (1994)
focused on patients who experienced their first schizophrenic episode. In comparison to the control group, their delta and theta waves were increased, while the alpha waves were decreased. ...
... Patients with bipolar affective disorder show similar results. According to Clementz et al. (1994)
, these abnormalities are often interpreted as results of subcortical changes during schizophrenia development. ...
EEG biofeedback in patients with schizophrenia: another possibility to influence cognitive deficit? Article Full-text available
Mar 2016
Veronika Vorackova Filip Spaniel
Pavel Mohr Mabel Rodriguez
View
... In another study however, no difference in EEG parameters has been detected between converters and non-converters (Lavoie et al., 2012). In relatives of schizophrenia patients, there is report of decreased alpha peak frequency (Clementz et al., 1994)
. Current data also suggest EEG abnormalities during NREM sleep in genetic high-risk subjects, while such data during prodromal stage are still missing. ...
... The reviewed literature reveals that several thalamus-related anomalies are present in unaffected relatives/siblings who do not meet the criteria for clinical high-risk (Table 2) and are potent endophenotypes. These include 1) reduced thalamus volume (Lawrie et al., 2001), 2) reduced GM particularly in the anterior region (Cooper et al., 2014;Harms et al., 2007;Pergola et al., 2017), 3) decreased NAA content (Legind et al., 2019;Tandon et al., 2013), 4) reduced structural and functional connectivity between thalamus and prefrontal cortex (Antonucci et al., 2016;Cho et al., 2019a), 5) decreased alpha peak frequency during resting EEG
(Clementz et al., 1994)
, 6) reduced spindles and slowwaves during NREM sleep (D'Agostino et al., 2018;Manoach et al., 2014;Schilling et al., 2017). These strongly support that the integrity and function of several thalamic nuclei (i.e. ...
Thalamus-related anomalies as candidate mechanism-based biomarkers for psychosis Article Full-text available
May 2019 SCHIZOPHR RES
Pascal Steullet
Identification of reliable biomarkers of prognosis in subjects with high risk to psychosis is an essential step to improve care and treatment of this population of help-seekers. Longitudinal studies highlight some clinical criteria, cognitive deficits, patterns of gray matter alterations and profiles of blood metabolites that provide some levels of prediction regarding the conversion to psychosis. Further effort is warranted to validate these results and implement these types of approaches in clinical settings. Such biomarkers may however fall short in entangling the biological mechanisms underlying the disease progression, an essential step in the development of novel therapies. Circuit-based approaches, which map on well-identified cerebral functions, could meet these needs. Converging evidence indicates that thalamus abnormalities are central to schizophrenia pathophysiology, contributing to clinical symptoms, cognitive and sensory deficits. This review highlights the various thalamus-related anomalies reported in individuals with genetic risks and in the different phases of the disorder, from prodromal to chronic stages. Several anomalies are potent endophenotypes, while others exist in clinical high-risk subjects and worsen in those who convert to full psychosis. Aberrant functional coupling between thalamus and cortex, low glutamate content and readouts from resting EEG carry predictive values for transition to psychosis or functional outcome. In this context, thalamus-related anomalies represent a valuable entry point to tackle circuit-based alterations associated with the emergence of psychosis. This review also proposes that longitudinal surveys of neuroimaging, EEG readouts associated with circuits encompassing the mediodorsal, pulvinar in high-risk individuals could unveil biological mechanisms contributing to this psychiatric disorder.
View Show abstract
... In this investigation we examined whether the dominant resting state brain oscillation -the alpha rhythm -was predictive of an endogenous visual function related to percept formation, and whether the association held in psychotic psychopathology. Investigations have repeatedly shown that psychotic psychopathology is characterized by abnormal resting state neural oscillations
(Clementz et al., 1994;
Venables et al., 2009;Hirano and Uhlhaas, 2021) that include a slower pace of the alpha rhythm (Ramsay and Lynn, 2021). Specifically, we found that the slowed pace of alpha oscillations noted in psychotic psychopathology was associated with longer percept durations measured using a binocular rivalry task. ...
Slowed alpha oscillations and percept formation in psychotic psychopathology
Article Full-text available
Jun 2023
Scott R Sponheim Joshua J. Stim Stephen Engel Victor Pokorny
Introduction
Psychosis is in part defined by disturbances in perception. Recent investigations have implicated the speed of alpha oscillations observed in brain electrical activity as reflective of a sampling rate of the visual environment and perception. Although both slowed alpha oscillations and aberrant percept formation are evident in disorders of psychotic psychopathology such as schizophrenia it is unclear whether slow alpha accounts for abnormal visual perception in these disorders.
Methods
To examine the role of the speed of alpha oscillations in perception in psychotic psychopathology we gathered resting-state magneto-encephalography data from probands with psychotic psychopathology (i.e., schizophrenia, schizoaffective disorder, and bipolar disorder with a history of psychosis), their biological siblings, and healthy controls. We appraised visual perceptual function without the confound of cognitive ability and effort through the use of a simple binocular rivalry task.
Results
We found a slowed pace of alpha oscillations in psychotic psychopathology that was associated with longer percept durations during binocular rivalry, consistent with the assertion that occipital alpha oscillations govern the rate of accumulation of visual information used to generate percepts. Alpha speed varied widely across individuals with psychotic psychopathology and was highly stable across several months indicating that it is likely a trait characteristic of neural function that is relevant to visual perception. Finally, a lower speed of alpha oscillation was associated with a lower IQ and greater disorder symptomatology implying that the effects of the endogenous neural oscillation on visual perception may have wider consequences for everyday functioning.
Discussion
Slowed alpha oscillations in individuals with psychotic psychopathology appear to reflect altered neural functions related to percept formation.
View Show abstract
... Increased power in the schizophrenia spectrum during the resting state in the theta or theta/alpha ranges has been reported in a number of studies (e.g., 2-21). However, in contrast to some studies, we did not also find significantly increased delta power (4,
(9)(10)(11)(12)(15)(16)(17)(18), which highlights the heterogeneity of spectral profiles observed in SZ (2). One possible explanation is that the separation of power spectra evident in the delta and low theta bands in Fig. 1 would be significant with a larger sample size. ...
Spectral Decomposition of Resting State Electroencephalogram Reveals Unique Theta/Alpha Activity in Schizophrenia Preprint
May 2023
Alexander Nakhnikian Naoya Oribe
Shogo Hirano Kevin M Spencer
Resting state electroencephalographic (EEG) activity in schizophrenia (SZ) is frequently characterized by increased power at slow frequencies, and/or a reduction of peak alpha frequency. Here we investigated the nature of these effects. As most studies to date have been limited by reliance on a priori frequency bands which impose an assumed structure on the data, we performed a data-driven analysis of resting EEG recorded in SZ patients and healthy controls (HC). The sample consisted of 39 chronic SZ and 36 matched HC. The EEG was recorded with a dense electrode array. Power spectral densities were decomposed via Varimax-rotated principal component analysis (PCA) over all participants and for each group separately. Spectral PCA was repeated at the cortical level on cortical current source density computed from standardized low resolution brain electromagnetic tomography. There was a trend for power in the theta/alpha range to be increased in SZ compared to HC, and peak alpha frequency was significantly reduced in SZ. PCA revealed that this frequency shift was due to the presence of a spectral component in the theta/alpha range (6-9 Hz) that was unique to SZ. The source distribution of this component involved mainly prefrontal and parahippocampal areas. Abnormal low frequency resting EEG activity in SZ was accounted for by a unique theta/alpha oscillation. Other reports have described a similar phenomenon suggesting that the neural circuits oscillating in this range are relevant to SZ pathophysiology.
View Show abstract
... EEG data are conventionally analyzed by sampling time depended signals into different frequency bands at different locations on the scalp and then looking for specific signatures in each band. For instance, resting state EEG in patients diagnosed with First Episode Psychosis and Bipolar Disorder revealed a general trend of increased delta (0.5-4 Hz) and theta (4-8 Hz) activity, and a decrease in alpha (8-13 Hz) activity (Clementz et al., 1994)
. Resting state EEG of bipolar patients has also been studied using complex network analysis in Kim et al. (2013), yielding differences from healthy control subjects across several network measures such as clustering coefficient or characteristic path length. ...
Information Optimized Multilayer Network Representation of High Density Electroencephalogram Recordings Article Full-text available
Sep 2021
Francesc Font-Clos Benedetta Spelta
Armando D'Agostino Caterina AM La Porta
High-density electroencephalography (hd-EEG) provides an accessible indirect method to record spatio-temporal brain activity with potential for disease diagnosis and monitoring. Due to their highly multidimensional nature, extracting useful information from hd-EEG recordings is a complex task. Network representations have been shown to provide an intuitive picture of the spatial connectivity underlying an electroencephalogram recording, although some information is lost in the projection. Here, we propose a method to construct multilayer network representations of hd-EEG recordings that maximize their information content and test it on sleep data recorded in individuals with mental health issues. We perform a series of statistical measurements on the multilayer networks obtained from patients and control subjects and detect significant differences between the groups in clustering coefficient, betwenness centrality, average shortest path length and parieto occipital edge presence. In particular, patients with a mood disorder display a increased edge presence in the parieto-occipital region with respect to healthy control subjects, indicating a highly correlated electrical activity in that region of the brain. We also show that multilayer networks at constant edge density perform better, since most network properties are correlated with the edge density itself which can act as a confounding factor. Our results show that it is possible to stratify patients through statistical measurements on a multilayer network representation of hd-EEG recordings. The analysis reveals that individuals with mental health issues display strongly correlated signals in the parieto-occipital region. Our methodology could be useful as a visualization and analysis tool for hd-EEG recordings in a variety of pathological conditions.
View Show abstract
... 103 Since then, several studies have reported reductions in the amplitude and connectivity of alpha-band power. [104][105][106] These deficits are already present in FEP-patients as well as in medication-free patients 107, 108
and are related to enlarged cerebral ventricles 104,109 and negative symptoms. 110,111 A consistent finding is elevated slow-wave activity in schizophrenia, such as increased delta [1-4 Hz] and theta [4-8 Hz]) power, particularly over frontal regions. ...
Current Findings and Perspectives on Aberrant Neural Oscillations in Schizophrenia Article Full-text available
Sep 2021
Yoji Hirano Peter J Uhlhaas
There is now consistent evidence that neural oscillation at low- and high-frequencies constitute an important aspect of the pathophysiology of schizophrenia. Specifically, impaired rhythmic activity may underlie the deficit to generate coherent cognition and behavior, leading to the characteristic symptoms of psychosis and cognitive deficits. Importantly, the generating mechanisms of neural oscillations are relatively well-understood and thus enable the targeted search for the underlying circuit impairments and novel treatment targets. In the following review, we will summarize and assess the evidence for aberrant rhythmic activity in schizophrenia through evaluating studies that have utilized Electro/Magentoencephalography to examine neural oscillations during sensory and cognitive tasks as well as during resting-state measurements. These data will be linked to current evidence from post-mortem, neuroimaging, genetics and animal models that have implicated deficits in GABAergic interneurons and glutamatergic neurotransmission in oscillatory deficits in schizophrenia. Finally, we will highlight methodological and analytical challenges as well as provide recommendations for future research.
This article is protected by copyright. All rights reserved.
View Show abstract
... Abnormal brain activity relative to healthy controls has been found in schizophrenia patients and bipolar patients in fMRI and EEG studies. 3, 4
The two disorders exhibit both common and specific neuroanatomical characteristics. ...
Altered Complexity of Spontaneous Brain Activity in Schizophrenia and Bipolar Disorder Patients Article Full-text available
Aug 2021
Nan Zhang Yan Niu Jie Sun Bin Wang
Slice images of the brain regions with significant difference Slice images showed the differences of (a) the effect of group and (b) the effect of interaction between the control and patient groups after adjusting for age, sex, and education (P < 0.05, GRF corrected). CAL.L: Calcarine fissure, DCG.L: Median Cingulate, LING.L: Lingual Gyrus, PCUN.L: Precuneus, IOG.R: Inferior Occipital Gyrus, MTG.R: Middle Temporal Gyrus, HIP.R: Hippocampus, THA.R: Thalamus, MFG.R: Middle Frontal Gyrus, MTG.L: Middle Temporal Gyrus by N. Zhang et al (586–595)
View Show abstract
... Abnormal brain activity relative to healthy controls has been found in schizophrenia patients and bipolar patients in fMRI and EEG studies. 3, 4
The two disorders exhibit both common and specific neuroanatomical characteristics. ...
Altered Complexity of Spontaneous Brain Activity in Schizophrenia and Bipolar Disorder Patients Article Full-text available
Feb 2021 J MAGN RESON IMAGING
Nan Zhang Yan Niu Jie Sun Bin Wang
Background:
Schizophrenia (SC) and bipolar disorder (BP) share elements of symptoms and the underlying neural mechanisms for both remain unclear. Recently, the complexity of spontaneous functional MRI (fMRI) signals in brain activity has been investigated in SC and BP using multiscale sample entropy (MSE) with inconsistent results.
Purpose:
To perform MSE analysis across five time scales to assess differences in resting-state fMRI signal complexity in SC, BP, and normal controls (NC).
Study type:
Retrospective.
Population:
Fifty SC, 49 BP, and 49 NC.
Field strength/sequence:
A 3 T, T2* weighted echo planar imaging (EPI) sequence.
Assessment:
The mean MSEs of all gray matter (GM) and of 12 regions of interest (ROIs) were extracted using masks across the five scales. The regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) in these ROIs were also determined and the relationship between the three measures was investigated. The correlations between cognitive assessment scores and MSE values were also explored.
Statistical tests:
Bonferroni correction, One-way ANOVA, Spearman rank correlation coefficient (r), Gaussian random field (GRF) correction.
Results:
There were decreased GM MSE values in the patient groups (F = 9.629, P < 0.05). SC and BP patients demonstrated lower complexity than NCs in the calcarine fissure, precuneus, inferior occipital gyrus, lingual gyrus and cerebellum, and higher complexity in the median cingulate, thalamus, hippocampus, middle temporal gyrus and middle frontal gyrus. There were significant differences between SC and BP patients in the precuneus (F = 4.890, P < 0.05) and inferior occipital gyrus (F = 5.820, P < 0.05). Calcarine fissure, cingulate, temporal gyrus, occipital gyrus, hippocampus, precuneus, frontal gyrus, and lingual gyrus MSE values were significantly correlated with both ReHo (r > 0.282, P < 0.05) and ALFF (r > 0.278, P < 0.05). Furthermore, median temporal MSE (r = -0.321, P < 0.05) on scale 3 and (r = -0.307, P < 0.05) on scale 4 and median cingulate MSE (r = -0.337, P < 0.05) on scale 5 was significantly negatively correlated with cognitive assessment scores.
Data conclusion:
These data highlight different patterns of brain signal intensity complexity in SC and BP.
Level of evidence:
1 TECHNICAL EFFICACY: Stage 1.
View Show abstract
... The identification of schizophrenic and normal patients has been carried out using spectral analysis [15,16]. A rhythm based risk rate evaluation of healthy and schizophrenic patients is used in [17]
. The alpha, delta, beta and gamma rhythms of occipital, central and frontal sites have been classified using the support vector machine (SVM) [18]. ...
Modelling and Analysis of Active Biopotential Signals in Healthcare, Volume 1 Chapter Full-text available
Aug 2020
Professor G R Sinha Smith Khare
Varun Bajaj Siuly Siuly
Please note that terms and conditions apply. You may also be interested in: Time domain features in combination with a support vector machine classifier for constructing the termite detection system M A Nanda, K B Seminar, D Nandika et al. Does thorax EIT image analysis depend on the image reconstruction method? Zhanqi Zhao, Inéz Frerichs, Sven Pulletz et al. Bacterial adherence to anodized titanium alloy C Pérez-Jorge Peremarch, R Pérez Tanoira, M A Arenas et al. Time series analysis of tool wear in sheet metal stamping using acoustic emission V. Vignesh Shanbhag, P. Michael Pereira, F. Bernard Rolfe et al. Mood states modulate complexity in heartbeat dynamics: A multiscale entropy analysis G. Valenza, M. Nardelli, G. Bertschy et al. Nitrous oxide emissions could reduce the blue carbon value of marshes on eutrophic estuaries Brittney L Roughan, Lisa Kellman, Erin Smith et al. Exhaled breath and oral cavity VOCs as potential biomarkers in oral cancer patients M Bouza, J Gonzalez-Soto, R Pereiro et al.
View Show abstract
... The identification of schizophrenic and normal patients has been carried out using spectral analysis [15,16]. A rhythm based risk rate evaluation of healthy and schizophrenic patients is used in [17]
. The alpha, delta, beta and gamma rhythms of occipital, central and frontal sites have been classified using the support vector machine (SVM) [18]. ...
Classification of schizophrenia patients through empirical wavelet transformation using electroencephalogram signals Chapter Full-text available
Aug 2020
Smith Khare Varun Bajaj Siuly Siuly Professor G R Sinha
View
... Таким образом, анализ литературы позволяет предполагать, что этот показатель является возможным эндофенотипом расстройства. Напротив, выявленные нами в ГРА изменения в бета 1 -и тета-диапазонах противоположны тем, которые наблюдались в клинических группах с аффективной патологией
[22,
42]. Бета 1 -диапазон связывают с процессами возбуждения, активации коры [19], следовательно, более низкие показатели спектральной мощности этого ритма в ГРА могут быть отражением меньшей активности соответствующих процессов. ...
Structural and functional brain characteristics in family risk groups for schizophrenia and affective spectrum disorders: results of multimodal series of studies (in Russian) Article Full-text available
Jul 2020
Yana R. Panikratova Alexander S Tomyshev Klochkova Inna Irina Lebedeva
The article describes the results of our first series of studies regarding structural and functional brain characteristics in unaffected relatives of patients with affective spectrum disorders (RA) and schizophrenia (RS). The studies were conducted by the laboratory of neuroimaging and multimodal analysis of Mental Health Research Center. The aim of the studies was to identify structural and functional parameters that reflect both endophenotypes of the disorders and resilience mechanisms which allow relatives of patients not to get ill despite the increased genetic risk. Data from structural, diffusion-weighted, and functional magnetic resonance imaging (MRI), electroencephalography, and several neuropsychological tests were analyzed. In the RA, compared to controls, lower values of the spectral power of bioelectric activity were observed in a number of subranges. The RS demonstrated changes in structural
and functional connectivity and increased gray matter thickness. There were no statistically significant
differences between both family risk groups and controls in neuropsychological tests. The results may indicate that several neurophysiological patterns represent possible endophenotypes and resilience factors to affective disorders. At the same time, some morphometric and functional connectivity characteristics can be considered as potential markers of resilience processes, and altered diffusion parameters in a number of tracts may reflect possible endophenotypes of schizophrenia.
View Show abstract
... Reductions in resting-state alpha oscillations in SZ have been reported previously in MEG studies during EC (Canive et al., 1996(Canive et al., , 1998 and EO (Zeev-Wolf et al., 2018) and with EEG (Boutros et al., 2008; Clementz et al., 1994;
Goldstein et al., 2015;Lund et al., 1995), while the underlying functional significance of these alpha differences is unclear. Patients with schizophrenia may have an intrinsic deficit in the ability to generate alpha band oscillations, as reflected by reduced alpha power at illness onset Goldstein et al., 2015), similar alpha power deficits in unmedicated and medicated patients (Canive et al., 1996) and similar alpha band connectivity disruptions between first episode and chronic durations of illness (Di Lorenzo et al., 2015;Sponheim et al., 1994). ...
Reduced parietal alpha power and psychotic symptoms: Test-retest reliability of resting-state magnetoencephalography in schizophrenia and healthy controls Article
Nov 2019 SCHIZOPHR RES
Felicha T Candelaria-Cook Megan Schendel Cesar J. Ojeda Julia M Stephen
Background:
Despite increased reporting of resting-state magnetoencephalography (MEG), reliability of those measures remains scarce and predominately reported in healthy controls (HC). As such, there is limited knowledge on MEG resting-state reliability in schizophrenia (SZ).
Methods:
To address test-retest reliability in psychosis, a reproducibility study of 26 participants (13-SZ, 13-HC) was performed. We collected eyes open and eyes closed resting-state data during 4 separate instances (2 Visits, 2 runs per visit) to estimate spectral power reliability (power, normalized power, alpha reactivity) across one hour and one week. Intraclass correlation coefficients (ICCs) were calculated. For source modeling, we applied an anatomically constrained linear estimation inverse model known as dynamic statistical parametric mapping (MNE dSPM) and source-based connectivity using the weighted phase lag index.
Results:
Across one week there was excellent test-retest reliability in global spectral measures in theta-gamma bands (HC ICCAvg = 0.87, SZ ICCAvg = 0.87), regional spectral measures in all bands (HC ICCAvg = 0.86, SZ ICCAvg = 0.80), and parietal alpha measures (HC ICCAvg = 0.90, SZ ICCAvg = 0.84). Conversely, functional connectivity had poor reliability, as did source spectral power across one hour for SZ. Relative to HC, SZ also had reduced parietal alpha normalized power during eyes closed only, reduced alpha reactivity, and an association between higher PANSS positive scores and lower parietal alpha power.
Conclusions:
There was excellent to good test-retest reliability in most MEG spectral measures with a few exceptions in the schizophrenia patient group. Overall, these findings encourage the use of resting-state MEG while emphasizing the importance of determining reliability in clinical populations.
View Show abstract
... In line with previous studies, we found significantly higher delta power in patients with FEP compared to HCs. 17, 32
It has been shown that the increased delta power found in psychosis patients reflected the pathophysiology of the disorder itself and was not related to patient characteristics such as the duration of the illness or the result of antipsychotic treatment. 33,34 Previous studies suggested that altered delta activity found in 37 which is apparent from the beginning of psychotic disorder and is correlated with the severity of prodromal psychotic symptoms. ...
Predicting Symptomatic and Functional Improvements over 1 Year in Patients with First-Episode Psychosis Using Resting-State Electroencephalography Article Full-text available
Aug 2019
Rinvil Renaldi Minah Kim Takhyung Lee Jun Soo Kwon
Objective:
Although early intervention from the beginning of a psychotic episode is essential for a better prognosis, biomarkers predictive of symptomatic and functional improvement in early psychotic disorders are lacking. This study aimed to investigate whether the spectral power of resting-state electroencephalography (EEG) can be used as a predictive marker of the 1-year prognosis in patients with first-episode psychosis (FEP).
Methods:
Twenty-four patients with FEP and matched healthy control (HC) subjects were examined with resting-state EEG at baseline. The symptomatic severity and functional status of FEP patients were assessed at baseline and reassessed after 1 year of usual treatment. Repeated measures analysis of variance was conducted to compare EEG spectral powers across the groups. Multiple regression analysis revealed EEG spectral powers predictive of symptomatic and functional improvement in FEP patients at the 1-year follow-up.
Results:
Delta band power in the frontal and posterior regions was significantly higher in patients with FEP than in HCs. Higher delta band power in the posterior region predicted later improvement of positive symptoms and general functional status. Lower delta band power in the frontal region predicted improvement of negative symptoms and general functioning after 1 year.
Conclusion:
These results suggest that increased delta absolute power is observed from the beginning of psychotic disorders. Furthermore, decreased delta power in the frontal region and increased delta power in the posterior region might be used as a predictive marker of a better prognosis of FEP, which would aid early intervention in clinical practice.
View Show abstract
... Later, several authors stated that EEG was not noise and that selectively synchro- nized alpha oscillations in the mammalian and human brain are part of the fundamental func- tional signaling of the central nervous system (Bas¸arBas¸ar, 1980;Lehmann, 1989;Klimesch, 1999;Bas¸arBas¸ar et al., 2001a,b;Nunez et al., 2001). In one study prior to ours (Bas¸arBas¸ar et al., 2012), alpha activity was found to be reduced in bipolar patients with psychotic characteristics and in patients with schizophrenia when compared to healthy controls (
Clementz et al., 1994)
. Several years later, the replication of a reduced alpha activity in bipolar disorder, this time in drug-free euthymic patients, demonstrated that the reduc- tion is neither associated with psychosis or any mood-related symptom, nor it can be explained by medication effect. ...
Brain oscillations in bipolar disorder in search of new biomarkers
Chapter
Feb 2013
Ayşegül Ozerdem Bahar Güntekin
Murat Ilhan Atagun Erol Basar
This report presents six cardinal results obtained with methods of oscillatory brain dynamics in euthymic and manic bipolar patients in comparison to healthy controls. Measurements include changes in oscillatory response activities in the theta, alpha, beta, and gamma frequency ranges. The analysis shows that spontaneous and response activities in the alpha range are highly reduced in euthymic and manic patients, respectively; conversely, beta responses are increased in euthymic and manic patients. Lithium use seems to be associated with further and significant increase in the beta frequency range in euthymic patients. Theta responses to auditory target stimulus during odd-ball paradigm appeared in two different frequency bands (4-6 and 6-8 Hz) in healthy participants. However, only fast theta responses were highly reduced under cognitive load in drug-free euthymic patients. The analysis of connectivity was performed by assessment of long-distance coherence function in the gamma frequency range. Both manic and euthymic patients presented significantly decreased fronto-temporal coherence function during visual odd-ball task, indicating a selective reduction in connectivity during cognitive processing. The present report also discusses that these six oscillatory parameters may serve as an ensemble of biomarkers for diagnostic purposes and tracking treatment response in bipolar disorder.
View Show abstract
... Indeed, in a heterogeneous BD group with only nine out of 30 patients showing psychotic symptoms, no resting EEG impairment was observed (Venables et al., 2009). In first-episode BP patients with psychotic features, increase low-frequency and alpha power was observed
(Clementz, Sponheim, Iacono, & Beiser, 1994)
, while only the increase in alpha band was reported in first-episode BP patients in acute hypomania or depressive state (Moeini et al., 2015). However, in light of the results available, it could be that the increased slow activity is specific to psychotic symptoms rather than schizophrenia itself. ...
Staging model in psychiatry: Review of the evolution of electroencephalography abnormalities in major psychiatric disorders Article
Jan 2019
Suzie Lavoie Andrea Polari
Sherilyn Goldstone Patrick D. McGorry
Aim
Clinical staging in psychiatry aims to classify patients according to the severity of their symptoms, from stage 0 (increased risk, asymptomatic) to stage 4 (severe illness), enabling adapted treatment at each stage of the illness. The staging model would gain specificity if one or more quantifiable biological markers could be identified. Several biomarkers reflecting possible causal mechanisms and/or consequences of the pathophysiology are candidates for integration into the clinical staging model of psychiatric illnesses.
Methods
This review covers the evolution (from stage 0 to stage 4) of the most important brain functioning impairments as measured with electroencephalography (EEG), in psychosis spectrum and in severe mood disorders.
Results
The present review of the literature demonstrates that it is currently not possible to draw any conclusion with regard to the state or trait character of any of the EEG impairments in both major depressive disorder and bipolar disorder. As for schizophrenia, the most promising markers of the stage of the illness are the pitch mismatch negativity as well as the p300 event‐related potentials, as these components seem to deteriorate with increasing severity of the illness.
Conclusions
Given the complexity of major psychiatric disorders, and that not a single impairment can be observed in all patients, future research should most likely consider combinations of markers in the quest for a better identification of the stages of the psychiatric illnesses.
View Show abstract
... Individual alpha frequency has been repeatedly linked to general cognitive abilities within and across individuals (Angelakis, Lubar, Stathopoulou, & Kounios, 2004;Grandy et al., 2013;Haegens, Cousijn, Wallis, Harrison, & Nobre, 2014); however see, (Anokhin & Vogel, 1996;Posthuma, Neale, Boomsma, & de Geus, 2001). Patients diagnosed with schizophrenia (Colombo et al., 1989;Giannitrapani & Kayton, 1974) as well as bipolar disorder
(Clementz, Sponheim, Iacono, & Beiser, 1994)
have been shown to have slower alpha frequency compared to healthy individuals. Our results may prompt examination of alpha frequency as a mediator of psychopathological behavior and personality traits. ...
Frequency of alpha oscillation predicts individual differences in perceptual stability during binocular rivalry Article Full-text available
Jan 2019 HUM BRAIN MAPP
Sucharit Katyal Sheng He Bin He
Stephen Engel
When ambiguous visual stimuli have multiple interpretations, human perception can alternate between them, producing perceptual multistability. There is a large variation between individuals in how long stable percepts endure, on average, between switches, but the underlying neural basis of this individual difference in perceptual dynamics remains obscure. Here, we show that in one widely-studied multistable paradigm—binocular rivalry—perceptual stability in individuals is predicted by the frequency of their neural oscillations within the alpha range (7—13 Hz). Our results suggest revising models of rivalry to incorporate effects of neural oscillations on perceptual alternations, and raise the possibility that a common factor may influence dynamics in many neural processes.
View Show abstract
... According to the results, the brain's alpha activity is significantly higher in adolescents with acute bipolar disorder (in both episodes). This finding is opposite to the results of some studies on bipolar disorder, [28] [29]
[30][31] but is consistent with the work by El-Badri et al. 21 Alpha activity has a negative correlation with attention, particularly selective attention, in healthy people at the resting state. ...
Abnormalities of Alpha Activity in Frontocentral Region of the Brain as a Biomarker to Diagnose Adolescents With Bipolar Disorder Article
Jan 2019
Ali Khaleghi Mohammad Reza Mohammadi Mahdi Moeini Mahbod Fadaei Fooladi
Objectives. To investigate brain abnormalities in adolescents with new-onset bipolar disorder (BD) during acute hypomanic and depressive episodes using electroencephalogram (EEG) analysis and to derive a computer-based method for diagnosis of the disorder. Methods. EEG spectral power and entropy of 21 adolescents with BD (included 11 patients in the hypomanic episode and 10 patients in the depressive episode) and 18 healthy adolescents were compared. Moreover, using significant differences and K-nearest-neighbors (KNN) classifier, it was attempted to distinguish the BD adolescents from normal ones. Results. The BD adolescents had higher values of spectral power in all frequency bands, particularly in the frontocentral, mid-temporal, and right parietal regions. Also, spectral entropy had significantly increased in delta, alpha, and gamma frequency bands for BD. A high accuracy of 95.8% was achieved by all significant differences in the alpha band in discriminating adolescents with BD. The depressive state showed higher values of spectral power and entropy in low-frequency bands (delta and theta) compared to the hypomanic state. Conclusion. Based on BD symptoms, especially inattention, increased alpha power is a rational finding which is associated with thalamus dysfunction. Thus, it seems that EEG alpha oscillation is the main source of abnormality in BD. Furthermore, EEG slowing in the depressive episode is related to inhibition of electrical activity and reduced cognitive functions.
View Show abstract
... healthy controls) most often with eyes closed (although see Venables et al., 2009;Hanslmayr et al., 2013;Narayanan et al., 2014 for three eyes open studies). In total, 37 schizophrenia studies were identified for this review
Sponheim et al., 1994;
Wada et al., 1994;Omori et al., 1995 with the average age of participants being 31 years old. As well as more conventional DSM/ICD measures, schizophrenia diagnosis and severity was typically assessed using the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) and the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). ...
EEG Frequency Bands in Psychiatric Disorders: A Review of Resting State Studies Article Full-text available
Jan 2019 FRONT HUM NEUROSCI
Jennifer Jane Newson Tara C. Thiagarajan
A significant proportion of the electroencephalography (EEG) literature focuses on differences in historically pre-defined frequency bands in the power spectrum that are typically referred to as alpha, beta, gamma, theta and delta waves. Here, we review 184 EEG studies that report differences in frequency bands in the resting state condition (eyes open and closed) across a spectrum of psychiatric disorders including depression, attention deficit-hyperactivity disorder (ADHD), autism, addiction, bipolar disorder, anxiety, panic disorder, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and schizophrenia to determine patterns across disorders. Aggregating across all reported results we demonstrate that characteristic patterns of power change within specific frequency bands are not necessarily unique to any one disorder but show substantial overlap across disorders as well as variability within disorders. In particular, we show that the most dominant pattern of change, across several disorder types including ADHD, schizophrenia and OCD, is power increases across lower frequencies (delta and theta) and decreases across higher frequencies (alpha, beta and gamma). However, a considerable number of disorders, such as PTSD, addiction and autism show no dominant trend for spectral change in any direction. We report consistency and validation scores across the disorders and conditions showing that the dominant result across all disorders is typically only 2.2 times as likely to occur in the literature as alternate results, and typically with less than 250 study participants when summed across all studies reporting this result. Furthermore, the magnitudes of the results were infrequently reported and were typically small at between 20% and 30% and correlated weakly with symptom severity scores. Finally, we discuss the many methodological challenges and limitations relating to such frequency band analysis across the literature. These results caution any interpretation of results from studies that consider only one disorder in isolation, and for the overall potential of this approach for delivering valuable insights in the field of mental health.
View Show abstract
... It is also considered a marker of brain pathology (Montgomery et al., 1991;Coutin-Churchman et al., 2003). Increased theta power has been observed in traumatic brain injuries (McClelland et al., 1994;Fenton, 1996), epilepsy (Clemens, 2004), schizophrenia
(Clementz et al., 1994;
Sponheim et al., 2000;Wichniak et al., 2015), or polysubstance abuse (Coutin-Churchman et al., 2003). ...
Abnormal Resting-State Quantitative Electroencephalogram in Children With Central Auditory Processing Disorder: A Pilot Study Article Full-text available
May 2018
Rafal Milner Monika Lewandowska
Małgorzata Ganc Henryk Skarzynski
In this study, we showed an abnormal resting-state quantitative electroencephalogram (QEEG) pattern in children with central auditory processing disorder (CAPD). Twenty-seven children (16 male, 11 female; mean age = 10.7 years) with CAPD and no symptoms of other developmental disorders, as well as 23 age- and sex-matched, typically developing children (TDC, 11 male, 13 female; mean age = 11.8 years) underwent examination of central auditory processes (CAPs) and QEEG evaluation consisting of two randomly presented blocks of “Eyes Open” (EO) or “Eyes Closed” (EC) recordings. Significant correlations between individual frequency band powers and CAP tests performance were found. The QEEG studies revealed that in CAPD relative to TDC there was no effect of decreased delta absolute power (1.5–4 Hz) in EO compared to the EC condition. Furthermore, children with CAPD showed increased theta power (4–8 Hz) in the frontal area, a tendency toward elevated theta power in EO block, and reduced low-frequency beta power (12–15 Hz) in the bilateral occipital and the left temporo-occipital regions for both EO and EC conditions. Decreased middle-frequency beta power (15–18 Hz) in children with CAPD was observed only in the EC block. The findings of the present study suggest that QEEG could be an adequate tool to discriminate children with CAPD from normally developing children. Correlation analysis shows relationship between the individual EEG resting frequency bands and the CAPs. Increased power of slow waves and decreased power of fast rhythms could indicate abnormal functioning (hypoarousal of the cortex and/or an immaturity) of brain areas not specialized in auditory information processing.
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Quantitative EEG in Patients with Schizophrenia
Chapter
May 2023
Gеorgi Panov
Schizophrenia is a chronic mental illness with a diverse clinical picture. Diagnosis is based on clinical symptoms as well as their duration over time. The use of routine EEG in the evaluation of patients with schizophrenia did not achieve the expected results—to give a pattern corresponding to the clinical picture. In the search for specific EEG findings, the use of quantitative methods of EEG analysis shows encouraging results in the study of intimate mechanisms underlying clinical symptoms. These provide hope for future studies to determine diagnostic specificity and associated therapeutic effectiveness.Key wordsElectroencephalographySchizophreniaQuantitative EEGAbsolute powerRelative powerCoherenceTreatment
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Cerebral Asymmetry in Bipolar Disorders: A Scoping Review
Article
Apr 2023 BIOL PSYCHOL
Lukas Moebus Markus Quirin Felix Ehrlenspiel
Current brain stimulation protocols for patients with bipolar disorders propose brain stimulation according to a model of opposing cerebral dominance in mania and bipolar depression by stimulating the right or left dorsolateral prefrontal cortex during manic or depressive episodes, respectively. However, there is very little observational, rather than interventional, research on such opposing cerebral dominance. In fact, this is the first scoping review that summarizes resting-state and task- related functional cerebral asymmetries measured with brain imaging techniques in manic and depressive symptoms or episodes in patients with formal bipolar disorder diagnoses. In a three-step search process MEDLINE, Scopus, APA PsycInfo, Web of Science Core Collection, and BIOSIS Previews databases as well as reference lists of eligible studies were searched. Data from these studies were extracted with a charting table. Ten resting-state EEG and task-related fMRI studies met inclusion criteria. In line with brain stimulation protocols, mania relates to cerebral dominance in regions of the left frontal lobe, such as the left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex. Bipolar depression relates to cerebral dominance in regions of the right frontal and temporal lobe, such as the right dorsolateral prefrontal cortex, orbitofrontal cortex and temporal pole. More observational research on cerebral asymmetries in mania and bipolar depression can advance brain stimulation protocols and potentially inform standard treatment protocols.
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The differential diagnosis of unipolar and bipolar depression based on EEG signals Article
Jan 2022 ZH NEVROL PSIKHIATR
S A Galkin Nikolay Bokhan
The relevance of timely detection and differential diagnosis of depressive disorder and bipolar affective disorder (BD) is beyond doubt. In complex differential diagnostic cases, clinicians can come to the aid of objective research methods, such as electroencephalography. This review summarizes and systematizes modern methods of differential diagnosis of unipolar and bipolar depression based on electroencephalography data. A literature search was conducted using the search terms «depression», «bipolar disorder», «unipolar depression», «differential diagnosis», «neuromarkers», «electroencephalography», «quantitative EEG». The search was conducted in the databases PubMed, NCBI, ResearchGate, RSCI, Scopus and Google Scholar in the period 2000 to 2022. In general, EEG indicators at rest in patients are characterized by ambiguity and require further clarification, however, there are some important findings on the differences in the asymmetry of electric activity, spectral power and coherence between patients with BD and unipolar depression. As for event-related potentials (ERP), similar results were obtained in a number of studies. There are a longer latency of P300 and a decrease in its amplitude in patients with BD compared to unipolar depression, which makes the ERP method more promising in solving the problem of differential diagnosis.
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Nucleus Reuniens: Circuitry, Function, and Dysfunction
Chapter
Sep 2022
Robert P Vertes Stephanie Linley
Tatiana Viena
The nucleus reuniens (RE) of the ventral midline thalamus is intimately connected with forebrain structures involved in higher-order functions and thus serves a critical role in those functions – both affective and cognitive behaviors. RE is strongly reciprocally linked with the hippocampus (HF) and medial prefrontal cortex (mPFC) and hence is pivotally positioned to affect these two structures – as well as their interactions. The HF distributes densely to the mPFC, but there are no return mPFC-HF projections; accordingly, RE is the main route of communication from the mPFC to the HF. Alterations of RE have been shown to disrupt various functions including working memory/spatial working memory (SWM), “executive functions,” and affective behaviors. Specifically, the inactivation of RE alters: (1) synchronous oscillations between the HF and mPFC and performance on SWM tasks; (2) executive functions such as attention, goal-directed behavior, and behavioral flexibility, mainly dependent on RE projections to the mPFC and orbital cortices; and (3) affective behavior, primarily fear and fear extinction, which have been associated with a RE-mediated disruption of mPFC actions on the hippocampus. RE cells in anesthetized and behaving animals exhibit a range of discharge characteristics consistent with the functional properties of RE. For instance, subpopulations of RE neurons (1) fire at significantly higher rates in active waking than in sleep with subsets discharging synchronously with the hippocampal theta rhythm; (2) display spatial properties – place cells, head direction cells, and border cells; and (3) exhibit “trajectory-dependent” activity; that is, RE discharge “predicts” directional choices (or intended movements) to thereby convey action plans from the mPFC to the HF for goal-directed behavior. Further, RE lesions significantly disrupt the stability of hippocampal place cells. Finally, alterations of RE have been linked to the CNS disorders, schizophrenia (SZ), and epilepsy. Regarding SZ, the disruption of RE produces abnormal HF-mPFC oscillations leading to an excessive release of dopamine and SZ-like effects including lapses of memory and cognition. Regarding epilepsy, RE is reportedly a primary conduit in the spread of HF-initiated seizure activity to other cortical regions in temporal lobe epilepsy. In summary, nucleus reuniens serves a critical role in mnemonic, executive, and affective functions, and alterations of RE would disrupt these functions possibly leading to CNS disorders.Key wordsRhomboid nucleusHippocampusMedial prefrontal cortexOrbital cortexPerseverative behaviorAffective behaviorSpatial working memorySchizophreniaEpilepsy
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Spectral perturbations of cortical dipoles during a dynamic visuo-spatial working memory task in schizophrenia Article
Aug 2022 PSYCHIAT RES-NEUROIM
Sunaina Soni Suriya Prakash Muthukrishnan Mamta Sood Ratna Sharma
Altered neural oscillations during prestimulus-task conditions have been reported to be associated with aberrant information processing in schizophrenia. Spectral perturbations induced by visuo-spatial working memory (VSWM) task was investigated in patients and their first-degree relatives in order to study the biomarkers in schizophrenia. EEG was recorded using 128-channel during VSWM task in 28 patients, 27 first-degree relatives and 27 controls. After pre-processing and ICA, current dipole was estimated for each IC. Total of 1609 independent and localizable EEG components across all groups were used to compute ERSP during different events of task. Patients deactivated DMN, RSN, auditory cortex more compared to controls during search period to perform VSWM task. Relatives showed altered activation of right medial and inferior frontal gyri during different events and loads of task in lower frequencies compared to controls. Relatives also showed hyperactivity in right cingulate and parahippocampal gyri compared to controls. This is suggestive of genetic predisposition in schizophrenia and could act as vulnerability markers, further strengthened by no significant differences between patients and relatives. Altered processing of simultaneous ongoing events in patients and relatives can serve as state and trait-specific features of schizophrenia.
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Association between abnormal brain oscillations and cognitive performance in patients with bipolar disorder; Molecular mechanisms and clinical evidence Article
Jul 2022
Zhou Lu Huixiao Wang Jiajie Gu Feng Gao
Brain oscillations have gained great attention in neuroscience during recent decades as functional building blocks of cognitive‐sensory processes. Research has shown that oscillations in “alpha,” “beta,” “gamma,” “delta,” and “theta” frequency windows are highly modified in brain pathology, including in patients with cognitive impairment like bipolar disorder (BD). The study of changes in brain oscillations can provide fundamental knowledge for exploring neurophysiological biomarkers in cognitive impairment. The present article reviews findings from the role and molecular basis of abnormal neural oscillation and synchronization in the symptoms of patients with BD. An overview of the results clearly demonstrates that, in cognitive‐sensory processes, resting and evoked/event‐related electroencephalogram (EEG) spectra in the delta, theta, alpha, beta, and gamma bands are abnormally changed in patients with BD showing psychotic features. Abnormal oscillations have been found to be associated with several neural dysfunctions and abnormalities contributing to BD, including abnormal GABAergic neurotransmission signaling, hippocampal cell discharge, abnormal hippocampal neurogenesis, impaired cadherin and synaptic contact‐based cell adhesion processes, extended lateral ventricles, decreased prefrontal cortical gray matter, and decreased hippocampal volume. Mechanistically, impairment in calcium voltage‐gated channel subunit alpha1 I, neurotrophic tyrosine receptor kinase proteins, genes involved in brain neurogenesis and synaptogenesis like WNT3 and ACTG2, genes involved in the cell adhesion process like CDH12 and DISC1, and gamma‐aminobutyric acid (GABA) signaling have been reported as the main molecular contributors to the abnormalities in resting‐state low‐frequency oscillations in BD patients. Findings also showed the association of impaired synaptic connections and disrupted membrane potential with abnormal beta/gamma oscillatory activity in patients with BD. Of note, the synaptic GABA neurotransmitter has been found to be a fundamental requirement for the occurrence of long‐distance synchronous gamma oscillations necessary for coordinating the activity of neural networks between various brain regions. This article is protected by copyright. All rights reserved
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The Characteristics of Power Spectral Density in Bipolar Disorder at the Resting State Article
Oct 2021
Masakazu Sunaga Yuichi Takei Yutaka Kato Masato Fukuda
Bipolar disorder (BD) is a common psychiatric disorder, but its pathophysiology is not fully elucidated. The current study focused on its electrophysiological characteristics, especially power spectral density (PSD). Resting state with eyes opened magnetoencephalography data were collected from 21 patients with BD and 22 healthy controls. The whole brain's PSD was calculated from source reconstructed waveforms at each frequency band (delta: 1-3 Hz, theta: 4-7 Hz, alpha: 8-12 Hz, low beta: 13-19 Hz, high beta: 20-29 Hz, and gamma: 30-80 Hz). We compared PSD values on the marked vertices at each frequency band between healthy and patient groups using a Mann-Whitney rank test to examine the relationship between significantly different PSD and clinical measures. The PSD in patients with BD was significantly decreased in lower frequency bands, mainly in the default mode network (DMN) areas (bilateral medial prefrontal cortex, bilateral precuneus, left inferior parietal lobe, and right temporal cortex in the alpha band) and salience network areas (SAL; left anterior insula [AI] at the delta band, anterior cingulate cortex at the theta band, and right AI at the alpha band). No significant differences in PSD were observed at low beta and high beta. PSD was not correlated with age or other clinical scales. Altered PSDs of the DMN and SAL were observed in the delta, theta, and alpha bands. These alterations contribute to the vulnerability of BD through the disturbance of self-referential mental activity and switching between the default mode and frontoparietal networks.
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Separating scale-free and oscillatory components of neural activity in schizophrenia Article Full-text available
Feb 2021
Frigyes Samuel Racz Kinga Farkas
Orestis Stylianou Andras Eke
Introduction:
Alterations in narrow-band spectral power of electroencephalography (EEG) recordings are commonly reported in patients with schizophrenia (SZ). It is well established however that electrophysiological signals comprise a broadband scale-free (or fractal) component generated by mechanisms different from those producing oscillatory neural activity. Despite this known feature, it has not yet been investigated if spectral abnormalities found in SZ could be attributed to scale-free or oscillatory brain function.
Methods:
In this study, we analyzed resting-state EEG recordings of 14 SZ patients and 14 healthy controls. Scale-free and oscillatory components of the power spectral density (PSD) were separated, and band-limited power (BLP) of the original (mixed) PSD, as well as its fractal and oscillatory components, was estimated in five frequency bands. The scaling property of the fractal component was characterized by its spectral exponent in two distinct frequency ranges (1-13 and 13-30 Hz).
Results:
Analysis of the mixed PSD revealed a decrease of BLP in the delta band in SZ over the central regions; however, this difference could be attributed almost exclusively to a shift of power toward higher frequencies in the fractal component. Broadband neural activity expressed a true bimodal nature in all except frontal regions. Furthermore, both low- and high-range spectral exponents exhibited a characteristic topology over the cortex in both groups.
Conclusion:
Our results imply strong functional significance of scale-free neural activity in SZ and suggest that abnormalities in PSD may emerge from alterations of the fractal and not only the oscillatory components of neural activity.
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Optogenetic perturbation of projections from thalamic nucleus reuniens to hippocampus disrupts spatial working memory retrieval more than encoding Article
Jan 2021
Faiyaz Rahman Roshan Nanu Nathan Schneider Hyun-Jae Pi
Background
Working memory deficits are key cognitive symptoms of schizophrenia. Elevated delta oscillations, which are uniquely associated with the presence of the illness, may be the proximal cause of these deficits. Spatial working memory (SWM) is impaired by elevated delta oscillations projecting from thalamic nucleus reuniens (RE) to the hippocampus (HPC); these findings imply a role of the RE-HPC circuit in working memory deficits in schizophrenia, but questions remain as to whether the affected process is the encoding of working memory, recall, or both. Here, we answered this question by optogenetically inducing delta oscillations in the HPC terminals of RE axons in mice during either the encoding or retrieval phase (or both) of an SWM task.
Methods
We transduced cells in RE to express channelrhodopsin-2 through bilateral injection of adeno-associated virus, and bilaterally implanted optical fibers dorsal to the hippocampus (HPC). While mice performed a spatial memory task on a Y-maze, the RE-HPC projections were optogenetically stimulated at delta frequency during distinct phases of the task.
Results
Full-trial stimulation successfully impaired SWM performance, replicating the results of the previous study in a mouse model. Task-phase-specific stimulation significantly impaired performance during retrieval but not encoding.
Conclusions
Our results indicate that perturbations in the RE-HPC circuit specifically impair the retrieval phase of working memory. This finding supports the hypothesis that abnormal delta frequency bursting in the thalamus could have a causal role in producing the WM deficits seen in schizophrenia.
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Prolonged functional cerebral asymmetry as a consequence of dysfunctional parvocellular paraventricular hypothalamic nucleus signaling: An integrative model for the pathophysiology of bipolar disorder Article
Nov 2020 MED HYPOTHESES
Kate Levenberg Andras Hajnal Daniel R George Erika F H Saunders
Approximately 45 million people worldwide are diagnosed with bipolar disorder (BD). While there are many known risk factors and models of the pathologic processes influencing BD, the exact neurologic underpinnings of BD are unknown. We attempt to integrate the existing literature and create a unifying hypothesis regarding the pathophysiology of BD with the hope that a concrete model may potentially facilitate more specific diagnosis, prevention, and treatment of BD in the future. We hypothesize that dysfunctional signaling from the parvocellular neurons of the paraventricular hypothalamic nucleus (PVN) results in the clinical presentation of BD. Functional damage to this nucleus and its signaling pathways may be mediated by myriad factors (e.g. immune dysregulation and auto-immune processes, polygenetic variation, dysfunctional interhemispheric connections, and impaired or overactivated hypothalamic axes) which could help explain the wide variety of clinical presentations along the BD spectrum. The neurons of the PVN regulate ultradian rhythms, which are observed in cyclic variations in healthy individuals, and mediate changes in functional hemispheric lateralization. Theoretically, dysfunctional PVN signaling results in prolonged functional hemispheric dominance. In this model, prolonged right hemispheric dominance leads to depressive symptoms, whereas left hemispheric dominance correlated to the clinical picture of mania. Subsequently, physiologic processes that increase signaling through the PVN (hypothalamic-pituitaryadrenal axis, hypothalamic- pituitary-gonadal axis, and hypothalamic-pituitary-thyroid axis activity, suprachiasmatic nucleus pathways) as well as, neuro-endocrine induced excito-toxicity, auto-immune and inflammatory flairs may induce mood episodes in susceptible individuals. Potentially, ultradian rhythms slowing with age, in combination with changes in hypothalamic axes and maturation of neural circuitry, accounts for BD clinically presenting more frequently in young adulthood than later in life.
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EEGs and ERPs in Bipolar Disorders
Chapter
May 2007
R. Hamish McAllister-Williams
View
EEG Frontal Asymmetry and Theta Power in Unipolar and Bipolar Depression Article
Jul 2020 J AFFECT DISORDERS
Kristin Koller-Schlaud Andreas Ströhle
Elisabeth Baerwolf Johannes Rentzsch
Background
Distinguishing between unipolar and bipolar depression is of high clinical relevance. However, there is sparse research directly comparing these groups in terms of EEG activity.
Method
We investigated 87 participants’ left and right EEG frontal alpha-1, alpha-2, and theta activity related to happy and sad face stimuli in unipolar (UD, n=33) and bipolar (BD, n=22) depressed participants, and controls without depression (HC, n=32).
Results
Post-hoc analysis of an observed hemisphere x group interaction (p< .037) showed significant differences in alpha-1 asymmetry only for the comparison of UD and HC (p< .006). Further analysis of a significant emotion x group interaction (p= .001) revealed a differential impact of stimulus valence on theta power between the groups (p< .001). The valence dependent theta power of the BD differed from that of the UD (p< .0002) and the HC (p< .004).
Alpha-1 asymmetry classified HC and both depressed groups with an accuracy of .69. Valence related theta classified BD from UD with an accuracy of .83. Leave-one-out cross validation results in some reduced accuracy.
Limitations
Important limitations were the small sample size and that subjects were not free of medication.
Conclusions
Our results demonstrate the value of simple task related EEG activity for differentiating not only healthy individuals and those with depression, but also between unipolar and bipolar depression.
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Altered parahippocampal gyrus activation and its connectivity with resting-state network areas in schizophrenia: An EEG study Article
Jun 2020 SCHIZOPHR RES
Sunaina Soni Suriya Prakash Muthukrishnan Mamta Sood Ratna Sharma
Synchronized and coherent activity in resting-networks during normal brain functioning could be altered in disconnection syndrome like schizophrenia. Study of neural oscillations as assessed by EEG appears to be a promising proposition to understand the pathophysiology of schizophrenia in patients and their first-degree relatives, where disturbances in neural oscillations point towards genetic predisposition. Therefore, present study aims at establishing EEG based biomarkers for early detection and management strategies. Thirty-two patients with schizophrenia, 28 first-degree relatives and 31 healthy controls (HC) participated in the study. Resting brain activity was recorded using 128-channel electroencephalography. After pre-processing and independent component analysis (ICA), an equivalent current dipole was estimated for each IC. Total of 1551 independent and localizable EEG components across all groups were used in subsequent analysis. Power spectral density and source coherence between IC clusters were computed. Patients and first-degree relatives displayed significantly higher power spectral density (PSD) than HC for all frequency bands in left parahippocampal gyrus (PHG) (−7, −26, 8; BA 27). Another region within left deep PHG (−4, −28, 1), however, distinguished patients from first-degree relatives and HC in terms of significantly lower PSD in higher frequency bands. Functional connectivity (FC) was found to be lower in patients and higher in relatives compared to HC between different resting-state network areas. In patients, connectivity was lower compared to first-degree relatives. Altered activity within left PHG and FC of primarily this with other areas in resting-state network can serve as state and trait markers of schizophrenia.
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Fluctuations of consciousness, mood and science: The interhemispheric switch and sticky switch models two decades on Article
May 2020
Steven M Miller
Science and medicine aim to identify verifiable and replicable truths. However, the paths to such truths are frequently characterised by swinging pendulums of opposing perspectives. This is especially so in human neuroscience and the brain‐based clinical sciences, where the target of investigation is the most complex of all biological systems. This paper overviews a set of interrelated neuroscientific and clinical hypotheses, models, experiments and predictions with which I have been involved for the last two decades. Traversing visual neuroscience, consciousness science, genetics, chronobiology, and biological and clinical psychiatry, the work illustrates how developments in science and medicine can occur through a combination of synthesis, serendipity and experimentation. The paper also reflects on doing science with the inimitable John ‘Jack’ Pettigrew, and outlines how Pettigrew and I conceived, proposed, tested and developed two new scientific models — one on neural mechanisms of binocular rivalry, the other on the pathophysiology of bipolar disorder. I also provide an update on various aspects of our models and data, and describe lessons learned from Pettigrew on how perspectives in science exhibit their own fluctuations, ironically like the very phenomena on which we worked.
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The relationship between resting electroencephalogram oscillatory abnormalities and schizotypal personality traits in the first-degree relatives of schizophrenia patients Article
Oct 2019 NEUROREPORT
Chen Chen Wei Huang Xianjun Chen
Xufeng Liu
Although a large amount of studies have manifested resting state electroencephalogram oscillatory abnormalities in schizophrenia and their first-degree relatives and in schizotype, the results are far from consistent and no research found any relationship between electroencephalograph (EEG) abnormalities and schizotypal personality in first-degree relatives. The present study is to verify the modifications of EEG power spectra in eyes-open resting state of schizophrenia and first-degree relatives, and to investigate associations between EEG band power and schizotypal personality traits in first-degree relatives of schizophrenia patients. Participant samples in this study consisted of 33 healthy normal controls, 35 unaffected first-degree relatives of schizophrenia patients and 35 schizophrenia patients. Group differences in resting EEG band power were examined via repeated-measures analysis of variance, and correlation between EEG power and schizotypal personality traits via Pearson Correlation analysis. The results showed that patients with schizophrenia exhibited increased delta, theta and alpha activity over anterior and central regions in eyes-open resting state compared with that of normal control. Gamma band power was found for the first time to be negatively correlated to schizotypal personality traits in first-degree relatives of schizophrenia patients. To conclusion, these findings suggested that low-frequency EEG activity might be neural manifestations of pathophysiological changes in the brain of schizophrenia, and gamma band activity might be an approach to measure the genetic liability of the disorder.
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Electroencephalography and Staging
Chapter
Jul 2019
Suzie Lavoie
Clinical Staging in Psychiatry - edited by Patrick D. McGorry August 2019
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Non-Negative Matrix Factorization Reveals Resting-State Cortical Alpha Network Abnormalities in the First Episode Schizophrenia-Spectrum Article
Jul 2019
Henry Phalen Brian Allen Coffman
Ghuman Singh Avniel Dean F Salisbury
Background:
Little is known about neural oscillatory dynamics in first-episode psychosis. Pathophysiology of functional connectivity can be measured through network activity of alpha oscillations, reflecting long-range communication between distal brain regions.
Methods:
Resting magnetoencephalographic activity was collected from 31 individuals with first-episode schizophrenia spectrum psychosis and 22 healthy control individuals. Activity was projected to the realistic cortical surface, based on structural magnetic resonance imaging. The first principal component of activity in 40 Brodmann areas per hemisphere was Hilbert transformed within the alpha range. Non-negative matrix factorization was applied to single-trial alpha phase-locking values from all subjects to determine alpha networks. Within networks, energy and entropy were compared.
Results:
Four cortical alpha networks were pathological in individuals with first-episode schizophrenia spectrum psychosis. The networks involved the bilateral anterior and posterior cingulate; left auditory, medial temporal, and cingulate cortex; right inferior frontal gyrus and widespread areas; and right posterior parietal cortex and widespread areas. Energy and entropy were associated with the Positive and Negative Syndrome Scale total and thought disorder factors for the first three networks. In addition, the left posterior temporal network was associated with positive and negative factors, and the right inferior frontal network was associated with the positive factor.
Conclusions:
Machine learning network analysis of resting alpha-band neural activity identified several aberrant networks in individuals with first-episode schizophrenia spectrum psychosis, including the left temporal, right inferior frontal, right posterior parietal, and bilateral cingulate cortices. Abnormal long-range alpha communication is evident at the first presentation for psychosis and may provide clues about mechanisms of dysconnectivity in psychosis and novel targets for noninvasive brain stimulation.
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Resting-state alpha and gamma activity in affective disorder with ADHD symptoms: Comparison between bipolar disorder and major depressive disorder Article
Jun 2019 INT J PSYCHOPHYSIOL
Ji Sun Kim Soohwan Oh Hong Jin Jeon Ji Hyun Baek
Although comorbid attention deficit/hyperactivity disorder (ADHD) symptoms are very common in mood disorder, its neurophysiological correlates have not been explored. This study aimed to examine clinical and neurophysiological correlates of ADHD symptoms in major depressive disorder (MDD) and bipolar disorder (BP). A total of 67 subjects with mood disorder, current depressive episode (38 subjects with MDD and 29 subjects with BP depression) were included in the analysis. Resting quantitative electroencephalography (qEEG) recordings were collected under eyes closed condition. ADHD symptoms, depression, anxiety, and lifetime hypomania were evaluated using self-report questionnaires. In MDD, ADHD symptoms did not show significant associations with anxiety and depression. In BP, ADHD symptoms showed significant associations with depression, anxiety and lifetime hypomania. Significant correlations with Adult ADHD self-report scales (ASRS) inattention score and total score were detected in left and right frontal alpha powers in MDD while significant correlation with ASRS hyperactivity score and ASRS total score were detected in right frontal gamma power in BP. Linear regression analyses revealed that left and right frontal alpha powers, depression and lifetime hypomania showed significant association with ASRS inattention score and ASRS total score in MDD. In BP, linear regression analysis showed ASRS hyperactivity score was associated with lifetime hypomania and the right frontal gamma power. MDD and BP showed different correlation patterns between frontal qEEG measures and ADHD symptoms. This might be associated with distinct neurobiological underpinnings of co-occurring ADHD symptoms in MDD and BP.
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Disorganization and cognitive impairment in schizophrenia: New insights from electrophysiological findings Article
Mar 2019 INT J PSYCHOPHYSIOL
A. Vignapiano Thomas Koenig
Armida Mucci Mario Maj
In subjects with schizophrenia (SCZ), the disorganization dimension is a strong predictor of real-life functioning. “Conceptual disorganization” (P2), “Difficulty in abstract thinking” (N5) and “Poor attention” (G11) are core features of the disorganization factor, evaluated using the Positive and Negative Syndrome Scale. The heterogeneity of this dimension and its overlap with neurocognitive deficits are still debated. Within the multicenter study of the Italian Network for Research on Psychoses, we investigated electrophysiological and neurocognitive correlates of disorganization and its component items to assess the heterogeneity of this dimension and its possible overlap with neurocognitive deficits. Resting state EEG was recorded in 145 stabilized SCZ and 69 matched healthy controls (HC). Spectral amplitude was averaged in ten frequency bands. Neurocognitive domains were assessed by MATRICS Consensus Cognitive Battery (MCCB). RAndomization Graphical User software explored band spectral amplitude differences between groups and correlations with disorganization and MCCB scores in SCZ. Correlations between disorganization and MCCB scores were also investigated. Compared to HC, SCZ showed increased delta, theta, and beta 1 and decreased alpha 2 activity. A negative correlation between alpha 1 and disorganization was observed in SCZ. At the item level, only “N5” showed the same correlation. MCCB neurocognitive composite score was associated with disorganization, “P2” and “N5”. Our findings suggest only a partial overlap between disorganization and neurocognitive impairment. The association of alpha 1 with the “N5” item suggests that some aspects of disorganization could be underpinned by the impairment of basic neurobiological functions that are only partially evaluated using MCCB.
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Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations Article Full-text available
Nov 2018 CEREB CORTEX
Tuomo Mäki-Marttunen Florian Krull
Francesco Bettella Gaute T Einevoll
Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia.
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Electrophysiological Assessment Methodology of Sensory Processing Dysfunction in Schizophrenia and Dementia of the Alzheimer Type Article Full-text available
Sep 2018 NEUROSCI BIOBEHAV R
Philippe Danjou Geoffrey Viardot
Damien Maurice Darrel J. Pemberton
Schizophrenia and Alzheimer's disease impacts on various sensory processings are extensively reviewed in the present publication. This article describes aspects of a research project whose aim is to delineate the neurobiology that may underlie Social Withdrawal in Alzheimer's disease, Schizophrenia and Major Depression. This is a European-funded IMI 2 project, identified as PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This paper focuses specifically on the selected electrophysiological paradigms chosen based on a comprehensive review of all relevant literature and practical constraints. The choice of the electrophysiological biomarkers were fundamentality based their metrics and capacity to discriminate between populations. The selected electrophysiological paradigms are resting state EEG, auditory mismatch negativity, auditory and visual based oddball paradigms, facial emotion processing ERP's and auditory steady-state response. The primary objective is to study the effect of social withdrawal on various biomarkers and endophenotypes found altered in the target populations. This has never been studied in relationship to social withdrawal, an important component of CNS diseases.
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EEGs and ERPs in bipolar disorders
Chapter
Apr 2016
R. Hamish McAllister-Williams
The first report of an electroencephalographic (EEG) recording from amammal was made more than a century ago (1) and the first human recording over 65 years ago (2). A search of PubMed for papers referring to EEG or event-related potentials (ERPs) and bipolar disorder (BD) flags nearly three hundred items (between 1966 and December 2005). However, of these papers, over two-thirds are more than 10 years old. EEG and ERP studies are not new but certainly are not increasing at the rate seen with other experimental methodologies in psychiatric illnesses, such as functional magnetic resonance imaging (fMRI) and molecular studies. Put bluntly, EEG is not a “sexy” topic. This stems largely from the technique not delivering important findings after years of study, with a few notable exceptions such as the diagnosis of epilepsy and sleep disorders. However, EEG and ERP techniques still have much to offer in the further elucidation of the pathophysiology of mood disorders if used in appropriate ways. In the past, much reliance has been placed on the visual inspection of paper and ink EEG recordings and rather simple ERP paradigms with no a priori hypothetical rationale behind their design. While this situation continues in clinical electrophysiology to a large extent, the increasing use of novel computational analysis of EEG and ERP data, often coupled with specific pharmacological or cognitive challenges, offers exciting prospects for the future. This chapter is a selective review of EEG and ERP data to illustrate this argument. It is not a comprehensive review of all of the EEG studies in BD. In particular, sleep EEG research is not covered at all. The chapter is written with the non-EEG specialist bipolar researcher in mind.
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Complexity analysis of spontaneous brain activity in mood disorders: A magnetoencephalography study of bipolar disorder and major depression Article
Apr 2018 COMPR PSYCHIAT
Alberto Fernández Ali H. Al-Timemy
Francisco Ferre Javier Escudero
Background and purpose.
The lack of a biomarker for Bipolar Disorder (BD) causes problems in the differential diagnosis with other mood disorders such as major depression (MD), and misdiagnosis frequently occurs. Bearing this in mind, we investigated non-linear magnetoencephalography (MEG) patterns in BD and MD.
Methods
Lempel-Ziv Complexity (LZC) was used to evaluate the resting-state MEG activity in a cross-sectional sample of 60 subjects, including 20 patients with MD, 16 patients with BD type-I, and 24 control (CON) subjects. Particular attention was paid to the role of age. The results were aggregated by scalp region.
Results
Overall, MD patients showed significantly higher LZC scores than BD patients and CONs. Linear regression analyses demonstrated distinct tendencies of complexity progression as a function of age, with BD patients showing a divergent tendency as compared with MD and CON groups. Logistic regressions confirmed such distinct relationship with age, which allowed the classification of diagnostic groups.
Conclusions
The patterns of neural complexity in BD and MD showed not only quantitative differences in their non-linear MEG characteristics but also divergent trajectories of progression as a function of age. Moreover, neural complexity patterns in BD patients resembled those previously observed in schizophrenia, thus supporting preceding evidence of common neuropathological processes.
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Appendix A. Manual for the expanded Brief Psychiatric Rating Scale (BPRS) Article Full-text available Jan 1986 David Lukoff Keith H Nuechterlein Joseph Ventura View Hypofrontality on topographic EEG in schizophrenia Article Full-text available Jul 1992 Wagner Gattaz Susanne Mayer Peter Ziegler Theo Gasser Topographic EEG was performed in 17 DSM-III-R schizophrenic patients and in 15 sex- and agematched healthy controls. Eleven patients were firstonset (neuroleptic naive) schizophrenics. EEG band power was compared with psychopathology, neuropsychology and neurological soft signs. The EEG was recorded at 14 topographic locations monopolarly and movements of the eye and of the lid were monitored by two bipolar electro-oculogram (EOG) derivations, one vertical and one horizontal. A multivariate correction of EOG artefacts was performed based on regression analysis with respect to EOG channels. Schizophrenic patients showed higher mean and median power in most bands. These differences were most marked in the delta band, in the fast alpha and beta bands, in particular at left frontal sites. Delta power at F7 was by far the best separating variable between schizophrenics and controls in a discriminant analysis. Significant positive correlations were found between the Brief Psychiatric Rating Scale scores Anxiety-depression and Activation and power in the fast bands and negative ones between Anergia and the beta bands. Positive significant correlations emerged between the total score in the Negative Symptoms Rating Scale and the amount of delta power, predominantly over the temporal region. Impairment in the Luria-Nebraska neuropsychological scores Rhythm and Memory correlated highly significantly with EEG band power. No correlations were found between neurological soft signs and EEG band power. Our results are in line with the hypothesis of a hypofrontality in schizophrenia. It is unlikely that these findings are an artefact of prior psychiatric treatment, as they were also observed in firstonset, neuroleptic naive schizophrenics. Moreover, our data suggest that these abnormalities are of clinical and functional relevance, as they correlated significantly with psychopathological and neuropsychological parameters. View Show abstract Lateralization of Norepinephrine in Human Thalamus Article Full-text available Jul 1978 Arvin Oke Richard Keller Ivan N Mefford Ralph N. Adams Norepinephrine has a strongly lateralized distribution in the human thalamus. In the pulvinar region the left hemisphere is
rich in norepinephrine, whereas in the somatosensory input area the right hemisphere has a higher concentration of this catecholamine.
Such naturally occurring left-right differences in concentration of a neurotransmitter represent a new aspect of hemispheric
specialization. View Show abstract Brain Magnetic Resonance Imaging: Approaches for Investigating Schizophrenia Article Full-text available Feb 1990 SCHIZOPHRENIA BULL Adolf Pfefferbaum Kar Onn Lim Margaret J Rosenbloom Robert B Zipursky Magnetic resonance imaging (MRI) offers the potential for identifying, in vivo, specific brain abnormalities associated with
schizophrenia. The detection of small morphological differences in areas such as the prefrontal cortex, limbic structures,
and basal gangalia requires attention to a number of technical and methodological details. The effects of age, height, sex,
head size, and overall tissue loss are of particular concern and are discussed. MRI acquisition and processing techniques
for improving gray/white tissue contrast and image resolution are described, as are techniques for quantitative, volumetric
measurement of localized regions of interest and specific brain structures as well as of the brain as a whole. Techniques
for evaluating frontal lobes, temporal lobes, and basal ganglia integrity are reviewed, and recent observations on these brain
regions in patients with schizophrenia are described. View Show abstract The Structured Interview for Schizotypy (SIS): A Preliminary Report Article Full-text available Feb 1989 SCHIZOPHRENIA BULL K S Kendler Jeffrey A Lieberman Damian Gerard Walsh This article presents a new interview-based research instrument for assessing schizotypal symptoms and signs. The Structured
Interview for Schizotypy (SIS), which was developed from experience gained in a large, controlled family study of schizophrenia
in the west of Ireland and has been field-tested in three other locations, differs from previously available interviews in
that it includes: (1) built-in contextual assessments of the pathological nature of certain symptoms (e.g., suspiciousness
or ideas of reference); (2) multiple independently scored items, most with closed response options, per symptom scale; (3)
extensive assessment of schizotypal signs; (4) symptom probes designed to make responding positively appear nondeviant; and
(5) coverage of potentially relevant symptoms and signs not required in current criteria for schizotypal personality disorder.
Schizotypal symptoms can be assessed with high reliability by the SIS. When sufficient variability is present, schizotypal
signs are also reliably assessed by the SIS, although the reliability is generally lower than that found for symptoms. In
three independent pilot studies, schizotypal symptoms and signs assessed by the SIS appear to discriminate significantly the
relatives of schizophrenic patients from relatives of controls. View Show abstract Psychiatric Diagnostic Discriminations with Combinations of Quantitative EEG Variables Article Full-text available Jul 1984 Charles Shagass Richard Roemer John J. Straumanis Richard C Josiassen The possible psychiatric diagnostic utility of certain quantitative EEG measures was evaluated by further analysis of previously reported data from 242 unmedicated patients and 94 non-patients. Time series of amplitude, frequency and wave symmetry measures for 12-lead EEGs (eyes closed and open) were factor analyzed across leads. Factor scores meeting specified criteria in multivariate analyses were entered into discriminant analyses comparing pairs of the following groups: non-patients, neurotics, personality disorders, overt schizophrenics, latent schizophrenics, major depressives and manics. The following discriminations were obtained with at least 50 per cent sensitivity, and diagnostic confidence rates from 69 to 92 per cent: (a) non-psychotic patients (neuroses, personality disorders) from overt schizophrenics, latent schizophrenics or manics; (b) major depressives from latent schizophrenics or manics; (c) non-patients from schizophrenics (overt and latent), depressives or manics. Most discriminations were replicable in split-half analyses. Possible utility of EEG measures in differential diagnosis is supported. View Show abstract Asymmetric neural control systems in human self-regulation Article Apr 1984 DM TUCKER PA WILLIAMSON View Structured clinical interview for the DSM-IV personality disorders (SCID-II) Book Jan 1987 Robert L. Spitzer Janet B W Williams M Gibbon View Toward a Biochemical Classification of Depressive Disorders Article Dec 1978 ARCH GEN PSYCHIAT Joseph J. Schildkraut • The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolites:Depression-type (D-type) score =
C,(MHPG) + C2(VMA) + C,(NE) + C,(NMN + MN)/VMA + C0 In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders. View Show abstract The National Institute of Mental Health Diagnostic Interview Schedule for Children Article Apr 1981 ARCH GEN PSYCHIAT Lee N. Robins • A new interview schedule allows lay interviewers or clinicians to make psychiatric diagnoses according to DSM-III criteria, Feighner criteria, and Research Diagnostic Criteria. It is being used in a set of epidemiological studies sponsored by the National Institute of Mental Health Center for Epidemiological Studies. Its accuracy has been evaluated in a test-retest design comparing independent administrations by psychiatrists and lay interviewers to 216 subjects (inpatients, outpatients, ex-patients, and nonpatients). View Show abstract Relationships Between Psychiatric Diagnosis and Some Quantitative EEG Variables Article Dec 1982 ARCH GEN PSYCHIAT Charles Shagass • Psychiatric diagnostic correlates of EEG measures were Investigated in 242 unmedicated patients and 94 nonpatients. Computer analysis of eyes-open and eyes-closed EEGs (12 leads) provided time series of amplitude, frequency, and wavesymmetry measures; mean levels and temporal variability Indexes were also factor analyzed across leads. Comparisons between various age-and sex-matched groups disclosed numerous differences. Compared with those of nonpatients, schizophrenics' EEGs showed lower amplitude variability, greater frequency variability, greater wave symmetry, and less reactivity to eye opening. The EEGs of schizophrenic subgroups, including latent schizophrenics, were similar and also like those of manics. The EEGs of manics and major depressives differed markedly. The EEGs of subjects with personality disorders and schizophrenics differed from nonpatients in opposite directions. Groups could be classed according to the level of EEG activation: high included manics and schizophrenics; normal, nonpatients and neurotics; and low, major depressives and those with personality disorders. View Show abstract Multivariate Analysis of Variance Article May 1987 D. D. V. Morgan James H Bray Scott E. Maxwell View Bootstrapping: Application to Psychophysiology Article Apr 1989 PSYCHOPHYSIOLOGY Stanley Wasserman Ulf Bockenholt This paper presents the statistical technique known as the bootstrap to the general audience of psychophysiologists. The bootstrap, introduced by Efron (1979), allows data analysts to study the distribution of sample statistics that might otherwise be too complicated to consider. The technique, which requires simple calculations, involves drawing repeated samples (with replacement) from the empirical--or the actual--data distribution and then building a distribution for a statistic by calculating a value of the statistic for each sample. The bootstrap can be used to obtain confidence intervals, standard errors, and even higher moments for the statistic. It is similar to the well-known jackknife of Quenouille and Tukey. After discussing the history and theory of both the bootstrap and the jackknife, we illustrate the use of the bootstrap in the statistical analysis of correlation coefficients and the general linear model. View Show abstract Structured clinical interview for DSM-IV Axis-II disorders Article Jan 1994 Rl Spitzer M Gibbon Michael B First Janet B W Williams View Applied Multiple Regression/Correlation Analysis For The Behavioral Sciences Article Jun 1985 Jacob Cohen Patricia Cohen View User's guide for the structured clinical interview for DSM-IV Axis II personality disorders (SCID-II) Article Jan 1990 Robert L. Spitzer Janet B W Williams Miriam Gibbon Michael B First The Structured Clinical Interview for DSM-III-R [Diagnostic and Statistical Manual, Revised] (SCID) is a semistructured interview for making the major Axis I and Axis II diagnoses. It is administered by a clinician or trained mental health professional who is familiar with the DSM-III-R classification and diagnostic criteria (1). The subjects may be either psychiatric or general medical patients or individuals who do not identify themselves as patients, such as subjects in a community survey of mental illness or family members of psychiatric patients. The language and diagnostic coverage make the SCID most appropriate for use with adults (age 18 or over), but with slight modification, it may be used with adolescents. (PsycINFO Database Record (c) 2012 APA, all rights reserved) View Show abstract EEG spectra in twins: Evidence for a neglected mechanism of genetic determination Article Mar 1982 David T. Lykken Auke Tellegen William Iacono EEG spectra were obtained from 50 monozygotic (MZ) and 26 same-sex dizygotic (DZ) pairs of 19–55 yr old twins. Spectra obtained from MZ twins showed striking within-pair similarity, while spectra of DZ twins were no more similar than those obtained from pairs of unrelated persons. At least one parameter of the EEG spectrum, the midfrequency of the alpha rhythm, was strongly correlated within pairs of MZ twins; its correlation within pairs of DZ twins was about zero. The frequency composition of the resting EEG may be an example of "emergenesis," in which the phenotypic character is determined by the interaction of independently heritable traits and is substantially altered if any genotypic component is changed. Such emergenic traits would not reveal their genetic origin in the usual analysis of pedigrees. (5 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved) View Show abstract Age of onset, temporal stability, and eighteen-month course of first-episode psychosis. Article Jan 1989 William Iacono Morton Beiser the MAP [Markers and Predictors of schizophrenia] project has many facets and objectives, not all of which can be addressed in this chapter / we . . . [will] address three issues from a developmental perspective / one involves individual differences in the age of onset of psychosis, both within and among different categories of psychosis and between the sexes / another concerns the developmental course of disorder as manifested in the temporal stability of diagnostic assignment during the year and a half that follows the first psychotic episode / the last relates to the prediction of the short-term outcome of psychosis (PsycINFO Database Record (c) 2012 APA, all rights reserved) View Show abstract Tables for clinicians to use to convert WAIS-R Short Forms Article Nov 1986 Barry H. Brooker J. J. Cyr Provides 3 tables for clinicians to use to obtain Full Scale IQ estimates in the use of short forms of the Wechsler Adult Intelligence Scale—Revised (WAIS—R). These tables are based on a method presented by J. J. Cyr and B. H. Brooker (see record
1985-02886-001) that jointly considers the validity and reliability of each subtest. None of the IQ equivalents will be in error by more than 1 point. (7 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved) View Show abstract Internal consistency reliability of resting EEG power spectra in schizophrenic and normal subjects Article Feb 1995 PSYCHOPHYSIOLOGY THOMAS R. LUND Scott R Sponheim William Iacono Brett Clementz The reliability of resting electroencephalogram (EEG) power spectra was assessed for 49 normal and 44 schizophrenic subjects. We specifically examined internal consistency reliability to determine how much EEG data are necessary to ensure small measurement error. Twenty-one 8-s epochs of resting EEG were collected from each subject from site Cz. Epochs containing artifacts or blinks were eliminated. Power was computed in the bands delta (0.125–3 Hz), theta (3.125–8 Hz), alpha (8.125–13 Hz), betal (13.125–20 Hz), beta2 (20.125–25 Hz), and beta3 (25.125–30 Hz). Internal consistency was computed using coefficient alpha (Cronbach, 1951). Results for both groups indicated that eight artifact-free epochs of data were sufficient to give a coefficient alpha value of around .9. The schizophrenic and normal groups did not differ with respect to coefficient alpha. The proportion of artifacts in the data from the schizophrenics indicated that to obtain eight artifact-free epochs from members of each group, 40% more data would be required from the schizophrenics. View Show abstract The common genetic liability between schizophrenia and bipolar disorder: A review Article Aug 2001 Elvira Bramon Pak Chung Sham Current psychiatric nosology, strongly influenced by Kraepelin’s dichotomy [1,2], classifies schizophrenia and bipolar disorder
as separate diagnostic categories. However, growing evidence indicates that the two disorders may be more closely related
than was thought in the past. Bipolar disorder and schizophrenia display considerable overlap in epidemiologic features; no
risk factor is known to be specific to either. Furthermore, family studies reveal familial co-aggregation of the two disorders,
and twin studies suggest a significant overlap in the genes contributing to schizophrenia, schizoaffective disorder, and mania.
Finally, despite the difficulties in the identification of convincing genetic loci for psychiatric disorders, there are at
least four genomic regions in which linkage has been shown for both schizophrenia and bipolar disorder. Thus, recent evidence
increasingly supports a dimensional approach in the understanding of the functional psychoses, and this is expected to have
implications for etiologic research and future clinical treatment. View Show abstract The Relation of Simple Response Time to Brain-Wave Frequency and the Effects of Age Article Mar 1963 Electroencephalogr Clin Neurophysiol Walter W. Surwillo An experiment was performed to verify a previous finding of a positive correlation (0.81) between response time and period of the EEG. Details of this relationship, with reference to age and to a hypothesis concerning the function of the brain-wave cycle in simple behavior, were investigated.Reaction times and average period of the EEG, recorded in the interval of time between stimulus and response, were determined for 100 subjects ranging in age from 28–99 years. The major results were: 1.1. The previous finding was confirmed. In the present study a correlation coefficient of 0.72 was obtained between average reaction time and the average period of the EEG.2.2. Excluding age from this relationship through the use of partial correlation, scarcely altered this coefficient. Age as a factor in the observed correlation was, therefore, ruled out.3.3. A highly significant positive correlation was obtained between age of the subjects and the average period of their brain waves.4.4. A low but statistically significant positive correlation was found relating average reaction time and age. This positive coefficient vanished and became negative when brain-wave period was “partialled out”. It was inferred, therefore, that EEG frequency is the central nervous system factor behind age-associated slowing in response time.5.5. Evidence derived from data of each subject taken singly showed the presence of a positive correlation between brain-wave period and reaction time in individual subjects.6.6. Taken as a whole, the data support the hypothesis that the brain-wave cycle is the basic unit of time in terms of which a response is programmed by the central nervous system. View Show abstract Introduction To Quantitative Genetics Article Jun 1962 POPULATION D. S. Falconer Trudy Mackay View Genetic polymorphism and breast cancer risk in young women / Article Malin. Bergman Thesis (doctoral)--Linköping University, 2004. View Show abstract Isolating low frequency in EEG spectrum analysis Article Mar 1979 Electroencephalogr Clin Neurophysiol Richard Coppola A method for isolating and removing very slow activity from EEG records prior to spectrum computation is presented. This is accomplished by an autoregressive filter whose frequency transfer characteristic can be easily controlled. Examples of spectra computed for various filter parameter values are shown. View Show abstract On certain aspects of the localization of cerebral systems regulating and determining action Article Sep 1979 BIOL PSYCHIAT Pierre Flor-Henry In this essay many lines of evidence relevant to the problem of the organization of the cerebral mood systems are surveyed: the study of penetrating head injuries, cerebrovascular accidents, cerebral tumors, psychiatric surgery, bilateral and unilateral nondominant and dominant ECT, temporal lobe epilepsy, the psychometrical and neuropsychological correlates of the endogenous psychoses, the power spectral EEG characteristics of depressive and manic psychoses, dichotic stimulation in the manic-depressive syndrome, the patterns of lateralized cognitive activation in normals, the electrodermal characteristics of depression, the differential hemispheric reactivity of the right and left brain in normals and depressives under carotid barbiturization, the characteristics of REM sleep, the lateralization of pain and of the orgasmic response in relation to mood, the evidence for the presence of lateralized neurochemical as well as neurophysiological and neuropsychological asymmetry in the nervous system, and the intrication of sinistrality, cerebral visuospatial organization, and gender. The synthesis of extremely diverse types of evidence not normally considered in the same perspective does not pretend to be a systematic review of the various fields discussed. Yet because certain underlying principles of cerebral organization and disorganization are in this manner suggested, it may have some heuristic value. View Show abstract Qualitative and Quantitative EEG Findings in Schizophrenia Article Feb 1977 SCHIZOPHRENIA BULL T M Itil Various conflicting EEG observations are reported in adult schizophrenia, childhood schizophrenia, neuroleptic treatment, and use of hallucinogenic compounds. The most important finding in the research over the past 40 yrs is seen as the confirmation that patients with schizophrenia have more low-voltage, fast EEGs and less well-organized alpha activity than controls. Findings of excessive fast activity and nonalpha activity in schizophrenics, as confirmed by quantitative EEG analysis, have been disavowed for the most part. Recent work has indicated no relationship between fast EEG activity in schizophrenics and muscle potential; this was again shown in the author's work on neuroleptics. The author has found that children of schizophrenic parents differed from controls in EEG measurements as did psychotic and adult schizophrenics from their respective control groups. These patterns were characterized by less alpha wave activity, more high-frequency beta activity, and more very slow low-voltage delta waves. Evidence for the hypothesis that the desynchronized high-frequency beta activity may be the electrophysiological representation of the genetic predisposition to schizophrenia is presented. All drugs effective in schizophrenia (neuroleptics) produce effects on quantitative EEGs that are almost diametrically opposite to those seen in schizophrenia. (117 ref) (PsycINFO Database Record (c) 2013 APA, all rights reserved) View Show abstract Toward a biochemical classification of depressive disorders. I. Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions Article Jan 1979 ARCH GEN PSYCHIAT Joseph J. Schildkraut Paul J. Orsulak Alan F Schatzberg R A LaBrie The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and other catecholamine metabolites was measured in a series of 63 patients with various clinically defined subtypes of depressive disorders. MHPG excretion was significantly lower in patients with bipolar manic-depressive depressions and schizo-affective depressions than in patients with unipolar nonendogenous depressions. Patients with schizophrenia-related depressions also excreted reduced levels of MHPG when compared with patients with unipolar nonendogenous depressions. Moreover, levels of urinary epinephrine and metanephrine were significantly lower in patients with schizophrenia-related depressions. These data, coupled with our recent finding that patients with schizophrenia-related depressions had significantly higher levels of platelet monoamine oxidase activity than control subjects of patients with unipolar endogenous depressions, suggest that we can discriminate three biochemically discrete subgroups of depressive disorders corresponding to the following clinically defined subtypes: (1) the bipolar manic-depressive depressions plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions; and (3) the schizophrenia-related depressions. View Show abstract Arousal, Activation, and Effort in the Control of Attention Article Apr 1975 Karl H. Pribram Diane McGuinness A review of neuropsychological and psychophysiological data on attention suggests that there are 3 separate, but interacting, neural systems: One controls arousal, which is defined in terms of phasic physiological responses to input. The arousal control circuits center on the amygdala. A 2nd system controls activation, which is defined in terms of tonic physiological readiness to respond. The readiness circuits center on the basal ganglia of the forebrain. A 3rd system is discerned which coordinates arousal and activation. This coordinating activity is defined as demanding effort. Its circuitry centers on the hippocampus. When arousal, activation, and effort are involved in problem solving, at least 2 further distinctions can be made. During categorizing, arousal precedes activation; during reasoning, activation precedes arousal. The question of whether effort in problem solving is to be attributed solely to peripheral muscular factors or whether direct monitoring of changes in brain organization can be productive of measurable indicators of effort is examined. (6 p ref) View Show abstract Clinical Correlates of Anhedonia and Perceptual Aberration in First-Episode Patients With Schizophrenia and Affective Disorder Article Mar 1992 Joanna Katsanis Lizabeth Lacey William Iacono Morton Beiser We examined the association between scales measuring physical anhedonia, social anhedonia, and perceptual aberration and premorbid functioning, clinical state, and current level of adjustment in 91 psychotic subjects. The patients were examined at the onset of their first psychotic episode and again 18 months later. For patients with schizophrenia, anhedonia was significantly related to premorbid functioning. No association was found between the scales and clinical state or level of adjustment at intake or follow-up. In affective disorder patients, no correlation was found between premorbid functioning (a stable characteristic) and scale scores, but moderately large correlations emerged between the scales and clinical state and level of adjustment at both assessment times. These results suggest that schizophrenic and affective disorder patients endorse items on these scales for different reasons. We hypothesize that for patients with schizophrenia, the scales assess enduring personality characteristics, whereas for the affective disorder patients, they assess clinical condition at the time of testing. View Show abstract Smooth-Pursuit Eye Tracking in First-Episode Psychotic Patients and Their Relatives Article Mar 1992 Margaret Moreau Tsung-Yi Lin William Iacono Morton Beiser We wished to determine the specificity of smooth-pursuit eye tracking dysfunction to schizophrenia and the prevalences of dysfunction among functionally psychotic and normal individuals. Therefore, we investigated pursuit tracking in a large sample of psychotic patients, normal subjects, and first-degree relatives (N = 482). Patients were recruited as part of an epidemiological study of first-episode psychosis that used a broadly based referral network to identify all cases in a major metropolitan area over a 2 1/2-year period. Patients received diagnoses of schizophrenia, schizophreniform disorder, psychotic mood disorder, and paranoid or other psychotic disorder based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1980). The distribution of tracking performance was bimodal for the schizophrenic patients and their relatives, perhaps reflecting major gene action. Moreover, poor tracking ran in families. Pursuit tracking dysfunction was relatively specific to schizophrenic patients and their relatives and occurred infrequently in other psychotic patients and normal subjects. View Show abstract A family study of nailfold plexus visibility in psychotic disorders Article Mar 1992 BIOL PSYCHIAT Brett Clementz John Ficken Morton Beiser William Iacono It has been proposed that the nailfold subpapillary plexus visibility score (PVS) may be a marker of susceptibility to schizophrenia. To further investigate this hypothesis, we evaluated plexus visibility in a sample of 61 chronic schizophrenics, a large sample of first-episode psychotic patients and their first-degree relatives (50 with schizophrenia, and 51 of their relatives; 29 with schizophreniform disorder, 30 of their relatives; 32 with major depression with psychotic features, 35 of their relatives; 33 with a bipolar disorder with psychotic features, 32 of their relatives), and 169 normal control subjects. Group comparisons demonstrated that (1) the probands with chronic schizophrenia, first episode schizophrenia, and schizophreniform disorder did not differ from one another on PVS; (2) these subjects combined had higher PVS ratings than the other two proband groups and normal subjects combined (who did not differ); and (3) none of the relative groups significantly differed from either one another or the normal subjects. On the other hand, relatives of schizophrenia spectrum probands with high PVS (greater than or equal to 10.0) had higher PVS ratings than the relatives of such probands with low PVS. Patterns of familial correlations suggested that PVS was moderately heritable (0.40). There was no evidence that nonadditive genetic variation influenced the trait. View Show abstract Individual Differences in Anterior Brain Asymmetry and Fundamental Dimensions of Emotion Article May 1992 Andrew J Tomarken Richard J. Davidson Robert E. Wheeler Robert C. Doss This research assessed whether individual differences in anterior brain asymmetry are linked to differences in basic dimensions of emotion. In each of 2 experimental sessions, separated by 3 weeks, resting electroencephalogram (EEG) activity was recorded from female adults during 8 60-s baselines. Mean alpha power asymmetry across both sessions was extracted in mid-frontal and anterior temporal sites. Across both regions, groups demonstrating stable and extreme relative left anterior activation reported increased generalized positive affect (PA) and decreased generalized negative affect (NA) compared with groups demonstrating stable and extreme relative right anterior activation. Additional correlational analyses revealed robust relations between anterior asymmetry and PA and NA, particularly among subjects who demonstrated stable patterns of EEG activation over time. Anterior asymmetry was unrelated to individual differences in generalized reactivity. View Show abstract Are schizophrenia and affective disorder related? A selective literature review Article Feb 1992 M A Taylor Although most modern investigators accept the Kraepelinian view that schizophrenia and affective disorder are biologically distinct, others have suggested the psychoses are on a continuum of liability. This article is a selective review of evidence for the continuum model.
The author focuses on family, twin, and adoption data that do not support the Kraepelinian view of psychosis. Evidence characterized to a lesser extent includes the frequency of intermediate forms of illness (i.e., schizoaffective disorder), the inability to separate psychoses by classical symptoms into well-defined clusters, and the inability of laboratory measures to clearly define psychotic subgroups.
The data demonstrate that schizophrenia and affective disorder do co-occur in some families. Whether this co-occurrence reflects true overlap is unclear, and significant pathophysiological heterogeneity may underlie clinical continuity. In some recent studies the inclusion of nonmelancholic depressions in the affective illness category may have masked overlap.
The author suggests that the Kraepelinian view of psychoses may need modification. Future research should focus on factors that may reveal overlap between schizophrenia and affective disorder: severity of schizophrenia and affective disorder in probands, severity of depression in relatives, the effect of the unipolar-bipolar disorder relationship on the co-occurrence of affective disorder and schizophrenia, and the relationship of nongenetic factors that might alter the clinical expression of a shared genotype. Also, investigators should not presume a dichotomy or continuum but should examine pure and mixed pedigrees and look for state- and trait-related endophenotypes, the convergence of which would provide the basis for focused molecular genetic study. View Show abstract The SPQ: A scale for the assessment of schizotypal personality based on DSM-III-R criteria Article Feb 1991 SCHIZOPHRENIA BULL Adrian Raine Existing self-report measures of schizotypal personality assess only one to three of the nine traits of schizotypal personality
disorder. This study describes the development of the Schizotypal Personality Questionnaire (SPQ), a self-report scale modeled
on DSM-III-R criteria for schizotypal personality disorder and containing subscales for all nine schizotypal traits. Two samples of normal
subjects (n = 302 and n = 195) were used to test replicability of findings. The SPQ was found to have high sampling validity, high internal reliability
(0.91), test-retest reliability (0.82), convergent validity (0.59 to 0.81), discriminant validity, and criterion validity
(0.63, 0.68), findings which were replicated across samples. Fifty-five percent of subjects scoring in the top 10 percent
of SPQ scores had a clinical diagnosis of schizotypal personality disorder. Thus, the SPQ may be useful in screening for schizotypal
personality disorder in the general population and also in researching the correlates of individual schizotypal traits. View Show abstract A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system Article Sep 1991 ARCH GEN PSYCHIAT Peter Mcguffin A. E. Farmer IH Harvey An operational criteria checklist for psychotic illness and computer programs designed to be used in conjunction with it constitute the OPCRIT system. This provides a simple and reliable method of applying multiple operational diagnostic criteria in studies of psychotic illness. The development of the OPCRIT system and an assessment of reliability are described. Diagnostic agreement between three raters is excellent. Item-by-item agreement, although less good, still achieves reasonable reliability despite the problem of low base rates for some items. View Show abstract Schizophrenia as a progressive disorder: Relations to EEG, CT. neuropathological and other evidence Article Feb 1989 PROG NEUROBIOL R Miller View EEG Mapping Applications in Psychiatric Disorders * Article Nov 1989 Herbert Kaye Peter C Williamson A number of techniques have been developed for EEG mapping in recent years. The clinical and research applications of these techniques in psychiatry are reviewed with regard to schizophrenia, affective disorder, learning disorders, dementia, psychopharmacology and ruling out neurological disorders. Limitations and advantages of EEG mapping as well as its relation to other imaging techniques are discussed. View Show abstract Computerized EEG in Schizophrenia Article Feb 1988 SCHIZOPHRENIA BULL Daniel R. Weinberger Craig N. Karson Richard Coppola David G. Daniel Despite advances in the processing and display of electroencephalographic (EEG) data, the utility of this inexpensive and noninvasive technique in the investigation of schizophrenia has not been well established. We studied the resting EEG in 19 medication-free patients with chronic schizophrenia and 21 normal controls. Patients with schizophrenia had increased delta activity which was not specific to the frontal regions. Schizophrenic patients also had increased fast activity, and this increase was left sided for the fast beta frequency. Alpha frequency was reduced (less than 10.2 Hz) in 7 of 16 schizophrenic patients. Moreover, those patients with an alpha frequency reduction had a significantly larger mean cerebral ventricular size. These results indicate that the EEG does detect neurophysiological changes in schizophrenia. Our understanding of these changes may be enhanced by other neuroimaging techniques such as computed tomography. View Show abstract Neurometrics: Computer-Assisted Differential Diagnosis of Brain Dysfunctions Article Feb 1988 E R John Leslie Prichep J Fridman Paul Easton Normative developmental equations provide reliable descriptors of brain electrical activity in people 6 to 90 years old. Healthy persons display only chance deviations beyond predicted ranges. Patients with neurological impairment, subtle cognitive dysfunctions, or psychiatric disorders (including dementia and primary depression) show a high incidence of abnormal values. The magnitude of the deviations increases with clinical severity. Different disorders are characterized by distinctive profiles of abnormal values of brain electrical features. Computerized differential classification of some of these disorders can be achieved with high accuracy. Such classification, providing objective corroboration of brain dysfunctions, may be a useful adjunct to psychiatric diagnosis, which relies primarily on subjective clinical impressions. These methods may provide independent criteria for diagnostic validity, evaluations of treatment efficacy, and more individualized therapy. View Show abstract Alpha frequency in schizophrenia: An association with enlarged cerebral ventricles Article Aug 1988 Craig N. Karson Richard Coppola David G. Daniel Low alpha frequency (less than 10.2 Hz) occurred more frequently in medication-free schizophrenic patients than in normal control subjects, as determined by quantitative EEG analysis. Furthermore, those patients with low alpha frequency had significantly larger lateral ventricles, as measured by CT scan, than did other schizophrenic patients (mean +/- SD ventricle-brain ratios = 9.8 +/- 1.9 versus 5.0 +/- 2.4; p less than 0.01). This finding suggests the existence of a relationship between cerebral structural pathology and the alpha rhythm that may be based on involvement of alpha-generating structures which border the cerebral ventricles. Future EEG studies of schizophrenia may resolve these questions in the context of other brain findings. View Show abstract Frontal spectral EEG findings in acutely Ill schizophrenics Article Sep 1987 BIOL PSYCHIAT Peter C Williamson Morty Mamelak View The Correction of EOG Artifacts by Frequency Dependent and Frequency Independent Methods Article Dec 1986 Theo Gasser Lothar Sroka Joachim Moecks Methods for correcting EEG which is contaminated by EOG artifacts, which are frequency dependent or frequency independent, were compared. EEG activity contaminated mainly by eye movements was treated separately from activity contaminated mainly by blinks. The statistical comparison was based on representative, real data incorporating differential effects over frequency. The influence of EOG activity on different derivations and bands, and the resulting need for correction of EOG artifacts were of interest too. Correction using a constant gain function proved to be consistently inferior to using a gain depending on frequency. For eye movements, differences were, however, not very large in practical terms, and this was true for all frequency bands. The correction of blinks by the time domain method (i.e., constant gain) may become misleading in the sub-delta band, which might have implications for very slow activity such as slow cortical potentials. Transfer functions not corrected for coherent EEG activity at the EOG electrodes overcompensated in the alpha and beta bands, in line with earlier results showing the need to incorporate coherent EEG activity into the determination of EOG-EEG transfer. It was found to be preferable to use sample average coefficients and gain functions, rather than individual ones, leading also to simpler computing. EOG correction is indispensable at frontal derivations, in particular for the delta and theta bands. It is advisable to correct at central and even at parietal derivations. View Show abstract Stability studies in schizophrenics and normals using computer analyzed EEG Article Jul 1974 BIOL PSYCHIAT M. Allen T M Itil B Saletu S Davis Utilizing digital computer period analysis, the stability of the computer EEG (CEEG) in chronic schizophrenics and normal volunteers was investigated over longer time periods. It was found that the CEEG patterns in both populations remained very stable from week to week, as well as from month to month. The average frequency of the primary wave fluctuated only up to 0.5 cycle/sec and the frequency deviation up to 1 cycle/sec, while the average frequency and frequency deviation of the first derivatives showed a maximal fluctuation of 2 cycles/sec. The average absolute amplitude and amplitude variability changes stayed within 1 and 3 μv, respectively. The frequency distribution was also very stable, with the greatest fluctuations occurring in the alpha frequency bands. Evaluation of 'individual' EEG variations over time demonstrated also a great stability of EEG measurements in the majority of schizophrenics and normals. Comparison of weekly and monthly alterations in the EEG of schizophrenics and normals, utilizing discriminant function and cluster analysis, revealed a higher consistency in the EEG patterns in normals than in schizophrenics. Finally, it was observed that there are significant differences between the CEEG patterns of chronic schizophrenics and age and sex matched normals and that these differences stay the same from week to week and from month to month. The differences were characterized by a statistically significant greater number of very slow waves and very fast activities, fewer alpha waves, greater average frequency and frequency deviation, and lower amplitude variability in schizophrenics than in normals. This study confirms previous findings of statistically significant differences in CEEGs of adult acute and chronic schizophrenics, psychotic children, and children of schizophrenic parents as compared with matched normal groups. View Show abstract EEG findings in chronic schizophrenics based on digital computer period analysis and analog power spectra Article Sep 1972 BIOL PSYCHIAT T M Itil B Saletu S Davis View Tucker, D. M. & Williamson, P. A. Asymmetric neural control systems in human self-regulation. Psychol. Rev. 91, 185-215 Article May 1984 Don M Tucker Peter A. Williamson Reviews the literature on the neurotransmitter substrates controlling motor readiness, showing that these substrates produce qualitative changes in the flow of information in the brain: Dopaminergic activation increases informational redundancy, whereas noradrenergic arousal facilitates orienting to novelty. Evidence that these neurotransmitter pathways are lateralized in the human brain is consistent with the left hemisphere's specialization for complex motor operations and the right hemisphere's integration of bilateral perceptual input. Principles of attentional control are suggested by the operational characteristics of neural control systems. The affective features of the activation and arousal systems are integral to their adaptive roles and may suggest how specific emotional processes dynamically regulate cognitive function. (4½ p ref) View Show abstract A new method for off-line removal of ocular artifact Article May 1983 Electroencephalogr Clin Neurophysiol Gabriele Gratton Michael G H Coles Emanuel Donchin A new off-line procedure for dealing with ocular artifacts in ERP recording is described. The procedure (EMCP) uses EOG and EEG records for individual trials in an experimental session to estimate a propagation factor which describes the relationship between the EOG and EEG traces. The propagation factor is computed after stimulus-linked variability in both traces has been removed. Different propagation factors are computed for blinks and eye movements. Tests are presented which demonstrate the validity and reliability of the procedure. ERPs derived from trials corrected by EMCP are more similar to a 'true' ERP than are ERPs derived from either uncorrected or randomly corrected trials. The procedure also reduces the difference between ERPs which are based on trials with different degrees of EOG variance. Furthermore, variability at each time point, across trials, is reduced following correction. The propagation factor decreases from frontal to parietal electrodes, and is larger for saccades than blinks. It is more consistent within experimental sessions than between sessions. The major advantage of the procedure is that it permits retention of all trials in an ERP experiment, irrespective of ocular artifact. Thus, studies of populations characterized by a high degree of artifact, and those requiring eye movements as part of the experimental task, are made possible. Furthermore, there is no need to require subjects to restrict eye movement activity. In comparison to procedures suggested by others, EMCP also has the advantage that separate correction factors are computed for blinks and movements and that these factors are based on data from the experimental session itself rather than from a separate calibration session. View Show abstract The National Institute of Mental Health Diagnostic Interview Schedule (Version III) Article May 1981 ARCH GEN PSYCHIAT Lee N. Robins John E Helzer Jack L. Croughan Kathryn Ratcliff A new interview schedule allows lay interviewers or clinicians to make psychiatric diagnoses according to DSM-III criteria, Feighner criteria, and Research Diagnostic Criteria. It is being used in a set of epidemiological studies sponsored by the National Institute of Mental Health Center for Epidemiological Studies. Its accuracy has been evaluated in a test-retest design comparing independent administrations by psychiatrists and lay interviewers to 216 subjects (inpatients, outpatients, ex-patients, and nonpatients). View Show abstract Statistical quantitative EEG studies of depression, mania, schizophrenia and normals Article Jan 1985 BIOL PSYCHOL Pierre Flor-Henry Z.J. Koles The EEG characteristics of 63 depressive psychotics, 75 manics and 53 schizophrenic patients, consecutive admissions satisfying research criteria, are presented. Statistical comparisons between the psychotic groups and of each psychotic group against 60 normal controls (all dextral) were undertaken for power, coherence and phase characteristics in the 8-13 Hz frequency band. The characteristic EEG-myogenic power spectra for frequencies up to 60 Hz, expressed as the log of the right/left parietal and temporal power ratios for the four groups are also graphically displayed. The results suggest the presence of increasing disorganization of the right hemisphere (least in depression, intermediate in mania and maximal in schizophrenia) together with left hemisphere disorganization (in both mania and schizophrenia; again maximal in schizophrenia). View Show abstract Bilateral Electrodermal Habituation-Dishabituation and Resting EEG in Remitted Schizophrenics Article Mar 1982 J NERV MENT DIS William Iacono This study examined bilateral electrodermal responding, heart rate, and resting EEG in schizophrenics who were not psychotic at the time of testing. Twenty-four carefully diagnosed, remitted schizophrenics were compared to 22 medical outpatient controls. Subjects were exposed to 17 pure tones; the 16th tone differed in frequency and duration from the others. Prior to the tone series, subjects engaged in 2 minutes of respiratory maneuvers followed by a 5-minute rest period during which EEG was recorded. Consistent with past reports examining chronic, hospitalized patients, the schizophrenics divided evenly into responding and nonresponding groups and skin conductance responding was associated with a higher rate of spontaneous activity, elevated tonic conductance levels, and more responding during the respiratory exercises. When those responding in the control and schizophrenic groups were compared for number and amplitude of tone-elicited responses, no group differences emerged. There were no differences in dishabituation between these two groups. A variety of analyses failed to reveal any evidence of electrodermal or cerebral asymmetry. There were no differences between the two schizophrenic groups in measures of heart rate or resting EEG. However, consistent with other reports using hospitalized patients, the schizophrenics as a group produced less EEG alpha and more delta than the normal subjects. These results are consistent with the hypothesis that the electrodermal and EEG phenomena identified in psychotic, hospitalized patients represent stable traits characteristic of schizophrenia. View Show abstract Show more
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Phlebotonics用于静脉功能不全 - Martinez-Zapata, MJ - 2020 | Cochrane Library
4-Aminobenzoic Acid [therapeutic use]; Angioedemas, Hereditary [drug therapy]; Calcium Dobesilate [therapeutic use]; Centella; Chronic Disease; Diosmin [analogs & derivatives, therapeutic use]; Edema [drug therapy]; Hematologic Agents [*therapeutic use]; Leg; Leg Ulcer [drug therapy]; para-Aminobenzoates [therapeutic use]; Phytotherapy [methods]; Pinus; Plant Extracts [*therapeutic use]; Quality of Life; Randomized Controlled Trials as Topic; Rutin [therapeutic use]; Venous Insufficiency [*drug therapy]
Cochrane Clinical Answers
What are the effects of phlebotonics on signs and symptoms of venous insufficiency?
Topics
Topics
Complementary & alternative medicine
Heart & circulation
Peripheral vascular disease
Heart & circulation
Chronic venous insufficiency
Figures and Tables -
Figure 1
Funnel plot of comparison: 1 Phlebotonics vs placebo, outcome: 1.1 Oedema in the lower legs (dichotomous variable).
Figures and Tables -
Figure 2
Study flow diagram.
Figures and Tables -
Figure 3
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
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Figure 4
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Analysis 1.1
Comparison 1: Phlebotonics versus placebo, Outcome 1: Oedema in the lower legs (dichotomous variable)
Analysis 1.2
Comparison 1: Phlebotonics versus placebo, Outcome 2: Ankle perimeter circumference (mm)
Analysis 1.3
Comparison 1: Phlebotonics versus placebo, Outcome 3: Volume of the leg (mL)
Figures and Tables -
Analysis 1.4
Comparison 1: Phlebotonics versus placebo, Outcome 4: Quality of life
Figures and Tables -
Analysis 1.5
Comparison 1: Phlebotonics versus placebo, Outcome 5: Ulcer healing
Analysis 1.6
Comparison 1: Phlebotonics versus placebo, Outcome 6: Trophic disorders (dichotomous variable)
Analysis 1.7
Comparison 1: Phlebotonics versus placebo, Outcome 7: Pain in the lower legs (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 8: Pain in the lower legs (continuous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 9: Cramps in the lower legs (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 10: Cramps in the lower legs (continuous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 11: Restless legs (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 12: Itching in the lower legs (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 13: Itching in the lower legs (continuous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 14: Heaviness in the lower legs (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 15: Heaviness in the lower legs (continuous variable)
Analysis 1.16
Comparison 1: Phlebotonics versus placebo, Outcome 16: Swelling in the lower legs (dichotomous variable)
Analysis 1.17
Comparison 1: Phlebotonics versus placebo, Outcome 17: Swelling in the lower legs (continuous variable)
Analysis 1.18
Comparison 1: Phlebotonics versus placebo, Outcome 18: Paraesthesia in the lower legs (dichotomous variable)
Analysis 1.19
Comparison 1: Phlebotonics versus placebo, Outcome 19: Paraesthesia in the lower legs (continuous variable)
Analysis 1.20
Comparison 1: Phlebotonics versus placebo, Outcome 20: Participant satisfaction (dichotomous variable)
Comparison 1: Phlebotonics versus placebo, Outcome 21: Participant satisfaction (continuous variable)
Analysis 1.22
Comparison 1: Phlebotonics versus placebo, Outcome 22: Adverse events
Analysis 2.1
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 1: Oedema in the lower legs (dichotomous variable)
Analysis 2.2
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 2: Ankle perimeter circumference (mm)
Analysis 2.3
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 3: Volume of the leg (mL)
Analysis 2.4
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 4: Quality of life
Analysis 2.5
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 5: Ulcer healing
Figures and Tables -
Analysis 2.6
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 6: Trophic disorders (dichotomous variable)
Figures and Tables -
Analysis 2.7
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 7: Pain in the lower legs (dichotomous variable)
Figures and Tables -
Analysis 2.8
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 8: Pain in the lower legs (continuous variable)
Figures and Tables -
Analysis 2.9
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 9: Cramps in the lower legs (dichotomous variable)
Analysis 2.10
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 10: Cramps in the lower legs (continuous variable)
Analysis 2.11
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 11: Restless legs (dichotomous variable)
Analysis 2.12
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 12: Itching in the lower legs (dichotomous variable)
Analysis 2.13
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 13: Itching in the lower legs (continuous variable)
Analysis 2.14
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 14: Heaviness in the lower legs (dichotomous variable)
Analysis 2.15
Comparison 2: Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 15: Heaviness in the lower legs (continuous variable)
Analysis 2.16
Figures and Tables -
Analysis 4.1
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 1: Oedema in the lower legs (dichotomous variable)
Analysis 4.2
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 2: Ankle perimeter circumference (mm)
Analysis 4.3
Analysis 4.4
Analysis 4.5
Analysis 4.6
Figures and Tables -
Analysis 4.7
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 7: Itching in the lower legs (dichotomous variable)
Figures and Tables -
Analysis 4.8
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 8: Itching in the lower legs (continuous variable)
Figures and Tables -
Analysis 4.9
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 9: Heaviness in the lower legs (dichotomous variable)
Analysis 4.10
Analysis 4.11
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 11: Swelling in the lower legs (dichotomous variable)
Figures and Tables -
Analysis 4.12
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 12: Swelling in the lower legs (continuous variable)
Navigate to figure in Review Print figure Open in new tab
Analysis 4.13
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 13: Participant satisfaction (dichotomous variable)
Figures and Tables -
Analysis 4.14
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 14: Participant satisfaction (continuous variable)
Analysis 4.15
Comparison 4: Sensitivity analysis based on low risk of bias, Outcome 15: Adverse events
Summary of findings 1. Do phlebotonics improve signs and symptoms of venous insufficiency when compared with placebo?
Phlebotonics compared with placebo for venous insufficiency Patient or population:patients with venous insufficiency Settings:hospital and ambulatory settings Intervention:phlebotonics Comparison:placebo Outcomes Anticipated absolute effects * Relative effect (95% CI) Number of participants (RCTs) Certainty of the evidence (GRADE) Comments Risk with placebo Risk with phlebotonics Oedema in the lower legs (dichotomous variable)Follow‐up: 1‐6 months 575 per 1000 403 per 1000(362 to 449) RR 0.70(0.63 to 0.78)1245(13 studies)⊕⊕⊕⊝ Moderate aPhebotonics probably slightly reduce oedema in the lower limb compared to placebo Oedema in the lower legs (ankle circumference, mm)Follow‐up: 1‐12 months‐Mean ankle circumference in the lower legs in the phlebotonic groups was 4.27 mm lower(5.61 to 2.93 lower) than in the placebo groups‐2010(15 studies)⊕⊕⊕⊝ Moderate bPhlebotonics probably slightly reduce ankle perimeter circumference compared to placebo Quality of life (CIVIQ and other questionnaires)Follow‐up: mean 2‐12 months‐The QoL in the phlebotonic groups was 0.06 SMD lower(0.22 lower to 0.1 higher) than in the placebo groups‐1639(5 studies)⊕⊕⊕⊝ Moderate cPhebotonics probably make little or no difference to QoL compared with placebo Ulcer healing (dichotomous variable)Follow‐up: 1‐12 months 381 per 1000 358 per 1000(301 to 430) RR 0.94(0.79 to 1.13)461(6 studies)⊕⊕⊝⊝ Low dPhlebotonics may make little or no difference to ulcer healing compared to placebo Adverse eventsFollow‐up: 1‐12 months 158 per 1000 180 per 1000(161 to 200) RR 1.14(1.02 to 1.27)5789(37 studies)⊕⊕⊕⊝ Moderate ePhlebotonics probably slightly increase adverse events compared to placebo* The risk in the intervention group(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effectof the intervention (and its 95% CI). CI:confidence interval; CIVIQ: Chronic Venous Insufficiency International Questionnaire; QoL: quality of life; RCT: randomised controlled trial; RR:risk ratio GRADE Working Group grades of evidence High certainty:we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty:we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty:our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty:we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aThe certainty of the evidence was downgraded (1 level) to moderate because of overall risk of bias (10 studies had an unclear risk of bias and two had a high risk of bias) bThe certainty of the evidence was downgraded (1 level) to moderate because of overall risk of bias (11 studies had an unclear risk of bias and one had a high risk of bias) cThe certainty of the evidence was downgraded (1 level) to moderate because of overall risk of bias (one study had an unclear risk of bias and two had a high risk of bias) dThe certainty of the evidence was downgraded (2 levels) to low because of overall risk of bias (four studies had an unclear risk of bias and two had a high risk of bias) and imprecision (low number of events) eThe certainty of the evidence was downgraded (1 level) to moderate because of overall risk of bias (28 RCTs had unclear risk of bias and four RCTs had high risk of bias)
Figures and Tables -
Summary of findings 1. Do phlebotonics improve signs and symptoms of venous insufficiency when compared with placebo?
Table 1. Results of all outcomes analysed (all phlebotonics)
Variables Dichotomous ContinuousOedemaRR 0.70 (0.63 to 0.78)‐Oedema (mm)‐MD ‐4.27 (‐5.61 to ‐2.93)Oedema (volume)‐SMD ‐0.24 (‐0.33 to ‐0.15)Ulcer curedNS‐Trophic disordersRR 0.87 (0.81 to 0.95)‐Pain‐SMD ‐0.35 (‐0.54, ‐0.17)CrampsRR 0.72 (0.58 to 0.89)‐Restless legsRR 0.81 (0.72 to 0.91)‐Itching‐‐Heaviness‐‐SwellingRR 0.63 (0.50 to 0.80)‐ParaesthesiaRR 0.67 (0.50 to 0.88)NSQuality of life‐NSGlobal assessment by the participant‐‐Adverse eventsRR 1.14 (1.02 to 1.27)‐Note: No measures of effect are specified when I 2was > 75% for the subgroupRR: risk ratioMD: mean differenceNS: non‐significantRR: risk ratioSMD: standardized mean difference
Figures and Tables -
Table 1. Results of all outcomes analysed (all phlebotonics)
Table 2. Results by pharmacological group: aminaftone
Variables Dichotomous ContinousOedemaRR 0.53 (0.28 to 0.99)SMD ‐0.17 (‐0.61 to 0.28)Ulcer curedNS‐Trophic disorderNS‐PainRR 0.43 (0.23 to 0.79)‐CrampsRR 0.56 (0.31 to 0.99)‐ItchingRR 0.53 (0.31 to 0.91)‐HeavinessRR 0.32 (0.17 to 0.60)‐Quality of live‐MD ‐10.00 (‐17.01 to ‐2.99)Adverse eventsNS‐Note: Only 1 study was analyzedMD: mean differenceNS: non‐significantRR: risk ratioSMD: standardized mean difference
Table 2. Results by pharmacological group: aminaftone
Table 3. Results by pharmacological group: calcium dobesilate
Variables Dichotomous ContinuousOedema‐‐Oedema (mm)‐NSOedema (volume)‐SMD ‐0.38 (‐0.51 to ‐0.24)Ulcer curedNS‐PainRR 0.53 (0.35 to 0.82)NSCrampsRR 0.65 (0.50 to 0.84)‐Restless legsRR 0.73 (0.59 to 0.91)NSItching‐NSHeavinessNSNSSwellingRR 0.19 (0.08 to 0.41)NSParaesthesiaNS‐Quality of life‐NSGlobal assessment by the participant‐SMD ‐0.52 (‐0.71 to ‐0.33)Adverse eventsRR 1.22 (1.0 to 1.49)‐Note: No measures of effect are specified when I 2was > 75% for the subgroupNS: non‐significantRR: risk ratioSMD: standardized mean difference
Table 3. Results by pharmacological group: calcium dobesilate
Table 4. Results by pharmacological group: Centella asiatica
Variables Dichotomous ContinuousHeavinessNS‐Global assessment by the participantRR 0.28 (0.14 to 0.57)‐Adverse eventsNS‐Note: Only 1 study was analyzedNS: non‐significantRR: risk ratio
Table 4. Results by pharmacological group: Centella asiatica
Table 5. Results by pharmacological group: diosmine, hidrosmine
Variables Dichotomous ContinuousOedemaRR 0.63 (0.46 to 0.86)‐Oedema (mm)‐MD ‐5.98 (‐7.78 to ‐4.18)Ulcer curedNS‐Trophic disorderRR 0.87 (0.81 to 0.94)‐PainNSSMD ‐0.23 (‐0.41 to ‐0.05)CrampsRR 0.83 (0.70 to 0.98)SMD ‐0.46 (‐0.78 to ‐0.14)Restless legsNS‐ItchingNS‐HeavinessNSSMD ‐0.69 (‐1.02 to ‐0.36)SwellingRR 0.70 (0.52 to 0.94)SMD ‐0.92 (‐1.26 to ‐0.58)ParaesthesiaNSNSQuality of life‐NSGlobal assessment by the participant‐SMD ‐0.81 (‐1.14 to ‐0.47)Adverse eventsNS‐Note: No measures of effect are specified when I 2was > 75% for the subgroupMD: mean differenceNS: non‐significantRR: risk ratioSMD: standardized mean difference
Table 5. Results by pharmacological group: diosmine, hidrosmine
Table 6. Results by pharmacological group: French maritime pine bark extract
Variables Dichotomous ContinuousPainRR 0.66 (0.48 to 0.91)SMD ‐1.39 (‐2.09 to ‐0.69)HeavinessNSSMD ‐1.50 (‐2.21 to ‐0.79)SwellingNSSMD ‐1.65 (‐2.38 to ‐0.92)Note: Only 1 study was analyzedNS: non‐significantRR: risk ratioSMD: standardized mean difference
Table 7. Results by pharmacological group: grape seed extract
Variables Dichotomous ContinuousOedemaNS‐Adverse eventsNSNSNote: Only 1 study was analyzedNS: non‐significant
Table 7. Results by pharmacological group: grape seed extract
Table 8. Results by pharmacological group: rutosides
Variables Dichotomous ContinuousOedemaRR 0.72 (0.64 to 0.81)‐Oedema (mm)‐NSOedema (volume)‐SMD ‐0.15 (‐0.16 to ‐0.03)Ulcer curedNS‐Trophic disorderNS‐Pain‐SMD ‐0.71 (‐1.23 to ‐0.19)CrampsRR ‐0.83 (‐1.50 to ‐0.16)NSRestless legsNS‐Itching‐SMD ‐0.58 (‐1.10 to ‐0.06)HeavinessRR 0.60 (0.48 to 0.74)‐SwellingRR 0.67 (0.50 to 0.88)NSParaesthesiasRR 0.55 (0.37 to 0.83)NSGlobal assessment by the participant‐‐Adverse eventsRR 1.22 (1.04 to 1.43)‐Note: No measures of effect are specified when I 2was > 75%NS: non‐significantRR: risk ratioSMD: standardized mean difference
Table 8. Results by pharmacological group: rutosides
Comparison 1. Phlebotonics versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size1.1 Oedema in the lower legs (dichotomous variable) Show forest plot131245Risk Ratio (M‐H, Fixed, 95% CI)0.70 [0.63, 0.78]1.1.1 Aminaftone182Risk Ratio (M‐H, Fixed, 95% CI)0.53 [0.28, 0.99]1.1.2 Calcium dobesilate2290Risk Ratio (M‐H, Fixed, 95% CI)0.72 [0.48, 1.07]1.1.3 Diosmine, Hidrosmine2144Risk Ratio (M‐H, Fixed, 95% CI)0.63 [0.46, 0.86]1.1.4 Grape seed extract175Risk Ratio (M‐H, Fixed, 95% CI)0.79 [0.58, 1.06]1.1.5 Rutosides7654Risk Ratio (M‐H, Fixed, 95% CI)0.72 [0.64, 0.81]1.2 Ankle perimeter circumference (mm) Show forest plot152010Mean Difference (IV, Fixed, 95% CI)‐4.27 [‐5.61, ‐2.93]1.2.1 Calcium dobesilate51122Mean Difference (IV, Fixed, 95% CI)‐1.69 [‐4.84, 1.47]1.2.2 Diosmine, Hidrosmine3286Mean Difference (IV, Fixed, 95% CI)‐5.98 [‐7.78, ‐4.18]1.2.3 Rutosides7602Mean Difference (IV, Fixed, 95% CI)‐2.45 [‐5.06, 0.15]1.3 Volume of the leg (mL) Show forest plot112072Std. Mean Difference (IV, Fixed, 95% CI)‐0.24 [‐0.33, ‐0.15]1.3.1 Aminaftone179Std. Mean Difference (IV, Fixed, 95% CI)‐0.17 [‐0.61, 0.28]1.3.2 Calcium dobesilate4826Std. Mean Difference (IV, Fixed, 95% CI)‐0.38 [‐0.51, ‐0.24]1.3.3 Rutosides61167Std. Mean Difference (IV, Fixed, 95% CI)‐0.15 [‐0.26, ‐0.03]1.4 Quality of life Show forest plot51639Std. Mean Difference (IV, Random, 95% CI)‐0.06 [‐0.22, 0.10]1.4.1 Aminaftone179Std. Mean Difference (IV, Random, 95% CI)‐0.64 [‐1.10, ‐0.19]1.4.2 Calcium dobesilate at 3 months of treatment3968Std. Mean Difference (IV, Random, 95% CI)‐0.03 [‐0.16, 0.10]1.4.3 Diosmine, Hidrosmine1592Std. Mean Difference (IV, Random, 95% CI)0.04 [‐0.12, 0.20]1.5 Ulcer healing Show forest plot6461Risk Ratio (M‐H, Random, 95% CI)0.94 [0.79, 1.13]1.5.1 Aminaftone1100Risk Ratio (M‐H, Random, 95% CI)0.75 [0.18, 3.18]1.5.2 Calcium dobesilate169Risk Ratio (M‐H, Random, 95% CI)1.09 [0.69, 1.74]1.5.3 Diosmine, Hidrosmine2133Risk Ratio (M‐H, Random, 95% CI)0.84 [0.69, 1.01]1.5.4 Rutosides2159Risk Ratio (M‐H, Random, 95% CI)1.28 [0.87, 1.86]1.6 Trophic disorders (dichotomous variable) Show forest plot6705Risk Ratio (M‐H, Fixed, 95% CI)0.87 [0.81, 0.95]1.6.1 Aminaftone197Risk Ratio (M‐H, Fixed, 95% CI)0.77 [0.41, 1.44]1.6.2 Diosmine, Hidrosmine4504Risk Ratio (M‐H, Fixed, 95% CI)0.87 [0.81, 0.94]1.6.3 Rutosides1104Risk Ratio (M‐H, Fixed, 95% CI)0.94 [0.71, 1.25]1.7 Pain in the lower legs (dichotomous variable) Show forest plot21Risk Ratio (M‐H, Random, 95% CI)Subtotals only1.7.1 Aminaftone197Risk Ratio (M‐H, Random, 95% CI)0.43 [0.23, 0.79]1.7.2 Calcium dobesilate5705Risk Ratio (M‐H, Random, 95% CI)0.53 [0.35, 0.82]1.7.3 Diosmine, Hidrosmine4271Risk Ratio (M‐H, Random, 95% CI)0.82 [0.63, 1.08]1.7.4 French maritime pine bark extract140Risk Ratio (M‐H, Random, 95% CI)0.66 [0.48, 0.91]1.7.5 Rutosides101485Risk Ratio (M‐H, Random, 95% CI)0.63 [0.48, 0.83]1.8 Pain in the lower legs (continuous variable) Show forest plot122232Std. Mean Difference (IV, Random, 95% CI)‐0.35 [‐0.54, ‐0.17]1.8.1 Calcium dobesilate51127Std. Mean Difference (IV, Random, 95% CI)‐0.14 [‐0.31, 0.03]1.8.2 Diosmine, Hidrosmine3846Std. Mean Difference (IV, Random, 95% CI)‐0.23 [‐0.41, ‐0.05]1.8.3 French maritime pine bark extract140Std. Mean Difference (IV, Random, 95% CI)‐1.39 [‐2.09, ‐0.69]1.8.4 Rutosides3219Std. Mean Difference (IV, Random, 95% CI)‐0.71 [‐1.23, ‐0.19]1.9 Cramps in the lower legs (dichotomous variable) Show forest plot141793Risk Ratio (M‐H, Random, 95% CI)0.72 [0.58, 0.89]1.9.1 Aminaftone197Risk Ratio (M‐H, Random, 95% CI)0.56 [0.31, 0.99]1.9.2 Calcium dobesilate2255Risk Ratio (M‐H, Random, 95% CI)0.65 [0.50, 0.84]1.9.3 Diosmine, Hidrosmine3214Risk Ratio (M‐H, Random, 95% CI)0.83 [0.70, 0.98]1.9.4 Rutosides81227Risk Ratio (M‐H, Random, 95% CI)0.70 [0.47, 1.02]1.10 Cramps in the lower legs (continuous variable) Show forest plot4Std. Mean Difference (IV, Random, 95% CI)Subtotals only1.10.1 Calcium dobesilate1415Std. Mean Difference (IV, Random, 95% CI)‐0.10 [‐0.29, 0.09]1.10.2 Diosmine, Hidrosmine1150Std. Mean Difference (IV, Random, 95% CI)‐0.46 [‐0.78, ‐0.14]1.10.3 Rutosides2164Std. Mean Difference (IV, Random, 95% CI)‐0.83 [‐1.50, ‐0.16]1.11 Restless legs (dichotomous variable) Show forest plot7652Risk Ratio (M‐H, Fixed, 95% CI)0.81 [0.72, 0.91]1.11.1 Calcium dobesilate2255Risk Ratio (M‐H, Fixed, 95% CI)0.73 [0.59, 0.91]1.11.2 Diosmine, Hidrosmine170Risk Ratio (M‐H, Fixed, 95% CI)0.90 [0.70, 1.15]1.11.3 Rutosides4327Risk Ratio (M‐H, Fixed, 95% CI)0.85 [0.72, 1.01]1.12 Itching in the lower legs (dichotomous variable) Show forest plot4Risk Ratio (M‐H, Random, 95% CI)Subtotals only1.12.1 Aminaftone197Risk Ratio (M‐H, Random, 95% CI)0.53 [0.31, 0.91]1.12.2 Diosmine, Hidrosmine134Risk Ratio (M‐H, Random, 95% CI)1.63 [0.51, 5.25]1.12.3 Rutosides2274Risk Ratio (M‐H, Random, 95% CI)0.68 [0.21, 2.21]1.13 Itching in the lower legs (continuous variable) Show forest plot2Std. Mean Difference (IV, Random, 95% CI)Subtotals only1.13.1 Calcium dobesilate1416Std. Mean Difference (IV, Random, 95% CI)0.09 [‐0.11, 0.28]1.13.2 Rutosides160Std. Mean Difference (IV, Random, 95% CI)‐0.58 [‐1.10, ‐0.06]1.14 Heaviness in the lower legs (dichotomous variable) Show forest plot19Risk Ratio (M‐H, Random, 95% CI)Subtotals only1.14.1 Aminaftone197Risk Ratio (M‐H, Random, 95% CI)0.32 [0.17, 0.60]1.14.2 Calcium dobesilate3305Risk Ratio (M‐H, Random, 95% CI)0.33 [0.08, 1.42]1.14.3 Centella asiatica163Risk Ratio (M‐H, Random, 95% CI)0.62 [0.32, 1.19]1.14.4 Diosmine, Hidrosmine4241Risk Ratio (M‐H, Random, 95% CI)0.60 [0.35, 1.05]1.14.5 French maritime pine bark extract140Risk Ratio (M‐H, Random, 95% CI)0.90 [0.76, 1.07]1.14.6 Rutosides91420Risk Ratio (M‐H, Random, 95% CI)0.60 [0.48, 0.74]1.15 Heaviness in the lower legs (continuous variable) Show forest plot10Std. Mean Difference (IV, Random, 95% CI)Subtotals only1.15.1 Calcium dobesilate2483Std. Mean Difference (IV, Random, 95% CI)‐0.05 [‐0.23, 0.13]1.15.2 Diosmine, Hidrosmine1150Std. Mean Difference (IV, Random, 95% CI)‐0.69 [‐1.02, ‐0.36]1.15.3 French maritime pine bark extract140Std. Mean Difference (IV, Random, 95% CI)‐1.50 [‐2.21, ‐0.79]1.15.4 Rutosides6441Std. Mean Difference (IV, Random, 95% CI)‐1.11 [‐1.87, ‐0.36]1.16 Swelling in the lower legs (dichotomous variable) Show forest plot141072Risk Ratio (M‐H, Random, 95% CI)0.63 [0.50, 0.80]1.16.1 Calcium dobesilate280Risk Ratio (M‐H, Random, 95% CI)0.19 [0.08, 0.41]1.16.2 Diosmine, Hidrosmine2104Risk Ratio (M‐H, Random, 95% CI)0.70 [0.52, 0.94]1.16.3 French maritime pine bark extract140Risk Ratio (M‐H, Random, 95% CI)0.80 [0.64, 1.02]1.16.4 Rutosides9848Risk Ratio (M‐H, Random, 95% CI)0.67 [0.50, 0.88]1.17 Swelling in the lower legs (continuous variable) Show forest plot6Std. Mean Difference (IV, Random, 95% CI)Subtotals only1.17.1 Calcium dobesilate1417Std. Mean Difference (IV, Random, 95% CI)‐0.05 [‐0.24, 0.15]1.17.2 Diosmine, Hidrosmine1150Std. Mean Difference (IV, Random, 95% CI)‐0.92 [‐1.26, ‐0.58]1.17.3 French maritime pine bark extract140Std. Mean Difference (IV, Random, 95% CI)‐1.65 [‐2.38, ‐0.92]1.17.4 Rutosides3264Std. Mean Difference (IV, Random, 95% CI)‐1.73 [‐3.50, 0.04]1.18 Paraesthesia in the lower legs (dichotomous variable) Show forest plot91456Risk Ratio (M‐H, Random, 95% CI)0.67 [0.50, 0.88]1.18.1 Calcium dobesilate3305Risk Ratio (M‐H, Random, 95% CI)0.74 [0.51, 1.08]1.18.2 Diosmine, Hidrosmine2144Risk Ratio (M‐H, Random, 95% CI)0.80 [0.62, 1.05]1.18.3 Rutosides41007Risk Ratio (M‐H, Random, 95% CI)0.55 [0.37, 0.83]1.19 Paraesthesia in the lower legs (continuous variable) Show forest plot2188Std. Mean Difference (IV, Fixed, 95% CI)‐0.15 [‐0.44, 0.13]1.19.1 Diosmine, Hidrosmine1150Std. Mean Difference (IV, Fixed, 95% CI)‐0.12 [‐0.44, 0.21]1.19.2 Rutosides138Std. Mean Difference (IV, Fixed, 95% CI)‐0.31 [‐0.96, 0.33]1.20 Participant satisfaction (dichotomous variable) Show forest plot16Risk Ratio (M‐H, Random, 95% CI)Subtotals only1.20.1 Calcium dobesilate3506Risk Ratio (M‐H, Random, 95% CI)0.72 [0.36, 1.46]1.20.2 Diosmine, Hidrosmine4451Risk Ratio (M‐H, Random, 95% CI)0.66 [0.43, 1.02]1.20.3 Centella asiatica180Risk Ratio (M‐H, Random, 95% CI)0.28 [0.14, 0.57]1.20.4 Rutosides81167Risk Ratio (M‐H, Random, 95% CI)0.50 [0.30, 0.84]1.21 Participant satisfaction (continuous variable) Show forest plot7Std. Mean Difference (IV, Random, 95% CI)Subtotals only1.21.1 Calcium dobesilate2448Std. Mean Difference (IV, Random, 95% CI)‐0.52 [‐0.71, ‐0.33]1.21.2 Diosmine, Hidrosmine1150Std. Mean Difference (IV, Random, 95% CI)‐0.81 [‐1.14, ‐0.47]1.21.3 Rutosides4283Std. Mean Difference (IV, Random, 95% CI)‐1.18 [‐1.96, ‐0.39]1.22 Adverse events Show forest plot375789Risk Ratio (M‐H, Fixed, 95% CI)1.14 [1.02, 1.27]1.22.1 Aminaftone179Risk Ratio (M‐H, Fixed, 95% CI)0.60 [0.06, 6.32]1.22.2 Calcium dobesilate81824Risk Ratio (M‐H, Fixed, 95% CI)1.22 [1.00, 1.49]1.22.3 Centella asiatica194Risk Ratio (M‐H, Fixed, 95% CI)1.14 [0.58, 2.23]1.22.4 Diosmine, Hidrosmine91429Risk Ratio (M‐H, Fixed, 95% CI)0.93 [0.72, 1.19]1.22.5 Grape seed extract175Risk Ratio (M‐H, Fixed, 95% CI)0.57 [0.19, 1.74]1.22.6 Rutosides172288Risk Ratio (M‐H, Fixed, 95% CI)1.22 [1.04, 1.43]
Comparison 1. Phlebotonics versus placebo
Comparison 2. Sensitivity analysis excluding studies that allowed the use of elastic stockings
Comparison 2. Sensitivity analysis excluding studies that allowed the use of elastic stockings
Comparison 3. Sensitivity analysis of published studies only
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Molecules | Free Full-Text | De Novo Biosynthesis of p-Coumaric Acid in E. coli with a trans-Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea
p-Coumaric acid is a commercially available phenolcarboxylic acid with a great number of important applications in the nutraceutical, pharmaceutical, material and chemical industries. p-Coumaric acid has been biosynthesized in some engineered microbes, but the potential of the plant CYP450-involved biosynthetic route has not investigated in Escherichia coli. In the present study, a novel trans-cinnamic acid 4-hydroxylase (C4H) encoding the LauC4H gene was isolated from Lycoris aurea (L’ Hér.) Herb via rapid amplification of cDNA ends. Then, N-terminal 28 amino acids of LauC4H were characterized, for the subcellular localization, at the endoplasmic reticulum membrane in protoplasts of Arabidopsis thaliana. In E. coli, LauC4H without the N-terminal membrane anchor region was functionally expressed when fused with the redox partner of A. thaliana cytochrome P450 enzyme (CYP450), and was verified to catalyze the trans-cinnamic acid to p-coumaric acid transformation by whole-cell bioconversion, HPLC detection and LC-MS analysis as well. Further, with phenylalanine ammonia-lyase 1 of A. thaliana, p-coumaric acid was de novo biosynthesized from glucose as the sole carbon source via the phenylalanine route in the recombinant E. coli cells. By regulating the level of intracellular NADPH, the production of p-coumaric acid was dramatically improved by 9.18-fold, and achieved with a titer of 156.09 μM in shake flasks. The recombinant cells harboring functional LauC4H afforded a promising chassis for biological production of p-coumaric acid, even other derivatives, via a plant CYP450-involved pathway.
De Novo Biosynthesis of p -Coumaric Acid in E. coli with a trans -Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea
by Yikui Li 1,2,† , Jie Li 1,† , Binbin Qian 1 , Li Cheng 1 , Sheng Xu 1,2 and Ren Wang 1,2,*
2
The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing 210014, China
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2018 , 23 (12), 3185; https://doi.org/10.3390/molecules23123185
Received: 30 September 2018 / Revised: 18 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
(This article belongs to the Special Issue Natural Product Enzymes in Biosynthesis and Biocatalysis )
Abstract
:
p
-Coumaric acid is a commercially available phenolcarboxylic acid with a great number of important applications in the nutraceutical, pharmaceutical, material and chemical industries.
p
-Coumaric acid has been biosynthesized in some engineered microbes, but the potential of the plant CYP450-involved biosynthetic route has not investigated in
Escherichia coli
. In the present study, a novel
trans
Lau
C4H gene was isolated from
Lycoris aurea
(L’ Hér.) Herb via rapid amplification of cDNA ends. Then,
N
-terminal 28 amino acids of
Lau
C4H were characterized, for the subcellular localization, at the endoplasmic reticulum membrane in protoplasts of
Arabidopsis thaliana
. In
E. coli
,
Lau
C4H without the
N
-terminal membrane anchor region was functionally expressed when fused with the redox partner of
A. thaliana
cytochrome P450 enzyme (CYP450), and was verified to catalyze the
trans
-cinnamic acid to
p
-coumaric acid transformation by whole-cell bioconversion, HPLC detection and LC-MS analysis as well. Further, with phenylalanine ammonia-lyase 1 of
A. thaliana
,
p
-coumaric acid was de novo biosynthesized from glucose as the sole carbon source via the phenylalanine route in the recombinant
E. coli
cells. By regulating the level of intracellular NADPH, the production of
p
-coumaric acid was dramatically improved by 9.18-fold, and achieved with a titer of 156.09 μM in shake flasks. The recombinant cells harboring functional
Lau
C4H afforded a promising chassis for biological production of
p
-coumaric acid, even other derivatives, via a plant CYP450-involved pathway.
Keywords:
p -coumaric acid
;
trans -cinnamic acid 4-hydroxylase
;
Lycoris aurea
;
Escherichia coli
;
synthetic biology
Graphical Abstract
1. Introduction
p -Coumaric acid is a commercially available phenolcarboxylic acid with a great number of important applications in the nutraceutical, pharmaceutical, material and chemical industries. p -Coumaric acid possesses potent anti-oxidant, antibacterial and anti-inflammatory properties, and serves as a conventional precursor for the production of flavors and fragrances used in edible and daily chemical products. p -Coumaric acid is also a starting material for the preparation of environmentally degradable thermoplastics with liquid crystalline behavior [ 1 ]. Recently, p -coumaric acid has been found to have many novel bioactivities, such as antiproliferative effect [ 2 ], anxiolytic effect [ 3 ], a nephroprotective role [ 4 ], melanogenesis inhibition [ 5 ], and neuroprotective effects [ 6 ]. In addition, p -coumaric acid, as an upstream metabolite in the plant phenylpropanoid pathway, is a common precursor for biosynthesizing numerous derivatives, such as other phenylpropanoids [ 7 , 8 ], flavonoids [ 9 , 10 ], stilbenes [ 11 ] and anthocyanins [ 12 ].
p -Coumaric acid has been biosynthesized mainly from tyrosine in engineered microbes. p -Coumaric acid, as a component of lignin, is ubiquitously present in plants at a low concentration [ 13 ]. In plants, the biosynthesis of p -coumaric acid involves two biochemical processes: phenylalanine ammonia-lyase (PAL) firstly catalyzes the conversion of phenylalanine to trans -cinnamic acid, which is then hydroxylated at the para position under the action of trans -cinnamic acid 4-hydroxylase (C4H) ( Figure 1 ) [ 14 , 15 ]. However, some PAL enzymes can accept tyrosine as an alternative substrate (PAL/TAL) and directly form p -coumaric acid from tyrosine without the intermediacy of trans -cinnamic acid ( Figure 1 ) [ 16 ]. Also, there are some aromatic amino acid ammonia-lyase homolog enzymes specific for tyrosine deamination (TAL) ( Figure 1 ) [ 17 ], so introducing a heterologous PAL/TAL or TAL, p -coumaric acid could be produced via the tyrosine route in recombinant cells such as Escherichia coli [ 18 , 19 , 20 ], Saccharomyces cerevisiae [ 21 ], Streptomyces lividans [ 22 ] and Pseudomonas putida [ 23 ].
In virtue of the plant biosynthetic route PAL-C4H, p -coumaric acid has been biosynthesized from phenylalanine only in engineered S. cerevisiae [ 18 ]. The enzyme C4H is a member of the CYP73A subfamily in cytochrome P450 enzymes (CYP450s) catalyzing a series of oxidation reactions with a CYP450 reductase as redox partner for supplying electrons from NADPH, and is supposed to commonly localize at the cytoplasmic side of endoplasmic reticulum (ER) membrane [ 14 ]. Given that prokaryotic microbes such as E. coli do not possess compartmentalized organelle(s), the functional expression of CYP450s is difficult [ 24 , 25 ]. Vannelli and his co-workers have functionally co-expressed the C4H and the CYP450 reductase from Helianthus tuberosus with a fungal PAL enzyme in S. cerevisiae cells, and produced p -coumaric acid from the central metabolite L-phenylalanine via the PAL-C4H route [ 18 ].
Though
p
-coumaric acid can be produced directly from tyrosine, it was necessary to investigate the potential of the plant CYP450-involved biosynthetic route from phenylalanine in
E. coli
which could to some extent expand the biosynthetic pathway of
p
-coumaric acid and offer an alternative approach to produce
p
-coumaric acid from phenylalanine as well as tyrosine. In the present study, based on our previous transcriptome data of
Lycoris aurea
(L’ Hér.) Herb [
26
], an ornamentally and medicinally important plant of the
Lycoris
genus of the Amaryllidaceae family, a novel C4H encoding gene was isolated from
L. aurea
, and designated as
Lau
C4H. Then
Lau
C4H was expressed truncatedly at the
N
-terminus in protoplasts of
A. thaliana
to identify the amino acids responsible for the subcellular localization. Moreover, in
E. coli
,
Lau
C4H without the N-terminal membrane anchor region was heterogeneously expressed for functional identification. PAL1 of
A. thaliana
was further introduced in the recombinant
E. coli
for
p
-coumaric acid de novo biosynthesis from glucose via the phenylalanine route. By regulating the level of intracellular NADPH, the production of
p
-coumaric acid was further increased by 9.18-fold, and a titer of 156.09 μM was achieved in shake flasks.
2. Results and Discussion
2.1. C4H Homology of L. aurea Transcriptome
Previously, de novo transcriptome sequencing has been performed to produce a comprehensive expressed sequence tag (EST) dataset for L. aurea using high-throughput sequencing technology [ 26 ]. The EST dataset of L. aurea provides a platform be critical in the speeding-up identification of a large number of related genes of secondary metabolite products. Further batch alignment results revealed that 226 contigs and unigenes were annotated to be responsible for the phenylpropanoid biosynthetic pathway. Of them, one unigene, namely unigene CL5217, showing high similarity with plant C4Hs was retrieved. Unigene CL5217 was 1794 bp with a predicted 1518 bp open reading frame (ORF), and was selected for further molecular cloning and functional characterization for the biosynthesis of p -coumaric acid.
2.2. Cloning of Full-length C4H Genes in L. aurea
By quantitative real-time polymerase chain reaction (qRT-PCR) and rapid amplification of cDNA ends (RACE) approaches, a cDNA encoding C4H homology was isolated from L. aurea . Firstly the quantitative PCR primer pairs annealing at the 3′-terminus of the predicted ORF and 3′-untranslational region were designed and used to determine the abundance of the unigene CL5217 in various tissues of L. aurea . qRT-PCR results revealed that the level of unigene CL5217 was highest in scape ( Figure 2 ).
Then, based on the sequence of unigene CL5217, the predicted ORF was cloned with the cDNA pool of scape as the template. Four gene variants were obtained with above 99% identity to each other at the nucleic acid level ( Appendix Figure A1 ) referring to two protein variants at the amino acid level ( Appendix Figure A2 ). Based on the genome size observed by flow cytometry, the plant material L. aurea used in this study is diploid (2n = 16) [ 27 ]. Therefore, a number of C4H paralogs were expected in the genome of L. aurea . Moreover, the plant used in this study was flowering and the bulb has been vegetatively propagated. For these reasons, the existence of multiple similar C4H transcripts was not surprising. This phenomenon was also reported in cloning the coding genes of norbelladine 4′- O -methyltransferase and para-para’ C–C phenol coupling CYP450 in the Amaryllidaceae plant Narcissus sp. aff. pseudonarcissus [ 28 , 29 ]. The deduced Lau C4H protein (variant 1) had a predicted molecular mass of 58.19 kDa and pI of 9.04.
Lau C4H possessed all the diagnostic features of the primary structure for CYP450s as well as the CYP73A subfamily. A hydrophobic membrane-spanning region was predicted in the N -terminus of Lau C4H between amino acid residues 9 and 26 by TMpred online program (Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland) and SignalP 3.0 server [ 30 ]. Following the N -terminal transmembrane sequence, a proline-rich region (PPGPLPVP) was present ( Figure 3 A). A conserved heme-binding motif (PFGVGRRSCPG) was also found near the C -terminus of Lau C4H ( Figure 3 A). In addition, the “PERF” consensus sequence and some conserved helices such as I-helix (AAIET), J-helix (PDIQQKLRNE), K-helix (KETLR) and K’-helix (AWWLANN) were also identified in Lau C4H sequence ( Figure 3 A). In the homologous tree, plant C4Hs were grouped into two classes as that implied by the differential N-terminus and C -terminus in the amino acid sequence alignment ( Figure 3 A,B), and Lau C4H showed higher identity with the C4Hs of Class I than those of Class II ( Figure 3 B).
2.3. Subcellular Localization of LauC4H
Further, an investigation of the subcellular localization of Lau C4H in plant cells was carried out. Lau C4H was firstly predicted to localize in the ER using the WoLF PSORT program [ 31 ], and its N-terminal sequence was considered responsible for anchoring to the membrane using the online software TMpred (SIB) and SignalP 3.0 [ 30 ]. Then, the whole ORF and the truncated sequences encoding the N -terminal 28 amino acids ( Lau C4H 1–28 ) and the Lau C4H without the N -terminal 28 amino acids ( Lau C4H Δ2–28 ), were fused with the enhanced green fluorescence protein (EGFP) gene, respectively. These fusion transgenes were transiently expressed in protoplasts prepared from the tender leaf of A. thaliana . Meanwhile, the fusion protein HDEL-mCherry with red fluorescence was used as the ER marker [ 32 ]. In Arabidopsis protoplasts containing Lau C4H-EGFP and HDEL-mCherry, the green fluorescence was present overlapping with the red fluorescence of the ER marker ( Figure 4 ), showing a typical fluorescence pattern of ER localization. A similar pattern was also observed for the Lau C4H 1–28 -EGFP fusion protein overlapping with the ER marker, though there was a small portion of green fluorescence not overlapped with the red fluorescence ( Figure 4 ). In Arabidopsis protoplasts containing Lau C4H Δ2–28 -EGFP, the fluorescence pattern was distinctly different from those of Lau C4H-EGFP and Lau C4H 1–28 -EGFP, and there was scarcely any overlap between the green fluorescence and the red fluorescence of the ER marker ( Figure 4 ). Thereby, our observation suggested that the N -terminal 28 amino acids spanning the hydrophobic transmembrane region was responsible for leading Lau C4H to localize in ER of plant cells. Previous studies showed that the CYP450 redox partners from A. thaliana and hybrid poplar were localized at the ER membrane of Arabidopsis protoplasts [ 33 , 34 ], those supported the notion that the N -terminus maybe confer Lau C4H to co-localize with the redox partner at the ER membrane and guide the electron transfer in plant cells ( Figure 5 A).
2.4. Functional Identification of LauC4H
Given that the oxygenation process of CYP450s requires a redox partner as electron supplier, the A. thaliana CYP450 redox partner ATR2 was employed for the functional exploration of Lau C4H in E. coli . Since there was no internal ER-like membrane in E. coli , both Lau C4H and ATR2 were expressed heterogenously without the N -terminal membrane anchor region, rather than in the full-length sequence, thus to avoid the so-called incompatibility between the membrane recognition signal of heterogenous proteins and the prokaryotic host [ 25 ]. In detail, the truncated ATR2 (ATR2 Δ2–74 ) was fused in the N-terminus of truncated Lau C4H ( Lau C4H Δ2–28 ) via a flexible octapeptide linker for electron supply ( Figure 5 B). The linker and the following proline-rich region in Lau C4H could orient optimally between ATR2 and Lau C4H [ 25 , 35 ]. When the recombinant E. coli cells harboring the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 protein were incubated with the substrate trans -cinnamic acid, a new product peak with the same retention time of p -coumaric acid was detected by HPLC analysis ( Figure 5 C). UV-Vis absorption spectra confirmed that the new product was identical to p -coumaric acid ( Figure 5 D).
The corresponding product was further examined using a liquid chromatography-mass spectrometry (LC-MS) in positive ion mode. LC-MS analysis of the targeted peak of the two LauC4H paralogs displayed the [M + H]
+
ions at m/z 165 (
Figure 5
E,F), corresponding to the calculated molecular weight of
p
-coumaric acid (MW = 164.16). In contrast, no any visible peak with the same retention time of p-coumaric acid was observed in the conversion systems with ATR2
Δ2–74
only as well as the empty vector pET29a, even though, with trans-cinnamic acid as the substrate. These results indicated that the new product synthesized with the chimeric ATR2
Δ2–74
-LauC4H
Δ2–28
protein was
p
-coumaric acid. Thus, the LauC4H is an authentic trans-cinnamic acid 4-hydroxylase able to participate the conversion of trans-cinnamic acid into p-coumaric acid with the plant CYP450 redox partner (
Figure 1
).
2.5. p-Coumaric Acid De Novo Biosynthesis Using LauC4H in E. coli
For the application of Lau C4H to de novo biosynthesize p -coumaric acid, the E. coli cells harboring the functional chimera ATR2 Δ2–74 - Lau C4H Δ2–28 were cultured in mineral medium added with glucose as the sole carbon source. However, no p -coumaric acid was detected ( Table 1 ), indicating that E. coli could not produce trans -cinnamic acid. When A. thaliana phenylalanine ammonia-lyase 1 ( Ath PAL1) was further introduced to the E. coli cells mentioned above, p -coumaric acid could be produced and accumulated in the medium of the recombinant cells with ATR2 Δ2–74 - Lau C4H Δ2–28 and Ath PAL1 ( Table 1 ). Therefore, the plant CYP450-involved p -coumaric acid biosynthesis pathway has been successfully established in procaryotic E. coli . Moreover, within a duration of 42 h induction with IPTG, the recombinant E. coli produced 17.22 μM of p -coumaric acid. The expression level and solubility of the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein were detected in Ec/ Lau C4H and Ec/ Lau C4H- Ath PAL ( Figure A3 ). As shown in Figure A3 , the expression level of the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein in Ec/ Lau C4H was more than that in Ec/ Lau C4H- Ath PAL. However, the level of the soluble ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein was comparable between Ec/ Lau C4H and Ec/ Lau C4H- Ath PAL. Comparably, E. coli cells only with Ath PAL1 or PAL/TAL from the yeast Rhodotorula glutinis ( Rgl PAL/TAL) [ 18 ] were also cultured as controls. In cells only with Ath PAL1, trans -cinnamic acid rather than p -coumaric acid was detected in the medium ( Table 1 ). In cells only with Rgl PAL/TAL, both trans -cinnamic acid and p -coumaric acid were accumulated, of which the concentration was 91.94 μM and 46.09 μM, respectively ( Table 1 ). Notably, there was 342.82 μM of trans -cinnamic acid detected in the medium of the recombinant cells with ATR2 Δ2–74 - Lau C4H Δ2–28 and Ath PAL1 ( Table 1 ).
2.6. p-Coumaric Acid Production Improved by Intracellular NADPH Regulation
The biochemical process of Lau C4H catalysis of the conversion of trans -cinnamic acid into p -coumaric acid needs two electrons per mole of substrate. ATR2 as a CYP450 redox partner is NADPH-dependent [ 33 , 34 ]. Since we observed that about 20-fold the substrate of Lau C4H still existed in the medium of strain Ec/ Lau C4H- Ath PAL ( Table 1 ), we were assuming that the output of p -coumaric acid was subjected to the level of intracellular NADPH ( Figure 1 ). For testing this assumption, we attempted to elevate the level of intracellular NADPH. Using synthetic small regulatory RNA (srRNA) anti(sthA) [ 36 ] to specific repression of the translation of the soluble transhydrogenase SthA (also referred to as UdhA) [ 37 ], the conversion of NADPH to NADH may be down-regulated when treated with anti(sthA) so that the content of NADPH would be relatively enhanced. As shown in Figure 6 , the introduction of the srRNA anti(sthA) accelerated cell growth and glucose utilization, and resulted in about 2-fold increase of the p -coumaric acid production. In addition, we also pursued overexpression of the membrane-bound transhydrogenase PntAB catalyzing the NADH to NADPH conversion [ 37 ]. When the overexpression of five-copy pntAB driven by a T7 promoter took place, the production of p -coumaric acid was dramatically improved by 7.93-fold up to 136.53 μM ( Figure 6 C). Both over-expressed PntAB and srRNA anti(sthA) resulted in a 9.18-fold increase, along with relative lower biomass and slower glucose consumption. Thus over-expressed PntAB and srRNA anti(sthA) played a synergetically positive effect on the de novo biosynthetic production of Lau C4H-mediated p -coumaric acid. The expression level and solubility of the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein in those p -coumaric acid producers were comparable ( Figure A3 ). Under such circumstance, there was a considerable amount of trans -cinnamic acid yet in the medium, indicating that the chimera ATR2 Δ2–74 - Lau C4H Δ2–28 was involved in a rate-limiting step for the formation of p -coumaric acid besides NADPH. Subsequently, there should be more approaches to be tested for improving the output of p -coumaric acid in E. coli . For example, the turnover of Lau C4H could be enhanced either by increasing the expression level of the chimera or by modulating the spatial structure of the chimera using modularized bioengineering tools in synthetic biology.
3. Materials and Methods
3.1. Plant Materials and Chemicals
The Lycoris aurea plants used in this study were collected from Nanjing Botanical Garden Mem. Sun Yat-Sen (Nanjing, China), and were about three-year old when the flowers bloom unless otherwise stated. A. thaliana wild-type (Columbia ecotype) plants used in this study were grown at 22 °C for four weeks after germination. Chemicals and reagents used in this study were purchased from either Sigma-Aldrich (St. Louis, MO, USA) or Sangon Biotech (Shanghai, China).
3.2. RNA Extraction and Isolation of LauC4H Genes
Total RNA from different tissues of
L. aurea
were extracted using the RNAprep pure Plant Kit (TIANGEN, Beijing, China). The cDNA pool was then synthesized by PrimerScript
TM
RT reagent Kit (TaKaRa, Dalian, China). To quantify the unigene CL5217 expression in different tissues, quantitative real-time polymerase chain reaction (qRT-PCR) was performed using AceQ
®
qPCR SYBR
®
Green Master Mix (High ROX Premixed) (Vazyme Biotech, Nanjing, China) with the gene
LauTIP41
as internal reference [
38
]. To obtain desired sequences, 5′- and 3′- rapid-amplification of cDNA ends (RACE) were carried out using the SMARTer
TM
RACE cDNA Amplification Kit (Clontech Laboratories, Inc., Mountain View, CA, USA) according to the manufacturer’s manual. The full-length cDNA were verified by re-amplification of the open reading frame (ORF) using forward primer
Lau
C4H-ORF-PF and reverse primer
Lau
C4H-ORF-PR. PCR protocols were as follows: one cycle of 5 min at 98 °C; 30 cycles with a denaturing time of 45 s at 95 °C, an annealing time of 45 s at 56 °C, and an elongation time of 90 s at 72 °C; and a final elongation step of 10 min at 72 °C. The PCR products of expected size were excised from the EtBr-stained 1% (
w
/
v
) agarose gels, purified using the DNA Gel Extraction Kit (BioTeke Corporation, Beijing, China) and ligated into the pMD19-T vector (TaKaRa) for sequencing. Each of the transcripts was obtained from at least three different monoclones. The primers used in this experiment are listed in
Appendix
Table A1
.
3.3. Sequence Aanalysis of LauC4H
The open reading frames (ORFs) in the obtained cDNA sequences were searched and the correspondingly encoded protein sequences were exported on NCBI ORFfinder webpage ( https://www.ncbi.nlm.nih.gov/orffinder/ ) (Bethesda, MD, USA). Then, homology search of the predicted protein were performed using regular blastp on NCBI BLAST webpage ( https://blast.ncbi.nlm.nih.gov/Blast.cgi ) (Bethesda, MD, USA). Molecular mass and isoelectric point of translated proteins were predicted on the SIB Bioinformatics Resource Portal ExPASy ( https://www.expasy.org/ ) (Lausanne, Switzerland). The subcellular localization in plant cells was predicted using the WoLF PSORT program ( https://wolfpsort.hgc.jp/ ) [ 31 ]. The prediction of signal sequence and transmembrane sequence was carried out using the SignalP 3.0 Server ( http://www.cbs.dtu.dk/services/SignalP-3.0/ ) [ 30 ] and the TMpred online program ( https://embnet.vital-it.ch/software/TMPRED_form.html ) (SIB). Amino acid sequences of full-length C4Hs were aligned and analyzed by the BioEdit Sequence Alignment Editor Version 7.1.3.0 [ 39 ] and the ClustalW program (SIB), respectively. The homologous tree was constructed via the software DNAMAN Version 8 (Lynnon Corporation, San Ramon, CA, USA).
3.4. Subcellular Localization Analysis of LauC4H
To determine the subcellular localization of
Lau
C4H, enhanced green fluorescent protein (EGFP) was in frame fused to the C-terminus of the
Lau
C4H protein sequence under the control of the dual cauliflower mosaic virus (CaMV) 35S promoter in the pAN580 vector. The plasmid pAN580 was digested by
Nco
I (TaKaRa, Dalian, China). The DNA fragments without termination codon encoding full-length
Lau
C4H,
N
-terminal 28 amino acids of
Lau
C4H (
Lau
C4H
1–28
) and N-terminal truncated
Lau
C4H (
Lau
C4H
Δ2–28
) were prepared with primer pairs pAN580-
Lau
C4H-PF and EGFP-
Lau
C4H-PR, primer pairs pAN580-
Lau
C4H-PF and EGFP-
Lau
C4H(N28)-PR, and primer pairs pAN580-
Lau
C4H(ΔN28)-PF and EGFP-
Lau
C4H-PR, respectively. The DNA fragments were assembled to linear pAN580 by ClonExpress One Step Cloning Kit (Vazyme Biotech) to create pDual35S::
Lau
C4H-EGFP, pDual35S::
Lau
C4H
1–28
-EGFP and pDual35S::
Lau
C4H
Δ2–28
-EGFP. Primers used to make these constructs were designed according to the product manual and are listed in
Appendix
Table A1
. The well-established fluorescent protein marker mCherry-HDEL [
32
] was used for the indication of the endoplasmic reticulum (ER). All transient expression constructs were transformed separately into
Arabidopsis
protoplasts with the mCherry-HDEL construct according to the method [
40
]. The transformed samples were incubated for 16–18 h before examination. Fluorescent images were observed by a laser scanning confocal microscope using a Zeiss LSM780 camera (Carl Zeiss Microscopy GmbH, Jena, Germany).
3.5. Heterologous Expression of LauC4H in Escherichia coli
Escherichia coli
Top10 was used as the host for molecular cloning. For gene expression in
E. coli
, Novagen
®
’s pET29a vector (EMD Millipore Corporation, Darmstadt, Germany) was used and digested by
Nde
I and
Xho
I (TaKaRa). The DNA fragment encoding
N
-terminal truncated
Lau
C4H (
Lau
C4H
Δ2–28
) were amplified with primer pairs 29a
Nde
I-
Lau
C4H(ΔN28)-PF and 29a
Xho
I-
Lau
C4H-PR. The DNA encoding the cytochrome P450 redox partner ATR2 without N-terminal 74 amino acids (ATR2
Δ2–74
) was obtained with the primer pairs 29a
Nde
I-ATR2(ΔN74)-PF and 29a
Xho
I-ATR2-PR from
A. thaliana
cDNA pool as the template. The DNA fragments was assembled to linear pET29a by ClonExpress One Step Cloning Kit (Vazyme Biotech) to create pET29a-
Lau
C4H
Δ2–28
and pET29a-ATR2
Δ2–74
. To express
Lau
C4H functionally in
E. coli
, the truncated ATR2 with a short flexible octapeptide (GSTSSGSG) was prepared with the primer pairs 29a
Nde
I-ATR2(ΔN74)-PF and
Lau
C4H(ΔN28)ATR2-PR, and was in frame fused to the N-terminus of
Lau
C4H
Δ2–28
into the
Nde
I site of pET29a-
Lau
C4H
Δ2–28
by ClonExpress One Step Cloning Kit (Vazyme Biotech) to create pET29a-ATR2
Δ2–74
Lau
C4H
Δ2–28
. Primers used to make these constructs are listed in
Appendix
Table A1
.
E. coli
Rosetta (DE3) (Vazyme Biotech) was used as the host for protein expression. Freshly transformed
E. coli
Rosetta (DE3) cells harboring pET29a-derived plasmids were grown at 37 °C and 220 rpm in M9Y minimal medium [
41
] with 20 g L
−1
glucose as carbon source to A
600
of 0.6–0.8, and then were induced with 0.1 mM isopropyl-β-D-thiogalactoside (IPTG) at 28 °C overnight.
3.6. Bioconversion of LauC4H with trans-Cinnamic Acid
Whole-cell bioconversion strategy was adopted to identify the function of Lau C4H. 50 mL cell cultures were harvested by centrifugation at 8000 rpm and 4 °C for 5 min, washed twice and re-suspended in 40 mL nitrogen-free M9Y mineral medium. The re-suspended cells were added 20 g L −1 glucose and 100 μM trans -cinnamic acid, and incubated at 28 °C with a stirring rate of 250 rpm for the whole-cell bioconversion. Samples were taken with an interval of 12 h, an equal volume of methanol was added to terminate the reaction and the samples were then subjected to HPLC analysis.
3.7. p-Coumaric Acid De Novo Biosynthesis in E. coli
To in vivo biosynthesize the substrate of Lau C4H in E. coli cells, the AthPAL1 gene encoding A. thaliana phenylalanine ammonia lyase 1 was overexpressed in pACYC184 vector [ 42 , 43 ] under a trc promoter induced by IPTG. For gene overexpression, pACYC184 was digested by Nco I and Eco RI (TaKaRa, Dalian, China) to get the plasmid skeleton with p15A origin of replication and tetracycline-resistant gene. Primer pairs 184-trc-lacO-PF and BBa_B0034-lacO-PR were annealed and elongated, and then purified to obtain the DNA fragment trcO-RBS containing the core-trc promoter (−10 box and −35 box), lacI binding site and the BioBrick ribosome binding site (RBS) BBa_B0034 chosen from the MIT Registry of Standard Biological Parts ( http://parts.igem.org/Main_Page ) (The International Genetically Engineered Machine (iGEM), Cambridge, MA, USA). Primer pairs BBa_B0034-BBa_B0015-PF and 184-BBa_B0015-PR were annealed and elongated, and then purified to obtain the DNA fragment BBa_B0015 containing the BioBrick terminator BBa_B0015 also chosen from the MIT Registry of Standard Biological Parts (iGEM, Cambridge, MA, USA). The three fragments, plasmid skeleton, trcO-RBS and BBa_B0015 terminator, sharing the overlap one by one, were assembled together by ClonExpress Ultra One Step Cloning Kit (Vazyme Biotech). The new plasmid was named as p15A-trcO3415. Then, the AthPAL1 gene was amplified from the A. thaliana cDNA pool with primers BBa_B0034- AthPAL1 -PF and BBa_B0015- AthPAL1 -PR and assembled into the linear p15A-trcO3415 by Nde I restriction endonuclease (TaKaRa) via ClonExpress One Step Cloning Kit (Vazyme Biotech) to create p15A-trcO Ath PAL1. Then p15A-trcO Ath PAL1 along with the plasmid pET29a-ATR2 Δ2–74 Lau C4H Δ2–28 were transformed into E. coli Rosetta (DE3) cells to obtain the recombinant strain Ec/ Lau C4H- Ath PAL. The empty vector p15A-trcO3415 along with the plasmid pET29a-ATR2 Δ2–74 Lau C4H Δ2–28 were transformed into E. coli Rosetta (DE3) cells to obtain the recombinant strain Ec/ Lau C4H. The plasmid p15A-trcO Ath PAL1 along with the empty vector pET29a were transformed into E. coli Rosetta (DE3) cells to obtain the recombinant strain Ec/ Ath PAL. The primers involved in this experiment are summarized in Appendix Table A1 .
The DNA sequence encoding the PAL/TAL from the yeast Rhodotorula glutinis [ 18 ] was optimized according to the codon preference of E. coli , and synthesized on the clone vector pUC57 to obtain pUC57-Opt Rgl PAL/TAL plasmid by Sangon Biotech (Shanghai) Co., Ltd (Shanghai, China). The RglPAL/TAL gene was amplified from the plasmid pUC57-Opt Rgl PAL/TAL with primers BBa_B0034- RglPAL/TAL -PF and BBa_B0015- RglPAL/TAL -PR and assembled into the linear p15A-trcO3415 by Nde I restriction endonuclease (TaKaRa) via ClonExpress One Step Cloning Kit (Vazyme Biotech) to create p15A-trcO Rgl PAL/TAL. Then p15A-trcO Rgl PAL/TAL plasmid along with the empty vector pET29a were transformed into E. coli Rosetta (DE3) cells to obtain the recombinant strain Ec/ Rgl PAL(TAL). The primers are summarized in Appendix Table A1 and the optimized DNA sequence of Rgl PAL/TAL was shown in Appendix A Figure A4 .
A single clone of the recombinant
E. coli
strains was incubated in 3 mL LB medium for 24 h. Then 1 mL of the cell cultures was collected, the supernatant was discarded, and the cell pellet was transferred into 50 mL fermentation medium and grown at 37 °C and 200 rpm. The fermentation medium contains 100 mM 3-(
N
-morpholino)propanesulfonic acid (MOPS), 28.71 mM K
2
HPO
4
, 25.72 mM KH
2
PO
4
, 26.50 mM (NH
4
)
2
HPO
4
, 10.00 mM citric acid, 5.00 mM MgSO
4
, 1 μg L
−1
vitamin B1, 0.5 μg L
−1
biotin, 166.67 mM glucose, 0.02 mM phenol red, and 10 mL trace element solution. The trace element solution was prepared in 100 mM HCl with 36.00 mM FeSO
4
, 7.82 mM ZnSO
4
, 4.00 mM CuSO
4
, 2.00 mM MnSO
4
, 0.60 mM Na
2
B
4
O
7
, 13.60 mM CaCl
2
, and 0.08 mM (NH
4
)
6
MO
7
O
24
. The cells were induced with 0.1 mM IPTG at 30 °C when grown to A
600
of 0.6–0.8. The pH in the medium was maintained at about 7.0 by adding ammonium hydroxide aperiodically. Samples were taken with an interval of 6 h and analyzed by HPLC.
3.8. Intracellular NADPH Regulation
For down-regulation of
EcoSthA
gene, the synthetic sRNA-based strategy [
36
] was applied. The plasmid skeleton with pSC101 origin of replication and spectinomycin-resistant gene was obtained from pCL1920 [
44
] as previously described [
45
]. The P
R
-MicC fragment including the constitutive P
R
promoter and the MicC scaffold was amplified from the wild-type
E. coli
MG1655 genome with primer pairs BBa_R0051-MicC-PF and BBa_B0015-MicC-PR. The BBa_B0015 terminator was amplified from the plasmid p15A-trcO3415 with primer pairs BBa_B0015-PF and BBa_B0015-PR. The P
R
-MicC-BBa_B0015 fragment was amplified with primer pairs pCL-BBa_R0051-PF and pCL-BBa_B0015-PR from both of P
R
-MicC fragment and BBa_B0015 terminator as the template. Then, the plasmid skeleton and the P
R
-MicC-BBa_B0015 fragment were assembled by ClonExpress One Step Cloning Kit (Vazyme Biotech) to construct the new plasmid pSC101-sRNA for synthetic sRNA production. Subsequently, the
N
-terminal 24 bp of
EcoSthA
gene was obtained by annealing and elongation with primer pairs anti(
sthA
)-PF and anti(
sthA
)-PR, and assembled into the linear pSC101-sRNA by
Nsi
I restriction endonuclease (TaKaRa) via ClonExpress One Step Cloning Kit (Vazyme Biotech) to create pSC101-anti(sthA).
For appropriate overexpression of NAD(P) transhydrogenase, the two genes
EcopntAB
were overexpressed with their native ribosome binding sites under a constitutive T7 promoter and transcriptionally terminated by the BioBrick terminator BBa_B1006 also chosen from the MIT Registry of Standard Biological Parts (iGEM, Cambridge, MA, USA). The
EcopntAB
DNA fragment was amplified from the wild-type
E. coli
MG1655 genome with primer pairs pCL-T7-
pntA
-PF and pCL-BBa_B1006-
pntB
-PR, and assembled into the
Kpn
I (TaKaRa) digested pSC101-sRNA and pSC101-anti(sthA) via ClonExpress One Step Cloning Kit (Vazyme Biotech) to create pSC101-OE(pntAB) and pSC101-anti(sthA)-OE(pntAB), respectively. Then pSC101-sRNA, pSC101-anti(sthA), pSC101-OE(pntAB) and pSC101-anti(sthA)-OE(pntAB), respectively, was transformed into strain Ec/
Lau
C4H-
Ath
PAL cells to obtain the recombinant strain Ec/
Lau
C4H-
Ath
PAL-sRNA, Ec/
Lau
C4H-
Ath
PAL-anti(sthA), Ec/
Lau
C4H-
Ath
PAL-PntAB, and Ec/
Lau
C4H-
Ath
PAL-PntAB-anti(sthA).
3.9. Protein Detection
Cells induced for 12 h were harvested by centrifugation at 8000 rpm for 5 min at 4 °C, washed twice with TNG buffer (20 mM Tris-HCl pH 7.9, 0.5 M NaCl, 10% Glycerol), and re-suspended in the same buffer containing 1 mM phenylmethylsulfonyl fluoride (PMSF). The suspended cells were sonicated on ice-bath followed by centrifugation at 12,000 rpm for 30 min at 4 °C. The supernatant was transferred out, and the sediment was re-suspended in the PMSF-contained TNG buffer. Proteins were assessed by SDS-PAGE.
3.10. High Performance Liquid Chromatography (HPLC) Analysis
All samples taken from the cultures were centrifuged at 12,000 rpm for 2 min and the supernatants were filtered through a 0.22 μm polytetrafluorethylene (PTFE) filter and analyzed by HPLC (Shimadzu LC-20A, Kyoto, Japan) with a reverse phase Shimadzu InertSustain C18 column (5 μm, 4.6 mm × 250 mm) and a Shimadzu SPD-M20A photodiode array detector. The mobile phase used was a gradient of solvent A (H
2
O containing 1.3% acetic acid) and solvent B (100% acetonitrile) applied as following time procedure: 0–20 min, 10–100% B linear; 20–20.5 min, 100%–10% linear; 20.5–30 min, 10% B isocratic. The flow rate was set at 1.0 mL·min
−1
, and the injection volume was 10 μL. The column was maintained at 35 °C, and the eluted compounds were monitored at 309 nm for
p
-coumaric acid and at 274 nm for
trans
-cinnamic acid respectively. The concentration of
trans
-cinnamic acid and
p
-coumaric acid were quantified by fitting the peak area with a standard curve (R
2
> 0.999) of the corresponding standard.
4. Conclusions
In the present study,
p
-coumaric acid was de novo produced via the plant CYP450-involved biosynthetic route in
Escherichia coli
. Firstly, a novel CYP73A from the Amaryllidaceae plant
Lycoris aurea
was cloned based on the transcriptome data, of which the
N
-terminal 28 amino acids were characterized responsible for localizing at the endoplasmic reticulum membrane in protoplasts of
Arabidopsis thaliana
. Then,
Lau
C4H was expressed functionally in
E. coli
when fused with the CYP450 redox partner from
A. thaliana
, and shown to catalyze the conversion of
trans
-cinnamic acid into
p
-coumaric acid. Further,
p
-coumaric acid was de novo biosynthesized via introducing a phenylalanine ammonia-lyase from
A. thaliana
into the recombinant
E. coli
cells. The production of
p
-coumaric acid was dramatically improved via regulation of the intracellular NADPH level of the constructed cell factory. The producer reported herein afforded a promising chassis for the biosynthesis of
p
-coumaric acid-derived molecules with great application value.
Author Contributions
Conceptualization, Y.L. and R.W.; Data Curation, Y.L. and J.L.; Formal Analysis, Y.L. and J.L.; Funding Acquisition, Y.L. and R.W.; Investigation, Y.L., J.L., B.Q. and L.C.; Methodology, Y.L., J.L., B.Q., L.C. and S.X.; Project Administration, R.W.; Resources, J.L., B.Q. and L.C.; Software, Y.L. and S.X.; Supervision, Y.L. and R.W.; Validation, J.L. and B.Q.; Visualization, Y.L. and J.L.; Writing-Original Draft Preparation, Y.L.; Writing-Review & Editing, Y.L., J.L. and R.W. All authors revised and approved the manuscript.
Funding
This work was financially supported by a research grant from the National Natural Science Foundation of China (NOs. 31600074 and 31770387), a grant from the Natural Science Foundation of Jiangsu Province (NO. BK20160599) and a grant from the Jiangsu Key Laboratory for the Research and Utilization of Plant Resources (NO. JSPKLB201837).
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A
Figure A1. Coding sequence alignment of Lau C4H variants. Four unique variants of Lau C4H gene are aligned against the original sequence predicted by the de novo assembled transcriptome. Dots are identical bases.
Figure A1. Coding sequence alignment of Lau C4H variants. Four unique variants of Lau C4H gene are aligned against the original sequence predicted by the de novo assembled transcriptome. Dots are identical bases.
Figure A2. Protein sequence alignment of Lau C4H variants. Four unique variants of Lau C4H protein are aligned against the original sequence predicted by the de novo assembled transcriptome. Dots are identical residues.
Figure A2. Protein sequence alignment of Lau C4H variants. Four unique variants of Lau C4H protein are aligned against the original sequence predicted by the de novo assembled transcriptome. Dots are identical residues.
Figure A3. The expression level and solubility of the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein in the p -coumaric acid producers. Strain 1, Ec/ Lau C4H; Strain 2, Ec/ Lau C4H- Ath PAL; Strain 3, Ec/ Lau C4H- Ath PAL-sRNA; Strain 4, Ec/ Lau C4H- Ath PAL-PntAB; Strain 5, Ec/ Lau C4H- Ath PAL-anti(sthA); Strain 6, Ec/ Lau C4H- Ath PAL-PntAB-anti(sthA). KDa, kilodalton; M, protein marker; WP, whole-cell proteins; IP, insoluble proteins; SP, soluble proteins. The arrows indicated the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein.
Figure A3. The expression level and solubility of the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein in the p -coumaric acid producers. Strain 1, Ec/ Lau C4H; Strain 2, Ec/ Lau C4H- Ath PAL; Strain 3, Ec/ Lau C4H- Ath PAL-sRNA; Strain 4, Ec/ Lau C4H- Ath PAL-PntAB; Strain 5, Ec/ Lau C4H- Ath PAL-anti(sthA); Strain 6, Ec/ Lau C4H- Ath PAL-PntAB-anti(sthA). KDa, kilodalton; M, protein marker; WP, whole-cell proteins; IP, insoluble proteins; SP, soluble proteins. The arrows indicated the chimeric ATR2 Δ2–74 - Lau C4H Δ2–28 fusion protein.
Figure A4. The codon-optimized DNA sequence of the yeast Rhodotorula glutinis PAL/TAL.
Figure A4. The codon-optimized DNA sequence of the yeast Rhodotorula glutinis PAL/TAL.
Table A1. Oligonucleotides used in this study. 1
Table A1. Oligonucleotides used in this study. 1
Name Sequence (5′ to 3′) RT-PCR RT- Lau C4H-PF AAGGGAAGCTTGATACCACTGAGAA RT- Lau C4H-PR GACAAATTAGAACAGTCTAGGCTTGGC RT- LauTIP41 -PF GCAACCATCCAAAGTTTAACTGCT RT- LauTIP41 -PR AATGTGCAAGCAGGGCTAGTAA cDNA cloning Lau C4H-ORF-PF ATCCTCCTCCTCCGACGAAATG Lau C4H-ORF-PR AGAGTACATTGCATGGGTAATAAGGAG Lau C4H-5′RACE-PR GAACTCGACCCCTTGTGTGTGC Lau C4H-3′RACE-PF GGCTATGACATCCCCGCTGA Subcellular localization pAN580- Lau C4H-PF AGGACCGGTCCCGGGGGATCC ATGGATCTCATTCTACTAGAAAAGTCACTC EGFP- Lau C4H-PR TCCTCGCCCTTGCTCACCAT GAACAGTCTAGGCTTGGCCACAATG EGFP- Lau C4H(N28)-PR TCCTCGCCCTTGCTCACCAT CCCGCGGAGTTTGGATATTATGAT pAN580- Lau C4H(ΔN28)-PF AGGACCGGTCCCGGGGGATCC ATGAAGAAGCTTAAGCTCCCCCCGG Functional expression 29a Nde I- Lau C4H(ΔN28)-PF AACTTTAAGAAGGAGATATACATATG AAGAAGCTTAAGCTCCCCCCGG 29a Xho I- Lau C4H-PR AGTGGTGGTGGTGGTGGTGCTCGAG TTAGAACAGTCTAGGCTTGGCCACAATG 29a Nde I-ATR2(ΔN74)-PF AACTTTAAGAAGGAGATATACATATG TCCGGTTCTGGGAATTCAAAA 29a Xho I-ATR2-PR AGTGGTGGTGGTGGTGGTGCTCGAG TGAGTGTGTGGCTTCAATAGTTTCG Lau C4H(ΔN28)ATR2-PR CCGGGGGGAGCTTAAGCTTCTTCAT ACCAGAACCAGAAGAGGTAGAACC CCATACATCTCTAAGATATCTTCCACTCGTTTG De novo biosynthesis 184-trc-lacO-PF GCCTTGCGTATAATATTTGCCCATGG TTGACAATTAATCATCCGGCTCGTATAATGTGTGGAATTGTGAGCGG BBa_B0034-lacO-PR CATATGTATTTCTCCTCTTTAGAT CTGGAATTGTTATCCGCTCACAATTCCACACATTATAC BBa_B0034-BBa_B0015-PF ATCTAAAGAGGAGAAATACATATG CTCGAGTAACCAGGCATCAAATAAAACGAAAGGCTCAGTCGAAAGACTGGGCCTTTCGTTTTATCTGTTGTTTGTCGGTGAACGCTCTCTACTA 184-BBa_B0015-PR GCCCGCCTGATGAATGCTCATCCGGAATTC TATAAACGCAGAAAGGCCCACCCGAAGGTGAGCCAGTGTGACTCTAGTAGAGAGCGTTCACCGACAAA BBa_B0034- Ath PAL1-PF ATCTAAAGAGGAGAAATACATATG GAGATTAACGGGGCACACAA BBa_B0015- Ath PAL1-PR TTATTTGATGCCTGGTTACTCGAG ACTTTATGGTAAGAAAAAAACAGAGGAC BBa_B0034- Rgl PAL/TAL-PF ATCTAAAGAGGAGAAATACATATG GCGCCGCGTCCGACCAGCCA BBa_B0015- Rgl PAL/TAL-PR TTATTTGATGCCTGGTTACTCGAG TTACGCCAGCATTTTCAGCAGA NADPH regulation BBa_R0051-MicC-PF TATTTTACCTCTGGCGGTGATAATGGTTGCATGCATTTTCTGTTGGGCCATTGCATTGC BBa_B0015-MicC-PR CGTTTTATTTGATGCCTGGCTCGAGAAAAAAAGCCCGGACGACTGTTC BBa_B0015-PF GCCAGGCATCAAATAAAACG BBa_B0015-PR TATAAACGCAGAAAGGCCCAC pCL-BBa_R0051-PF ACCCGTCTTACTGTCGGGAATTC TAACACCGTGCGTGTTGACTATTTTACCTCTGGCGGTGAT pCL-BBa_B0015-PR ACGTTGTAAAACGACGGCCAGT GGTACCTATAAACGCAGAAAGGCCCAC anti( sthA )-PF CCTCTGGCGGTGATAATGGTTGC ATCGTAATCGTAGGAATGTGGCAT anti( sthA )-PR ATGCAATGGCCCAACAGAAAATG CCACATTCCTACGATTACGAT pCL-T7- pntA -PF GGGCCTTTCTGCGTTTATAGGTACC AAATTAATACGACTCACTATAGGGGAATCTAGAGGGAATATCATGCGAATTGGCATACC pCL-BBa_B1006- pntB -PR TTGTAAAACGACGGCCAGTGGATCC AAAAAAAACCCCGCCCTGTCAGGGGCGGGGTTTTTTTTTAAGCTTGGGTTACAGAGCTTTCAGGATTGC
1 The sequences with single underline and double underline are the homologous arms for one-step cloning and the flexible linker for the protein fusion, respectively.
References
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Sample Availability: Samples of the compounds are not available from the authors.
Figure 1. The biosynthetic routes of p -coumaric acid. The phenylalanine route (PAL-C4H) presents ubiquitously in plants and the tyrosine route (PAL/TAL and TAL) exists in some microbes.
Figure 1. The biosynthetic routes of p -coumaric acid. The phenylalanine route (PAL-C4H) presents ubiquitously in plants and the tyrosine route (PAL/TAL and TAL) exists in some microbes.
Figure 2. The abundance of C4H candidate gene (unigene CL5217) in various tissues of L. aurea . The values and error bars represent the mean ± standard error from three independent samples in three replicates per sample.
Figure 2. The abundance of C4H candidate gene (unigene CL5217) in various tissues of L. aurea . The values and error bars represent the mean ± standard error from three independent samples in three replicates per sample.
Figure 3.
Sequence alignment (
A
) and homology analysis (
B
) of the full-length amino acid sequence of
Lau
C4H with other C4Hs reported in
A. thaliana
(NP_180607),
Glycine max
(NP_001237317, XP_003544934, XP_003555891),
Nicotiana tabacum
(NP_001312254, NP_001312445, NP_001313000, NP_001313097, XP_016493546, XP_016505655),
Oryza sativa
Japonica (XP_015623447, XP_015626579, XP_015635394, XP_015639656),
Sorghum bicolor
(XP_002452044, XP_002458683, XP_002461939) and
Zea mays
(NP_001140681, NP_001140726, NP_001151365, XP_008657127). GenBank accession numbers are indicated in parentheses. The threshold for shading in panel A was 100%. CYP98A3 (NP_850337) from
A. thaliana
and CYP96T1 (AMO65741) from
Narcissus
sp.
aff. pseudonarcissus
were additionally analyzed in panel B.
Figure 3. Sequence alignment ( A ) and homology analysis ( B ) of the full-length amino acid sequence of Lau C4H with other C4Hs reported in A. thaliana (NP_180607), Glycine max (NP_001237317, XP_003544934, XP_003555891), Nicotiana tabacum (NP_001312254, NP_001312445, NP_001313000, NP_001313097, XP_016493546, XP_016505655), Oryza sativa Japonica (XP_015623447, XP_015626579, XP_015635394, XP_015639656), Sorghum bicolor (XP_002452044, XP_002458683, XP_002461939) and Zea mays (NP_001140681, NP_001140726, NP_001151365, XP_008657127). GenBank accession numbers are indicated in parentheses. The threshold for shading in panel A was 100%. CYP98A3 (NP_850337) from A. thaliana and CYP96T1 (AMO65741) from Narcissus sp. aff. pseudonarcissus were additionally analyzed in panel B.
Figure 4. Subcellular localization of Lau C4H. “Green” panels show the fluorescence of Lau C4H variants fused with the enhanced green fluorescent protein (EGFP), “mCherry” panels indicate the fluorescence of endoplasmic reticulum marker (HDEL), and “Chlorophyll” panels indicate the auto-fluorescence of chloroplast. “Merged” panels represent the combined fluorescence from EGFP and mCherry. Bars = 10 μm.
Figure 4. Subcellular localization of Lau C4H. “Green” panels show the fluorescence of Lau C4H variants fused with the enhanced green fluorescent protein (EGFP), “mCherry” panels indicate the fluorescence of endoplasmic reticulum marker (HDEL), and “Chlorophyll” panels indicate the auto-fluorescence of chloroplast. “Merged” panels represent the combined fluorescence from EGFP and mCherry. Bars = 10 μm.
Figure 5.
Functional identification of
Lau
C4H. (
A
) Diagram of endoplasmic reticulum co-localization of
Lau
C4H and
A. thaliana
cytochrome P450 reductase 2 (ATR2) in plant cells. (
B
) Heterologous fusion expression of
Lau
C4H and ATR2 via a flexible linker in
E. coli
without both N-terminal membrane anchor region. (
C
) HPLC analysis of reaction products from pET29a-ATR2
Δ2–74
(1), pET29a (2), pET29a-ATR2
Δ2–74
Lau
C4H.1
Δ2–28
(3) and pET29a-ATR2
Δ2–74
Lau
C4H.2
Δ2–28
(4) using
trans
-cinnamic acid as the substrate. Standards (5) refer to HPLC analysis result of standard substance mixture of
p
-coumaric acid (a) and
trans
-cinnamic acid (b). (
D
) UV absorption spectra of the new product and the standard
p
-coumaric acid. (
E
,
F
) LC-MS identification of reaction products generated by recombinant
Lau
C4H.1 (
E
) and
Lau
C4H.2 (
F
).
Figure 5. Functional identification of Lau C4H. ( A ) Diagram of endoplasmic reticulum co-localization of Lau C4H and A. thaliana cytochrome P450 reductase 2 (ATR2) in plant cells. ( B ) Heterologous fusion expression of Lau C4H and ATR2 via a flexible linker in E. coli without both N-terminal membrane anchor region. ( C ) HPLC analysis of reaction products from pET29a-ATR2 Δ2–74 (1), pET29a (2), pET29a-ATR2 Δ2–74 Lau C4H.1 Δ2–28 (3) and pET29a-ATR2 Δ2–74 Lau C4H.2 Δ2–28 (4) using trans -cinnamic acid as the substrate. Standards (5) refer to HPLC analysis result of standard substance mixture of p -coumaric acid (a) and trans -cinnamic acid (b). ( D ) UV absorption spectra of the new product and the standard p -coumaric acid. ( E , F ) LC-MS identification of reaction products generated by recombinant Lau C4H.1 ( E ) and Lau C4H.2 ( F ).
Figure 6. Regulation of intracellular NADPH to improve the p -coumaric acid production. ( A ) cell growth; ( B ) glucose utilization; ( C ) p -coumaric acid biosynthesis; ( D ) trans -cinnamic acid accumulation. The p -coumaric acid producers were Ec/ Lau C4H- Ath PAL-sRNA (black square), Ec/ Lau C4H- Ath PAL-anti(sthA) (red circle), Ec/ Lau C4H- Ath PAL-PntAB (magenta triangle), and Ec/ Lau C4H- Ath PAL-PntAB-anti(sthA) (blue diamond). The error bars represent the standard error of the mean from three independent experiments of each strain.
Figure 6. Regulation of intracellular NADPH to improve the p -coumaric acid production. ( A ) cell growth; ( B ) glucose utilization; ( C ) p -coumaric acid biosynthesis; ( D ) trans -cinnamic acid accumulation. The p -coumaric acid producers were Ec/ Lau C4H- Ath PAL-sRNA (black square), Ec/ Lau C4H- Ath PAL-anti(sthA) (red circle), Ec/ Lau C4H- Ath PAL-PntAB (magenta triangle), and Ec/ Lau C4H- Ath PAL-PntAB-anti(sthA) (blue diamond). The error bars represent the standard error of the mean from three independent experiments of each strain.
Table 1. p -Coumaric acid de novo biosynthesis using Lau C4H in E. coli . 1
Table 1. p -Coumaric acid de novo biosynthesis using Lau C4H in E. coli . 1
Strain Biomass (OD 600 ) Glucose Utilization (g/L) trans -Cinnamic Acid (μM) p -Coumaric Acid (μM) Ec/ Lau C4H 5.56 ± 0.72 13.50 ± 0.72 ND 2 ND 2 Ec/ Ath PAL 8.92 ± 0.85 24.50 ± 0.65 241.32 ± 13.24 ND 2 Ec/ Rgl PAL(TAl) 9.73 ± 1.24 25.08 ± 0.75 91.94 ± 6.32 46.09 ± 2.96 Ec/ Lau C4H- Ath PAL 7.66 ± 0.83 24.78 ± 1.26 342.82 ± 15.80 17.22 ± 1.23
1 The data represent the mean ± the standard error from three independent experiments of each strain. 2 ND, not detected.
MDPI and ACS Style
Li, Y.; Li, J.; Qian, B.; Cheng, L.; Xu, S.; Wang, R. De Novo Biosynthesis of p-Coumaric Acid in E. coliwith a trans-Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea. Molecules 2018, 23, 3185.
https://doi.org/10.3390/molecules23123185
Li Y, Li J, Qian B, Cheng L, Xu S, Wang R. De Novo Biosynthesis of p-Coumaric Acid in E. coliwith a trans-Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea. Molecules. 2018; 23(12):3185.
https://doi.org/10.3390/molecules23123185
Li, Yikui, Jie Li, Binbin Qian, Li Cheng, Sheng Xu, and Ren Wang. 2018. "De Novo Biosynthesis of p-Coumaric Acid in E. coliwith a trans-Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea" Molecules23, no. 12: 3185.
https://doi.org/10.3390/molecules23123185
Article Metrics
Li, Y.; Li, J.; Qian, B.; Cheng, L.; Xu, S.; Wang, R. De Novo Biosynthesis of p-Coumaric Acid in E. coliwith a trans-Cinnamic Acid 4-Hydroxylase from the Amaryllidaceae Plant Lycoris aurea. Molecules 2018, 23, 3185.
https://doi.org/10.3390/molecules23123185
| https://www.mdpi.com/1420-3049/23/12/3185/xml |
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Description
SOW This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in FAR Subpart 12.6 as supplemented with additional information included in this notice. This announcement constitutes the only solicitation; proposals are being requested and a written solicitation will not be issued. The solicitation number, HSFE50-14-Q-0013 is issued as a Request for Quote (RFQ), is for the repair, repaint and apply decals to Mobile Communications Office Vehicle (MCOV) vehicles to comply with Depart of Homeland Security branding specifications on three (3) each vehicles for Department of Homeland Security (DHS) FEMA Bothell, MERS/MCOV Program. The solicitation document and incorporated provisions and clauses are those in effect through Federal Acquisition Circular 2005-58. This RFQ is being issued as a Total Small Business Set-aside. The NAICS code for this requirement is 811121, for which the Small Business Size Standard is $7 million dollars. Only one award will result from this solicitation, via the issuance of firm-fixed-price contract. FOB Destination pricing is preferred. SPECIFIC TASKS: Successful contractor shall provide delivery of three (3) newly painted vehicles and any other necessary expenses to complete changes to vehicles as mentioned in Statement of Work. Please provide the Unit and extended price for each. Services shall be completed within 120 days after receipt of award. Service and transportation to and from of three (3) each vehicle will be made to the following address: 200 228th St. SW Bothell, WA 98021 All contractor personnel requiring access to the Government facility must have a current valid ID indicating US citizenship and for contractor personnel actually driving onto the facility a valid driver's license is required. Site Visit: There will be a coordinated site visit on Thursday, May 15, 2014 at 9:00 a.m. The site address will be 200 228th St. SW, Bothell, WA 98021. Contact Ryan Owings at 540-542-2226 or email [email protected] to confirm your attendance for the site visit by COB, 4 p.m., Tuesday, May 13, 2014. Please provide your company name as the names of the individual attendees. Each individual must show a photo I.D. to gain access to the FEMA facility. If driving you will also need a valid driver's license, proof of vehicle registration and insurance. Please allow additional time (approx. 20-30 minutes) for facility access and to locate parking. See attached statement of work for the minimum requirements for the painting of the three (3) vehicles. a. Delivery Time ARO: ________________________ b. FOB Destination or Origin: _________________. c. DUNS Number: ________________________ d. TIN Number: ________________________ e. CCR CAGE:_______________________ BASIS FOR AWARD: The Gov't will make award to the responsible/responsive offeror whose proposal will be most advantageous to the Gov't based on lowest price/technically acceptable factors. Offerors shall provide a detailed price proposal to include the cost of all labor costs; associated labor costs and other associated costs (e.g., excise tax, etc.). The price proposal shall be broken down and totaled in order for the Government to perform a complete evaluation of the proposed price. In order for an offeror to be considered technically acceptable, the following mandatory requirements must be met: (a) Offeror must provide the breakdown of the prices along with a description for the items requested in the statement of Work, (b) offeror must provide three (3) references and projects that are similar to this project including phone numbers of references. Quality of past performance will be evaluated on a pass/fail basis. Offeror's must be registered in the SAM database (via the Internet at http://www.sam.gov) which includes the electronic annual representations and certifications. Offer needs to include a completed copy of the provision 52.212-3, Offeror Representations and Certifications-Commercial Items, unless the SAM page is up to date. The provision at FAR 52.212-1 "Instructions to Offerors--Commercial" applies to this acquisition. The following FAR clauses also apply: 52.204-10 "Reporting Executive Compensation and First-Tier Subcontract Awards," 52.212-4 "Contract Terms and Conditions--Commercial Items," 52.212-5 "Contract Terms and Conditions Required to Implement Statutes or Executive Orders--Commercial Items," with the following clauses cited in 52.212-5 being applicable to this acquisition: 52.203-6 "Restrictions on Subcontractor Sales to the Government," 52.219-8 "Utilization of Small Business Concerns," 52.222-3 "Convict Labor," 52.222-19 "Child Labor--Cooperation with Authorities and Remedies," 52.222-21 "Prohibition of Segregated Facilities," 52.222-26 "Equal Opportunity," 52.222-35 "Equal Opportunity for Special Disabled Veterans, Veterans of the Vietnam Era, and Other Eligible Veterans," 52.222-36 "Affirmative Action for Workers with Disabilities," 52.222-37 "Employment Reports on Special Disabled Veterans, Veterans of the Vietnam Era, and Other Eligible Veterans," 52.225-1 "Buy American Act--Supplies," 52.225-13 "Restrictions on Certain Foreign Purchases," and 52.232-33 "Payment by Electronic Funds Transfer--Central Contractor Registration." The aforementioned provision and clauses can be accessed electronically at http://www.gsa.gov/far. Prospective sources are reminded that award can only be made to a Contractor who is registered in the SAM database. Due date for receipt of responses to this RFQ will be 1:00PM/EST, 05/22/2014 to Mr. Ryan Owings at e-mail address: [email protected] or fax number at 540-542-2632 or 2631. Mr. Owings telephone number is: 540-542-2226. Electronic responses are required. Amendments to this RFQ, if needed, will be published in the same manner as the initial synopsis/solicitation.
Web Link
FBO.gov Permalink
(https://www.fbo.gov/spg/DHS/FEMA/MWEAC/HSFE50-14-Q-0013/listing.html)
Place of Performance
Address:
200 228th St. SW, Bothell, Washington, 98021, United States
Zip Code:
98021
Record
SN03360945-W 20140510/140509021806-4e074fff7dc4248aab0720d984e5054e (fbodaily.com)
Source
(may not be valid after Archive Date)
| http://www.fbodaily.com/archive/2014/05-May/10-May-2014/FBO-03360945.htm |
Thomas William Lawson McCall (1913-1983)
Tom McCall, more than any leader of his era, shaped the identity of modern Oregon. As governor from 1967 to 1975, McCall, a Republican, pioneered a doctrine of…
Oral History Interview with Tom McCall
Tom McCall, more than any leader of his era, shaped the identity of modern Oregon. As governor from 1967 to 1975, McCall, a Republican, pioneered a doctrine of balancing economic growth with environmental protections and took the lead in establishing safeguards for the state’s beaches, rivers, and farmlands by curbing pollution and suburban sprawl. His leadership, defined by bold actions and lyrical speeches, helped transform Oregon from a political backwater to a state renown for progressive ideals.
Thomas William Lawson McCall was born on March 22, 1913, in Egypt, Massachusetts, on an estate owned by his maternal grandfather, Thomas W. Lawson, a wealthy Boston stock promoter. Lawson had given McCall’s parents, Henry McCall and Dorothy Lawson McCall, a central Oregon ranch along the Crooked River near Prineville , and that is where Tom grew up.
In 1936, Tom McCall graduated from the University of Oregon with a journalism degree. He worked as a sportswriter in Idaho and as a reporter for the Oregonian and a radio news announcer for KGW in Portland before serving in the U.S. Navy during World War II. After the war, he returned to Portland to take a job as a radio host for his own news show on KEX. His flair for language and his distinctive voice—influenced by his parents’ Boston accents—became his trademarks.
McCall was inspired to enter politics by the career of his other grandfather, Samuel Walker McCall, who had been a Massachusetts congressman and governor. In 1949, he left his radio job to work as secretary to Oregon Governor Douglas McKay. After returning toPortlandradio in 1951, he ran for Congress, challenging an eight-term incumbent, U.S. Representative Homer Angell, in the 1954 Republican primary. McCall’s upset victory over Angell primed him as a rising political star, but in November he lost a bitter general election race to Democrat Edith Green, a former teacher and union official. McCall blamed himself for allowing right-wing businessmen to manipulate him and his campaign message, and the loss taught him to value political independence.
McCall returned to broadcasting, this time in the emerging medium of television. As a commentator at KGW-TV in Portland , his candor and evenhanded analysis of public affairs earned him growing respect and popularity. McCall also produced landmark documentaries, including Farewell at Celilo in 1959 and Crisis in the Klamath Basin in 1958, which examined the fight over southern Oregon timberlands controlled by the Klamath tribe. In 1962, he co-wrote and anchored P ollution in Paradise , an hour-long documentary on unchecked industrial pollution, especially in the waste-choked Willamette River . The documentary shocked Oregonians, who had never seen such a visceral depiction of the state’s pollution or known its harm to the state’s economy. The documentary inspired legislative reforms that gave the state the authority to shut down polluters, and it established McCall as a champion for what he called Oregon’s “livability.”
In 1964, McCall won election as Oregon secretary of state, and two years later he campaigned to replace outgoing Governor Mark O. Hatfield. In the general election, McCall faced State Treasurer Robert W. Straub, a Democrat and devoted environmentalist. Their debates, nicknamed the “Tom & Bob Show,” revealed more similarities than differences as each sought to persuade voters that he was most committed to protecting the state’s natural resources. McCall won the race with 55 percent of the vote.
During his first term as governor, McCall championed protections for Oregon’s beaches, which were facing threats from private development. He denounced anyone (including fellow Republicans) who stood in the way of protecting the beaches, and lawmakers passed the 1967 Beach Bill as a bulwark against coastal development. McCall also threatened to close polluting mills, and in 1969 won legislative approval to establish theDepartment of Environmental Qualityto enforce stronger standards.
McCall struggled as chief executive, and his first term saw political setbacks. An early advocate for prison reform, his administration mishandled management of the Oregon State Penitentiary . Prisoners rioted in March 1968, taking guards as hostages and burning several buildings. The riot ended with the hostages unharmed after McCall fired the warden and conceded to prisoners’ demands for better conditions. He considered the riot to be the single biggest disgrace during his time as governor.
In 1970, McCall sought re-election in a tough rematch against Straub. That summer, the FBI warned McCall that Vietnam War protestors planned a confrontation in Portland during the national American Legion convention in September, only weeks before election day. Most state and local leaders advocated for tough police action against protestors, but McCall preferred another approach. He opened Milo McIver State Park in Estacada , twenty-five miles southeast of Portland, for a government-sanctioned rock festival. Forty thousand people swarmed the festival, known as Vortex I. McCall’s bold political gamble paid off, and the Legion convention and anti-war protests went off in Portland without incident. He easily won re-election.
The victory emboldened him. In January 1971, McCall told a national television audience that Oregon was willing to protect its beauty and livability even if it meant controlling growth and discouraging newcomers. “Come visit us again and again,” he said. “But for heaven’s sake, don’t come here to live.” His statement—shorthanded as “Visit but don’t stay”—made international headlines and defined Oregon for years. McCall denied he was making the state inhospitable and said he was underscoring Oregon’s new efforts to manage growth. Critics later blamed McCall’s message for frustrating the state’s economic development.
In 1971, McCall led the successful fight for the Oregon Bottle Bill, which became the nation’s first mandatory container deposit law. The bill overcame fierce opposition from beverage manufacturers who would be required to impose a five-cent deposit on cans and bottles. McCall and the bill’s other supporters first championed the idea as an anti-littering law, but he soon saw its potential to promote recycling and conservation and to end what he called the national “no-deposit, no-return ways of waste.”
When the nation faced energy shortages in 1973 and 1974, McCall told businesses to shut off commercial lights. Gas shortages created long lines at Oregon service stations, and the governor ordered an “odd/even” gas rationing plan—a vehicle could get fuel only on odd- or even-numbered days, depending on the last digit of its license plate. As governor, he lacked the legal authority to enforce these measures, but for the most part Oregonians complied. His outspoken advocacy for energy conservation helped create the foundation for the sustainability movement .
McCall’s most ambitious and enduring success was the creation of statewide land-use planning. In a January 1973 speech that defined his tenure as governor, McCall warned against the “shameless threat” from “sagebrush subdivisions, coastal ‘condomania,’ and the ravenous rampage of suburbia in Willamette Valley .” The 1973 legislature passed Senate Bill 100 , a landmark law that established statewide goals for planning and development.
Forced from office by term limits, McCall returned to television in 1975 as a commentator at KATU. In 1978, he sought to reclaim his former office, running as a Republican even though he felt alienated from an increasingly conservative GOP. State Senator Vic Atiyeh, a Republican from Beaverton , defeated him in the primary, ending McCall’s political career.
In 1980, the Oregon economy collapsed under a crushing recession, the worst since the Great Depression. The state’s primary economic engine, the timber industry, lost 25 percent of its jobs. The causes of the recession ran deep, but critics tried to blame McCall’s anti-growth policies and promoted a 1982 ballot measure that would repeal statewide land-use planning. A frail McCall—he had been diagnosed with terminal cancer—spent his final months fighting Ballot Measure 6. Oregonians listened, and voters in November 1982 upheld the land-use planning he had helped put in place.
McCall in the Navy.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall campaigning in Roseburg, Aug. 1966.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Tom McCall.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall (left) fishing on the Crooked River, 1925.
Courtesy Oregon Hist. Soc. Research Lib., OrHi97326
McCall interviewing Robert Kennedy during vice commission hearings, c.1956.
Courtesy Oregon Hist. Soc. Research Lib., OrHi97325
Audrey and Tom McCall, 1966, after successful campaign.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall governor campaign card.
Courtesy Oregon Hist. Soc. Research Lib., Mss1513
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Oregonian news staff, McCall in back center-right; Earl Snell in center.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
Boivin, second from left, on Tom McCall's KGW-TV show, Viewpoint, 1961.
Other guests were Robert Duncan, Anthony Yturri, and F.F. Montgomery Courtesy Oregon Hist. Society Research Lib., Oregon Journal, 012491
Douglas McKay, 1952.
Courtesy Oregon Hist. Soc. Research Lib., 012518
Pres. Eisenhower greets McCall after 1954 primary win over Angell.
Courtesy Oregon Hist. Soc. Research Lib.
McCall's congressional campaign, 1954.
Courtesy Oregon Hist. Soc. Research Lib.
McCall concedes to Edith Green, Nov. 1954.
Courtesy Oregon Hist. Soc. Research Lib., 37444
Secretary of State campaign mailer.
McCall campaigning on the Willamette river, 1964.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
The opening of the Secretary of State campaign headquarters in Portland, 1964.
Monte Ballou and the Castle Jazz Band Courtesy Oregon Hist. Soc. Research Lib.
Secretary of State McCall at a press conference, 1966.
Courtesy Oregon Hist. Soc. Research Lib., OrHi90703
McCall campaign sticker.
Courtesy Oregon Hist. Soc. Research Lib., Mss1513
McCall campaign event, c1966.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall campaigning in c.1966.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall campaigning for governor, 1966.
Courtesy Oregon Hist. Soc. Research Lib., OrHi97349
Campaign billboard near Medford, 1966.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Audrey and Tom McCall, 1966.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall and Nixon, 1954, at an Oregon masonic temple.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
Beaches are for Kids event, 1968.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall in a helicopter flying over Oregon beaches, 1967.
Courtesy Oregon Hist. Soc. Research Lib., ba17646
First beach cleanup day, possibly Seaside..
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall meeting with the Willamette Oregon Council of the Blind.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall working from his hospital bed, Aug. 1, 1973.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall on Meet the Press, 1974, to talk about Watergate.
Governor Jimmy Carter sits in the front row. Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall dedicating the Oregon Friendship Forest in Israel, 1973.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall greets Bob Hope.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall with Sam, Tad, and Audrey, 1967.
Courtesy Oregon Hist. Soc. Research Lib., OrHi97357
Tom and Audrey at son Tad's wedding to Barbara Jean Pyle, 1971.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Dorothy McCall with Tom at a book signing.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall and Howard Lane fishing, 1970.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
McCall at an unknown Vikings-themed event.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
McCall participating in a Grants Pass Cavemen event .
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Audrey and Tom McCall, 1964, following Sec. of State win.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 1335
Audrey and Tom McCall.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
Tom and Audrey McCall.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
Tom and Audrey McCall, 1981, following Tom's hospital stay.
Courtesy Oregon Hist. Soc. Research Lib., Org Lot 353
| https://www.oregonencyclopedia.org/articles/mccall_thomas_l/ |
April 19, 2007 House Committee on International Relations, The Current Situation in Darfur
April 19, 2007 House Committee on International Relations, The Current Situation in Darfur
Statement of Chairman Tom Lantos at hearing, "The Current Situation in Darfur" House Committee on Foreign Affairs
Just after this hearing, Congress will solemnly commemorate the Holocaust, as it does every year, in the hushed Rotunda of the United States Capitol. To many, the events of the Holocaust seem to be part of the very distant past, a discrete event with a definite ending. But unfortunately, their echoes resonate with us today.
They haunt us with another inconceivable genocide: the slaughter of as many as 400,000 people in the Darfur region of Sudan. The Sudanese government has been allowed to perpetrate a shocking campaign of terror for far too long. And complacent governments around the world have stood on the sidelines for far too long. So today, the question faces us: Will we again fail to recognize the profound message of the candles we shall light in a couple of hours to commemorate the Holocaust?
I have been saying for over three years that the international community has not been doing nearly enough about Darfur. Signs of progress emerged this week, even if it has come too late for the dead. The Sudanese government agreed to let a 3,000-person United Nations peacekeeping force join the African Union troops who are already there. It made the decision under pressure and only after months of unnecessary backtracking and delay. But the brutal Sudanese government has resisted the efforts of the United Nations to send some 20,000 peacekeepers to Darfur. I have no doubt that they will continue to procrastinate. Let me be clear: the difference between a small force and a substantial deployment is no mere sticking point. It is absolutely essential.
It is essential to stop the Arab militias from continuing to carry out the government's dirty deeds. It is essential to clearing the path for crucial food and water and health supplies to reach the desperate refugee camps. And it is essential because injustice is only really addressed when it is obliterated, not when it is slowed to a painful trickle of displacement, harassment, and disrupted lives. We must have that bigger U.N. force in Sudan without any additional delay.
Let me just digress for a moment from my prepared comments. The President's speech yesterday at the Holocaust museum focuses attention again on this matter. And I wish there would have been action, immediate action, connected to that speech. But the Secretary-General of the United Nations, our friend Ban Ki-moon, requested a few additional weeks to attempt to gain cooperation from the Sudanese government, and the President chose to give it to him. I want to serve notice on the President of the United States that while we can go along with two or three weeks of delay, this committee and this Congress will not rest any longer and we are demanding action.
To ensure smooth coordination between the African Union command and the UN deployment, the UN ought to send a transitional force. These troops would also stop Khartoum from disrupting the new peacekeeping force. The presence of this transition force would not be subject to negotiation with the Sudanese and it would need to be deployed in the next two weeks.
Those of us who have been in the forefront of the Darfur issue worry that the Sudanese government simply wants to complete the horrific job of eliminating the minority there. New evidence surfaced this week that the government is undermining the fragile calm in Darfur by trying to inject violence. An unpublished UN report alleges the Sudanese government is delivering arms and military equipment to its murderous minions in Darfur. Just as disturbing is the claim that they are painting their own military airplanes white to disguise them as UN or African Union aircraft. There is proof that at least one plane had the letters "U.N." painted on it to complete the deception. The report says Khartoum is doing next to nothing to stop the militias, which are still terrorizing the individuals in the Darfur countryside.
All of these insidious actions are in direct violation of Security Council resolutions. The Sudanese should and will be held to account. I propose a no-fly zone that would prohibit any Sudanese military planes from taking to the air. If they violate this provision, we need to destroy their Air Force. It's as simple as that. I think this would put a stop to their aircraft shenanigans.
There is a larger issue here, one that should be illuminated by the candles we light to remember the Holocaust. In conflicts where we witness slaughter on a grand scale, we have a tendency to believe the situation has stabilized when violence has ebbed from its most vicious moment. We think there is no grave and imminent danger. But as long as the dynamics that led to murder and displacement and abduction are still in place, as long as those who flee are starving and unsettled and bullied, a real danger for increased bloodshed exists.
The government in Sudan cannot be trusted to enforce agreements when it has ignored its commitments in the past. And the leaders in Khartoum cannot be believed when they say they are ready for the United Nations when all they have done is to stall. The U.S. and other members of the UN Security Council must demand that Sudan not only welcome the initial 3,000 peacekeepers, but permit without delay a full 20,000-person force-now. Sanctions are not enough.
Ever since the Holocaust, many in our society have routinely pledged "never again." But here we are, in a different time, in a different place, but with motives and brutality no less sinister. Time and again, recalling my own experience as a genocide survivor, I have called on this government and the United Nations to intervene. Today again, I urge our own government and the United Nations to stop the genocide in Darfur. I am hopeful that the latest concession by Khartoum will lead to a larger force that will finally put Sudan on a road to peace.
I am more hopeful than I have been for a long time. But from this hearing room I will go to the Rotunda, to help light the candles and again wonder if we will let them flicker out before we truly honor their meaning.
| https://www.globalsecurity.org/military/library/congress/2007_hr/070419-lantos.htm |
Sensors | Free Full-Text | Electrochemical DNA Biosensor Based on Immobilization of a Non-Modified ssDNA Using Phosphoramidate-Bonding Strategy and Pencil Graphite Electrode Modified with AuNPs/CB and Self-Assembled Cysteamine Monolayer
The present paper describes an alternative approach to the traditionally used covalent immobilization methods that require cost-intensive and complicated chemistry modification of a single-stranded DNA (ssDNA) capture probe. The low-cost pencil graphite electrode (PGE) modified with carbon black (CB) and gold nanoparticles (AuNPs) was used as an electrochemical platform and the non-modified ssDNA was immobilized on a self-assembled cysteamine modified AuNPs/CB–PGE through a phosphoramidate bond between the 5′-terminal phosphate group of ssDNA and the primary amine group of cysteamine. The microRNA-21 was used as a target model in the fabrication of this electrochemical DNA biosensor and the hybridization process with the complementary probe was monitored by differential pulse voltammetry using methylene blue (MB) as an electrochemical hybridization indicator. The decreased reduction peak current of MB shows a good linear correlation with the increased concentration of microRNA-21 target sequences because the MB signal is determined by the amount of exposed guanine bases. The linear range of the fabricated DNA biosensor was from 1.0 × 10−8 to 5.0 × 10−7 M with a detection limit of 1.0 × 10−9 M. These results show that the covalent immobilization of a non-modified ssDNA capture probe through a phosphoramidate-bonding strategy could serve as a cost-effective and versatile approach for the fabrication of DNA biosensors related to a wide range of applications that cover the fields of medical diagnostic and environmental monitoring. The fabricated electrochemical DNA biosensor was used to analyze microRNA-21 in a (spiked) human serum sample and it showed satisfactory and encouraging results as an electrochemical DNA biosensor platform.
Electrochemical DNA Biosensor Based on Immobilization of a Non-Modified ssDNA Using Phosphoramidate-Bonding Strategy and Pencil Graphite Electrode Modified with AuNPs/CB and Self-Assembled Cysteamine Monolayer
by Hamza Moustakim , Hasna Mohammadi and Aziz Amine *
Chemical Analysis and Biosensors Research Group, Laboratory of Process Engineering and Environment, Faculty of Sciences and Techniques, Hassan II University of Casablanca, P.A. 146, Mohammedia 28806, Morocco
Author to whom correspondence should be addressed.
Sensors 2022 , 22 (23), 9420; https://doi.org/10.3390/s22239420
Received: 2 November 2022 / Revised: 19 November 2022 / Accepted: 30 November 2022 / Published: 2 December 2022
(This article belongs to the Section Biosensors )
:
The present paper describes an alternative approach to the traditionally used covalent immobilization methods that require cost-intensive and complicated chemistry modification of a single-stranded DNA (ssDNA) capture probe. The low-cost pencil graphite electrode (PGE) modified with carbon black (CB) and gold nanoparticles (AuNPs) was used as an electrochemical platform and the non-modified ssDNA was immobilized on a self-assembled cysteamine modified AuNPs/CB–PGE through a phosphoramidate bond between the 5′-terminal phosphate group of ssDNA and the primary amine group of cysteamine. The microRNA-21 was used as a target model in the fabrication of this electrochemical DNA biosensor and the hybridization process with the complementary probe was monitored by differential pulse voltammetry using methylene blue (MB) as an electrochemical hybridization indicator. The decreased reduction peak current of MB shows a good linear correlation with the increased concentration of microRNA-21 target sequences because the MB signal is determined by the amount of exposed guanine bases. The linear range of the fabricated DNA biosensor was from 1.0 × 10
−8
to 5.0 × 10
−7
M with a detection limit of 1.0 × 10
−9
M. These results show that the covalent immobilization of a non-modified ssDNA capture probe through a phosphoramidate-bonding strategy could serve as a cost-effective and versatile approach for the fabrication of DNA biosensors related to a wide range of applications that cover the fields of medical diagnostic and environmental monitoring. The fabricated electrochemical DNA biosensor was used to analyze microRNA-21 in a (spiked) human serum sample and it showed satisfactory and encouraging results as an electrochemical DNA biosensor platform.
Keywords:
electrochemical DNA biosensors
;
pencil graphite electrode
;
DNA immobilization
;
phosphoramidate-bonding
;
methylene blue
;
differential pulse voltammetry
1. Introduction
The massive quantities of genetic information obtained through modern DNA sequencing technologies and the capability of bioinformatics tools to give us specific base sequences related to some well-known genetic and infectious diseases are very important resources nowadays in medical diagnostic and environmental monitoring [ 1 , 2 ]. Latest progress in transcriptomics technologies and computational strategies allows us to go even farther and integrate a new set of sequences known as non-coding RNA sequences [ 3 , 4 , 5 ]. These non-coding RNAs play an important role in regulating gene expression at the transcriptional and post-transcriptional levels [ 6 ]. The well-characterized non-coding RNAs known as microRNAs are listed in the miRBase database with no less than 4571 entries for the human species and their deregulation is associated with a wide range of diseases such as cancers and cardiovascular diseases [ 7 , 8 , 9 , 10 ]. These growing challenges and threats, as well as the established bioinformatics databases, lead to the fast expansion of several detection methods for specific DNA and RNA sequences [ 11 , 12 , 13 ]. The conventional methods that are commonly used for the detection of specific base sequences are accurate and reliable, but they present some limitations such as technical complexity and the requirement of sophisticated instrumentations [ 14 , 15 ]. These limitations lead to an increasing development of electrochemical DNA biosensors because they provide a simple and low-cost detection method that can be used quickly and efficiently in a point-of-care environment and for a wide range of applications [ 16 , 17 ].
The immobilization of a single-stranded DNA (ssDNA) probe on the electrode surface to recognize its complementary target sequence through a hybridization process is the crucial step in the fabrication of electrochemical DNA biosensors [ 29 ]. There are several approaches for immobilizing an ssDNA probe such as electrostatic adsorption [ 30 ], avidin-biotin interaction [ 31 ], and covalent bonding [ 32 ]. The covalent bonding of ssDNA to the electrode surface has been widely adopted as the usual method for the preparation of DNA biosensors. This approach is preferred because it allows a high binding strength and good vertical orientation, which can result in high hybridization efficiency with the complementary target sequence [ 33 ]. The ssDNA capture probe is usually linked with thiol [-SH] or amine [-NH 2 ] groups at the 5′-terminal end to make covalent bonding with metal or specific functional groups introduced to the electrode surface [ 34 , 35 ]. The modification of the ssDNA capture probe with some common functional groups used for covalent immobilization can be, however, a tedious and expensive process. The immobilization of a non-modified ssDNA capture probe as an alternative is usually done by electrostatic adsorption but it has some limitations such as the high risk of desorption from the electrode surface, as well as the random orientation of the immobilized ssDNA capture probe, which can influence the hybridization efficiency with the complementary target sequence [ 36 ]. The development of an immobilization strategy based on the covalent bonding of a non-modified ssDNA capture probe can therefore be an interesting and effective alternative to the usual immobilization methods.
Different approaches have been explored for the detection of hybridization between the immobilized ssDNA capture probe and the complementary target sequence. These approaches include direct detection methods based on guanine bases oxidation [ 37 ], as well as indirect methods based on nanoparticles [ 38 ], enzyme-labels [ 39 ], and redox-active indicators [ 40 ]. The incorporation of redox-active indicators to the DNA surface is the most popular way to monitor hybridization between the immobilized ssDNA capture probe and the complementary target sequence [ 41 ]. These redox-active indicators include metal complexes such as Co(phen) 3 3+ and Ru(NH 3 ) 6 3+ [ 42 , 43 ], anticancer drugs such as daunomycin and doxorubicin [ 44 , 45 ], and some organic dyes such as meldola blue and methylene blue [ 46 , 47 ]. The use of methylene blue (MB) as an electrochemical redox hybridization indicator has become a popular choice because of its great benefits including low required potential and high discrimination of binding affinities between single and double-stranded DNA sequences. The pioneering work on the use of MB as an electrochemical hybridization indicator has been successfully demonstrated by Erdem et al. [ 48 ]. Their work reported that the obtained MB current response was higher at the ssDNA-modified electrode in comparison with the dsDNA-modified electrode. The research group concluded that this finding is essentially due to the high affinities of MB to the free guanine bases on ssDNA and that less accessible guanine bases after hybridization because of the formation of DNA duplex leads to a low current response. This conclusion was in agreement with other previous studies and shows that this interaction can be used as an effective approach for the electrochemical monitoring of the hybridization process [ 49 , 50 , 51 , 52 ].
Here we present an alternative approach for the fabrication of electrochemical DNA biosensors based on the covalent immobilization of a non-modified ssDNA capture probe from its 5′-terminal phosphate group. The low-cost PGE modified with AuNPs/CB was used as an electrochemical platform and the non-modified ssDNA capture probe was immobilized on a self-assembled cysteamine-modified AuNPs/CB–PGE through a phosphoramidate bond between the 5′-terminal phosphate group of ssDNA and the primary amine group of cysteamine. The microRNA-21 was used as a model in the fabrication of this electrochemical DNA biosensor and the hybridization process with the complementary probe was monitored by differential pulse voltammetry using MB as an electrochemical hybridization indicator. The fabricated electrochemical DNA biosensor was further used to analyze microRNA-21 in (spiked) human serum sample to investigate if it can be used as an electrochemical DNA biosensor for a wider range of applications that cover the fields of medical diagnostic and environmental monitoring.
2. Materials and Methods
2.1. Chemicals and Reagents
Carbon black (CB) N220 (32 nm) was obtained from Cabot Corporation (Ravenna, Italy). Dimethylformamide (DMF) was purchased from VMW International (Roquemaure, France). Chloroauric acid (HAuCl
4
) was purchased from Sigma-Aldrich (Saint Louis, MO, USA). Sulfuric acid (H
2
SO
4
) and potassium nitrate (KNO
3
) were obtained from Loba Chemie (Mumbai, India). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was purchased from Merck (Darmstadt, Germany). Methylene blue (MB) was obtained from Breckland Scientific Supplies (Norfolk, UK). Bovine serum albumin (BSA) was obtained from VWR Life Science (Dublin, Ireland). Cysteamine (CysAm) and imidazole were obtained from Sigma-Aldrich (Buchs, Switzerland). All other chemicals and reagents were of analytical grade and used without further purification. All buffers were prepared in ultrapure water obtained from a Millipore Milli-Q purification system (18.2 MΩ·cm).
The synthesized and HPLC-purified oligonucleotides used in this study were obtained from Eurofins Genomics (Ebersberg, Germany). The oligonucleotide sequences are as follows: 5′–TCA ACA TCA GTC TGA TAA GCT A–3′ (complementary sequence of microRNA-21); 5′–UAG CUU AUC AGA CUG AUG UUG A–3′ (target microRNA-21 sequence); and 5′–UCC CUG AGA CCC UUU AAC CUG UGA–3′ (non-complementary microRNA-125a sequence). Stock solutions (100 µM) of all oligonucleotides were prepared with ultrapure water and kept frozen at −20 °C until use.
2.2. Apparatus and Instruments
The electrochemical measurements were carried out using PalmSens 2 Potentiostat obtained from PalmSens BV and the control and data acquisition were done through PSTrace 5.9 software from PalmSens BV (Houten, The Netherlands). The OriginPro 2022 (9.9) software from OriginLab (Northampton, MA, USA) was used for data analysis and graphing. The measurements were based on a conventional three-electrode system. The Ag/AgCl electrode was used as a reference electrode and a platinum wire was used as a counter electrode. The graphite lead (Faber-Castell HB 0.5 mm) was used as a working electrode called a pencil graphite electrode (PGE). The mechanical pencil (Pentel P250) was used as a holder for the graphite lead. The electrical contact with the lead was established by soldering a metallic wire to the metallic part of the mechanical pencil. The pencil lead was retained vertically with 1.5 cm of the lead protruding outside and 1 cm submerged in the solution. All measurements were performed at room temperature (20–25 °C).
The characterization with Fourier transform infrared (FTIR) spectroscopy was recorded with an IRAffinity-1S spectrophotometer (SHIMADZU) in the range of 2000–500 cm
−1
at the attenuated total reflectance mode.
2.3. Preparation of AuNPs/CB Modified PGE
The PGE was pretreated in an acetate buffer solution (20 mM, pH 4.8) containing 20 mM NaCl and at an applied potential of +1.4 V during 60 s.
The pretreated PGE was incubated in 100 µL of CB dispersion during 1 h and kept drying for 20 min to obtain CB-modified PGE. The CB dispersion was prepared by sonicating 10 mg of CB in 10 mL of DMF for 1 h. The AuNPs synthesis was carried out onto the CB-modified PGE surface from an aqueous solution of 0.1 M KNO 3 containing 2 mM of HAuCl 4 by using cyclic voltammetry in a potential range from +0.9 to −0.3 V and at a scan rate of 50 mV·s −1 as reported in [ 53 ]. The AuNPs/CB-modified PGE was activated by running cyclic voltammetry in a potential range from +0.2 to +1.6 V in 0.5 M H 2 SO 4 until a reproducible voltammogram was obtained and then the AuNPs/CB-modified electrode was washed with ultrapure water.
2.4. Preparation of Self-Assembled CysAm Monolayer and ssDNA Immobilization
The AuNPs/CB-modified PGE was incubated in 100 µL of 0.1 M of CysAm and allowed to react for 2 h at room temperature. After that, the self-assembled CysAm monolayer with primary amine groups was formed and then the surface of the electrode was washed with ultrapure water before the ssDNA immobilization. The CysAm/AuNPs/CB-modified PGE was immersed in an imidazole buffer solution (0.1 M, pH 6.0) containing 0.1 M EDC and then allowed to react with the non-modified ssDNA overnight at 4 °C. The incorporation of imidazole with EDC allows the activation of the 5′-terminal phosphate group of the ssDNA capture probe by forming a highly reactive diester intermediate known as phosphorylimidazolide, as shown in
Scheme 1
. The reactive phosphorylimidazolide will react with the primary amine group of CysAm to form a phosphoramidate bond with the non-modified ssDNA capture probe.
The obtained ssDNA/CysAm/AuNPs/CB-modified PGE was washed several times with phosphate-buffered saline (PBS) (0.1 M, pH 7.4) to remove the unimmobilized ssDNA capture probe and then immersed in BSA solution 1% (
m
/
v
) for 20 min at room temperature to avoid nonspecific adsorption on the modified electrode surface.
2.5. MicroRNA-21 Hybridization and Electrochemical Measurements
The hybridization is carried out through the incubation of the obtained modified electrode referred to as BSA/ssDNA/CysAm/AuNPs/CB/PGE in various concentrations of microRNA-21 ranging from 1.0 × 10
−8
to 5.0 × 10
−7
M in PBS buffer (0.1 M, pH 7.4) and kept for 30 min at room temperature. The obtained electrode after hybridization referred to as miRNA-21/BSA/ssDNA/CysAm/AuNPs/CB/PGE was washed several times with the same buffer to remove the non-hybridized target sequences and then immersed into Tris-HCl buffer (20 mM, pH 7.00) containing 20 µM MB and 20 Mm NaCl to avoid the electrostatic interactions between MB and ssDNA or ssDNA-microRNA-21 hybrids. The accumulation of the electrochemical indicator was done for 5 min and then the electrode was washed with the same Tris-HCl buffer containing 20 mM of NaCl.
The reduction signal of accumulated MB was performed by using differential pulse voltammetry in a potential range from +0.1 to −0.8 V with an amplitude of 10 mV and at a scan rate of 50 mV·s
−1
in Tris-HCl buffer (20 mM, pH 7.00) containing 20 mM of NaCl. The cyclic voltammetry measurements were conducted at a potential range from −0.2 to +0.65 V and at a scan rate of 50 mV·s
−1
in 5 mM [Fe (CN)
6
]
3−/4−
including 0.1 M KCl.
3. Results and Discussion
3.1. Electrochemical Characterization of Different Modified Electrodes
The cyclic voltammetry (CV) of different modified electrodes in 5 mM [Fe(CN)
6
]
3−/4−
redox couple containing 0.1 M KCl at a scan rate of 50 mV·s
−1
is shown in
Figure 1
. The bare PGE (A) shows a couple of quasi-reversible and well-defined redox peaks of [Fe(CN)
6
]
3−/4−
. After modification of the PGE with CB (B) and CB/AuNPs (C), the redox peak current of [Fe(CN)
6
]
3−/4−
showed an increase, while the peak-to-peak separation was decreased compared to the bare PGE. These improvements could be attributed to the large specific surface area and good electron transfer capability of CB and AuNPs [
23
,
26
]. The redox peak current of [Fe(CN)
6
]
3−/4−
increased even more after the subsequent modification of AuNPs/CB/PGE with CysAm (D). This increase could be explained by the electrostatic attraction between the positive-charged amine groups of CysAm and the negative-charged [Fe(CN)
6
]
3−/4−
redox couple.
The properties of the modified electrodes were further investigated using the differential pulse voltammetry (DPV) reduction current of MB. Figure 2 shows the reduction current of MB for different modified electrodes after incubation in 20 µM of MB for 5 min at Tris-HCl (20 mM, pH 7.00) containing 20 mM of NaCl and washing with the same Tris-HCl buffer containing 20 mM of NaCl.
The bare PGE shows a low reduction current of MB. The reduction current of MB showed an increase compared to the bare PGE after the modification with CB and CB/AuNPs. These improvements could be attributed to the large specific surface area and good electron transfer capability of CB and AuNPs. The reduction current decreased after the subsequent modification of AuNPs/CB/PGE with CysAm. This decrease is due to the electrostatic repulsion between the positive-charged amine groups of CysAm and the MB. These results confirm those obtained with CV.
3.2. Characterization of ssDNA Immobilization and Microrna-21 Hybridization
The covalent immobilization of the ssDNA capture probe on the surface of CysAm/AuNPs/CB/PGE was realized through a phosphoramidate bond between the 5′-terminal phosphate group of ssDNA and the amine group of the electrode. The CV of CysAm/AuNPs/CB/PGE before (D) and after (E) covalent immobilization of non-modified ssDNA in 5.0 mM [Fe(CN)
6
]
3−/4−
redox couple containing 0.1 M KCl at a scan rate of 50 mV·s
−1
is shown in
Figure 3
. The high redox peak current at CysAm/AuNPs/CB/PGE is attributed, as mentioned before, to the electrostatic attraction between the positive-charged amine groups of CysAm and the negative-charged [Fe(CN)
6
]
3−/4−
redox couple. The immobilization of the non-modified ssDNA capture probe on CysAm/AuNPs/CB/PGE caused a decrease in the redox peak current of [Fe(CN)
6
]
3−/4−
. This decrease is attributed to the electrostatic repulsion between the negative-charged phosphate backbone of the immobilized ssDNA capture probe and the negative-charged [Fe(CN)
6
]
3−/4−
redox couple. This result suggests that the ssDNA capture probe has been effectively immobilized to the electrode surface. The redox peak current of [Fe(CN)
6
]
3−/4−
decreased even further after the hybridization between the immobilized ssDNA capture probe and their complementary target sequence (F). This decrease is related to an increase in the negative-charged phosphate backbone resulting from the formation of ssDNA-microRNA-21 hybrids.
The covalent immobilization of the ssDNA capture probe was further investigated using the differential pulse voltammetry reduction current of MB.
Figure 4
shows the reduction current of MB before and after covalent immobilization of the ssDNA capture probe. The primary reduction current at CysAm/AuNPs/CB/PGE is attributed, as mentioned before, to the ability of CB and AuNPs to promote more electron transfers and to the large specific surface area. The immobilization of the ssDNA capture probe on CysAm/AuNPs/CB/PGE caused an increase in the reduction current of MB. This increase in the reduction current is actually due to the strong affinity between MB and the free guanine bases of the ssDNA capture probe. This result also confirms that the ssDNA capture probe has been effectively immobilized on the electrode surface.
The reduction current of MB was decreased after the hybridization between the immobilized ssDNA capture probe and its complementary microRNA-21 target sequence, as shown in
Figure 4
. This decrease is due to the ssDNA-microRNA-21 hybrids preventing the interaction between MB and guanine bases of the ssDNA capture probe. The differential pulse voltammetry results were in good agreement with those from CV. Both results of DPV and CV indicated that the electrochemical DNA biosensor has been successfully fabricated. Further investigation was done through infrared spectroscopy from 2000–500 cm
−1
as shown in
Figure 5
.
The region between 1550 and 1750 cm −1 has stronger bands that correspond to the N-H bending and double-bond stretching vibrations of DNA bases. Peaks around 1100 and 1245 cm −1 are attributed to the symmetric and antisymmetric phosphate stretching vibrations of the phosphate backbone of the immobilized ssDNA capture probe. These results are in good agreement with those from the CV and DPV, as well as with the observed vibrational modes from surface-immobilized ssDNA reported in the literature [ 54 ].
3.3. Optimization of the Immobilized ssDNA Capture Probe Concentration
The effects of ssDNA capture probe concentration on the performance of the constructed biosensor were investigated.
Figure 6
shows the reduction current of MB after the covalent immobilization of different concentrations of the ssDNA capture probe. The reduction current of MB increased with the increase in ssDNA capture probe concentration from 0.1 to 1 µM. This increase was actually due to the strong affinity between MB and the free guanine bases related to the immobilized concentration of the ssDNA capture probe. The reduction current of MB decreased beyond the ssDNA capture probe concentration of 1 µM. This decreased reduction current of MB observed at the ssDNA capture probe concentration of 10 µM could be due to the steric hindrance caused by the larger quantity of the immobilized ssDNA capture probe. The reduction current of MB obtained with the ssDNA capture probe concentration of 0.05 µM is less than the previously reported at the surface of CysAm/AuNPs/CB/PGE. This obtained reduction current of MB is due to the large free surface without ssDNA capture probes. This large free surface is blocked with BSA, which consequently decreases the electron transfer. The ssDNA capture probe concentrations of 0.1 and 1 µM were consequently evaluated to obtain the most optimal hybridization response. Both ssDNA probe concentrations of 0.1 and 1 µM are evaluated with three different concentrations of microRNA-21 to determine the most appropriate probe concentration for the quantitative analysis.
The capture probe concentration of 0.1 µM shows no significant difference before and after hybridization with 10, 50, and 500 nM of microRNA-21 target sequence concentrations (
Figure 7
A). This result could be attributed to the small amount of the immobilized ssDNA capture probe, which does not allow good hybridization even under the saturating concentration of microRNA-21. The ssDNA capture probe concentration of 1 µM shows a significant and proportional difference (
Figure 7
B). This is due to the sufficient concentration of the ssDNA capture probe, which allows a good and efficient hybridization with microRNA-21 target sequence concentrations. The ssDNA probe concentration of 1 µM was selected as the optimal capture probe concentration according to the MB reduction current obtained results.
3.4. Hybridization Selectivity and the Quantitative Analysis
The selectivity of the fabricated biosensor was evaluated through hybridization between the capture probe and its complementary and non-complementary (microRNA-125a) sequence. The change in the reduction current of MB after hybridization with complementary and non-complementary target sequences is shown in
Figure 8
. The reduction current of MB was decreased using the complementary target sequence and it obviously shows that hybridization occurs successfully. The reduction current of MB was not changed significantly after the interaction with the non-complementary target sequence and it indicates that there is no successful hybridization. This means that the surface properties of the fabricated biosensor remained unchanged after its interaction with the non-complementary target sequence. These results demonstrate that the fabricated biosensor has good selectivity for discriminating differences between microRNA-21 and other non-complementary target sequences.
The quantitative analysis capability of the fabricated biosensor was also evaluated using different concentrations of microRNA-21. The change in the reduction current of MB (ΔI) after hybridization with different concentrations of microRNA-21 is shown in
Figure 9
. The ΔI was found to be well-proportional to the logarithmic value of the microRNA-21 concentration ranging from 1.0 × 10
−8
to 5.0 × 10
−7
M. The regression equation is ΔI = 0.68 × Log [miRNA-21] − 0.20 (R
2
= 0.9954) and the detection limit was estimated to be 1 nM (3σ). These results showed that the fabricated biosensor was good enough for the sensitive detection of microRNA-21 and showed encouraging results as a platform to use for other specific sequences related to some well-known diseases.
The developed electrochemical DNA biosensor reproducibility was studied using three parallel sensors known as CysAm/AuNPs/CB/PGE and modified with 1 µM of ssDNA probe and BSA (1%) and at two different concentrations of microRNA-21. At a small concentration of microRNA-21 (1.0 × 10
−8
M), the RSD% (n = 3) was equal to 2.91% and at high concentration (5.0 × 10
−7
M) the RSD% was equal to 5.24%, and this show that the fabricated electrochemical DNA biosensor has a satisfactory reproducibility for microRNA-21 detection.
There are, as discussed before and as shown in
Table 1
, several ssDNA immobilization strategies developed in recent years and they are all based on three important mechanisms: physical adsorption, biotin-avidin affinity interaction, and covalent bonding. Physical adsorption is the simplest immobilization method because it does not require any prior modification of ssDNA. In this case, the immobilization is based on electrostatic interaction occurring between the negative-charged phosphate backbone of ssDNA and the positive charges covering the surface of the sensor. The limitation of the physical adsorption method is the random orientation and weak attachment of ssDNA to the surface, as noted before. The covalent immobilization gives us good vertical orientation and high binding strength, but it presents also some limitations such as the need to modify the ssDNA with some functional groups such as the thiol [-SH], amine [-NH
2
], and carboxylic [-COOH] groups. The immobilization strategy presented in this work combines the advantages of physical adsorption and the covalent bonding and leads to the immobilization of the ssDNA capture probe without need for any prior modification and with vertical orientation and good binding capacity.
The obtained limit of detection, in contrast, seems to be relatively low and is, in consequence, more suitable for specific disease biomarkers, as well as for the monitoring of particular environmental pollutants. This introduced immobilization strategy, as well as using pencil graphite lead as a sensor, could be adapted with modern amplification strategies based on enzymes [ 59 ] and nanozymes [ 60 ] for the detection of a wider range of disease biomarkers and for the monitoring of additional environmental pollutants.
3.5. Analysis of microRNA-21 in Serum Sample
The analysis of microRNA-21 was performed in diluted serum (20×). Different concentrations of MiRNA-21 were added to the human serum sample. Table 2 shows the average ΔI current obtained for three different concentrations of microRNA-21. The obtained results in Table 2 also showed a recovery of 98.4–102.13%.
These results suggest that the fabricated DNA biosensor has an acceptable detection performance in (spiked) human serum and it can be practically applied to detect microRNA-21 in real samples.
4. Conclusions
In conclusion, we have reported a simple and cost-effective alternative approach to the traditionally used covalent immobilization strategies. The presented method is based on the covalent immobilization of a non-modified ssDNA through a phosphoramidate bond between the 5′-terminal phosphate group of ssDNA and the amine-modified electrode surface so as to develop electrochemical DNA biosensors. The microRNA-21 was used as a model in this work, and the encouraging results obtained on human serum sample using a modified pencil graphite lead as a sensor open the way for further developments and applications such as the fabrication of cheap and innovative electrochemical DNA biosensor devices. This immobilization method, as well as the used pencil graphite lead, can be adapted with modern amplification strategies for the detection of a wider range of disease biomarkers and for the monitoring of environmental pollutants.
Ethical review and approval were waived for this study due to the fact that the participants were not patients, but students and professors from our faculty who usually participates in blood donation, including the authors of this article. The participant data were anonymized and no personal identification data were included.
Conflicts of Interest
References
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Scheme 1. Attachment of the non-modified ssDNA capture probe from its 5′-terminal phosphate group to the CysAm-modified AuNPs/CB/PGE using a phosphoramidate-bonding strategy.
Scheme 1. Attachment of the non-modified ssDNA capture probe from its 5′-terminal phosphate group to the CysAm-modified AuNPs/CB/PGE using a phosphoramidate-bonding strategy.
Figure 1. Cyclic voltammograms of bare PGE (A), CB/PGE (B), AuNPs/CB/PGE (C), and CysAm/AuNPs/CB/PGE (D) recorded in 5 mM [Fe(CN) 6 ] 3−/4− containing 0.1 M KCl.
Figure 1. Cyclic voltammograms of bare PGE (A), CB/PGE (B), AuNPs/CB/PGE (C), and CysAm/AuNPs/CB/PGE (D) recorded in 5 mM [Fe(CN) 6 ] 3−/4− containing 0.1 M KCl.
Figure 2. Differential pulse voltammetry reduction current of MB on bare PGE (RSD% = 5.55%), CB/PGE (RSD% = 8.43%), AuNPs/CB/PGE (RSD% = 1.19%), and CysAm/AuNPs/CB/PGE (RSD% = 3.73%) after incubation 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 2. Differential pulse voltammetry reduction current of MB on bare PGE (RSD% = 5.55%), CB/PGE (RSD% = 8.43%), AuNPs/CB/PGE (RSD% = 1.19%), and CysAm/AuNPs/CB/PGE (RSD% = 3.73%) after incubation 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 3. Cyclic voltammograms of CysAm/AuNPs/CB/PGE (D), BSA/ssDNA/CysAm/AuNPs/CB/PGE (E), and miRNA-21/BSA/ssDNA/CysAm/AuNPs/CB/PGE (F) recorded in 5 mM [Fe(CN) 6 ] 3−/4− containing 0.1 M KCl.
Figure 3. Cyclic voltammograms of CysAm/AuNPs/CB/PGE (D), BSA/ssDNA/CysAm/AuNPs/CB/PGE (E), and miRNA-21/BSA/ssDNA/CysAm/AuNPs/CB/PGE (F) recorded in 5 mM [Fe(CN) 6 ] 3−/4− containing 0.1 M KCl.
Figure 4. Differential pulse voltammetry reduction current of MB on CysAm/AuNPs/CB/PGE (RSD% = 3.73%), BSA/ssDNA/CysAm/AuNPs/CB/PGE (RSD% = 4.18%), and miRNA-21/BSA/ssDNA/CysAm/AuNPs/CB/PGE (RSD% = 5.24%) after incubation in 20 µM of MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and being washed with the same buffer including 20 mM NaCl (n = 3).
Figure 4. Differential pulse voltammetry reduction current of MB on CysAm/AuNPs/CB/PGE (RSD% = 3.73%), BSA/ssDNA/CysAm/AuNPs/CB/PGE (RSD% = 4.18%), and miRNA-21/BSA/ssDNA/CysAm/AuNPs/CB/PGE (RSD% = 5.24%) after incubation in 20 µM of MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and being washed with the same buffer including 20 mM NaCl (n = 3).
Figure 5. FTIR spectra of immobilized ssDNA capture probe on the CysAm/AuNPs/CB/PGE.
Figure 5. FTIR spectra of immobilized ssDNA capture probe on the CysAm/AuNPs/CB/PGE.
Figure 6. Differential pulse voltammetry reduction current of MB on CysAm/AuNPs/CB/PGE after immobilization of different concentrations of the ssDNA capture probe from 0.05 to 10 µM (RSD% = 9.69%, 3.81%, 4.18%, 8.68%). Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 6. Differential pulse voltammetry reduction current of MB on CysAm/AuNPs/CB/PGE after immobilization of different concentrations of the ssDNA capture probe from 0.05 to 10 µM (RSD% = 9.69%, 3.81%, 4.18%, 8.68%). Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 7. Differential pulse voltammetry reduction current of MB on BSA/ssDNA/CysAm/AuNPs/CB/PGE after the immobilization of 0.1 µM ( A ) (RSD% = 7.20%, 3.76%, 4.25%) and 1 µM ( B ) (RSD% = (5.28%, 2.75%, 5.24%) of ssDNA capture probe and the incubation with 10, 50, and 500 nM of microRNA-21 target concentration. Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 7. Differential pulse voltammetry reduction current of MB on BSA/ssDNA/CysAm/AuNPs/CB/PGE after the immobilization of 0.1 µM ( A ) (RSD% = 7.20%, 3.76%, 4.25%) and 1 µM ( B ) (RSD% = (5.28%, 2.75%, 5.24%) of ssDNA capture probe and the incubation with 10, 50, and 500 nM of microRNA-21 target concentration. Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 8. Differential pulse voltammetry reduction current of MB on BSA/ssDNACysAm/AuNPs/CB/PGE before and after hybridization with complementary (microRNA-21) (RSD% = 2.75%) and non-complementary (microRNA-125a) sequences (RSD% = 2.81%). Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 8. Differential pulse voltammetry reduction current of MB on BSA/ssDNACysAm/AuNPs/CB/PGE before and after hybridization with complementary (microRNA-21) (RSD% = 2.75%) and non-complementary (microRNA-125a) sequences (RSD% = 2.81%). Incubation in 20 µM MB at Tris-HCl buffer (20 mM, pH 7.00) including 20 mM NaCl for 5 min and washing with the same buffer including 20 mM NaCl (n = 3).
Figure 9. Calibration curve of ΔI value of current response of MB as a function of different microRNA-21 target concentration (from 1.0 × 10 −8 to 5.0 × 10 −7 M). The concentration of the capture probe was 1 µM. Measurements (DPV) were done in Tris–HCl buffer (20 mM, pH 7.0) including 20 mM of NaCl.
Figure 9. Calibration curve of ΔI value of current response of MB as a function of different microRNA-21 target concentration (from 1.0 × 10 −8 to 5.0 × 10 −7 M). The concentration of the capture probe was 1 µM. Measurements (DPV) were done in Tris–HCl buffer (20 mM, pH 7.0) including 20 mM of NaCl.
Table 1. Comparison of different strategies of ssDNA probe immobilization on different matrix.
Table 1. Comparison of different strategies of ssDNA probe immobilization on different matrix.
Immobilization Matrix Immobilization Technique Chemical Interaction DNA Modification Advantages Drawbacks LOD (M) Ref. Poly-L-Lysine Adsorption Electrostatic adsorption No modification Simple, fast, and direct (no linker molecules) Desorption risk and random orientation 4.4 × 10 −9 [ 49 ] Chitosan 1.6 × 10 −11 [ 55 ] Avidin-Chitosan/MWCNTs Avidin-Biotin Avidin-Biotin affinity Biotin-modified DNA Improved orientation, high specificity, and reversible Use of biocompatible linker and expensive 1.0 × 10 −16 [ 56 ] Avidin-MWCNTs 1.5 × 10 −7 [ 57 ] GTD/Chitosan-MWCNTs Covalent Aldimine bond Amine-modified DNA Good orientation, high binding strength, and adaptative linker Use of linker molecules and expensive 8.5 × 10 −14 [ 33 ] Cysteine film Au-S bond Thiol-modified DNA 18 × 10 −8 [ 58 ] CysAm/AuNPs/CB Covalent Phosphoramidate bond No modification Good orientation, high binding strength, and no linker molecules needed Reaction time and irreversible 1 × 10 −9 This work
Table 2. Analytical results for microRNA-21 detection in (spiked) diluted (20×) human serum sample using the fabricated electrochemical DNA biosensor (n = 3).
Table 2. Analytical results for microRNA-21 detection in (spiked) diluted (20×) human serum sample using the fabricated electrochemical DNA biosensor (n = 3).
Added (nM) Detected (nM) ΔI (µA) Recovery (%) RSD (%) 10 9.84 0.443 98.4 2.15 50 47.37 0.942 94.74 2.75 125 127.66 1.309 102.13 2.87
| https://www.mdpi.com/1424-8220/22/23/9420/xml |
McCallon v. Key Energy Servs., 20-634 - Louisiana - Case Law - VLEX 917008181
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Louisiana
McCallon v. Key Energy Servs., 20-634
Court Court of Appeal of Louisiana (US) Writing for the Court KYZAR, Judge Citation 343 So.3d 844 Parties Michael MCCALLON v. KEY ENERGY SERVICES Docket Number 20-634 Decision Date 15 December 2021
343 So.3d 844
Michael MCCALLON v. KEY ENERGY SERVICES
20-634
Court of Appeal of Louisiana, Third Circuit.
December 15, 2021
Michael Edward Parker, Allen & Gooch, Post Office Drawer 81129, Lafayette, LA 70598-1129, (337) 291-1000, COUNSEL FOR DEFENDANT/APPELLANT: Key Energy Services
Brian D. Calvit, 7920 Wrenwood Blvd, Suite F, Baton Rouge, LA 70809, (225) 926-2222, COUNSEL FOR PLAINTIFF/APPELLEE: Michael McCallon
Court composed of Billy Howard Ezell, Van H. Kyzar, and Jonathan W. Perry, Judges.
KYZAR, Judge
343 So.3d 847
On September 2, 2020, the Office of Workers’ Compensation (OWC) granted Plaintiff Michael McCallon's Motion to Enforce Judgment, awarding temporary total indemnity benefits from the time period of August 2015 to June 2016, medical expenses, interests and costs, penalties pursuant to La.R.S. 23:1201 (F), and attorney fees. Both parties appealed the judgment of the workers’ compensation judge, with Plaintiff's appeal being lodged under docket number 20-635. For the reasons found herein and in the corresponding appeal McCallon v. Key Energy Servs., LLC , 20-635 (La.App.3 Cir. 12/15/21), 342 So.3d 1059 , we affirm as amended.
FACTS AND PROCEDURAL HISTORY
This workers’ compensation claim arises out of an automobile accident which occurred on February 3, 2015, in Williston, North Dakota. Plaintiff eventually filed a motion to enforce judgment, and Plaintiff and Key Energy both appealed that judgment of the workers’ compensation judge (WCJ). The facts and history of this case are laid out in Plaintiff's corresponding appeal McCallon v. Key Energy Servs., LLC , 20-635 (La.App.3 Cir. 12/15/21), 342 So.3d 1059 .
In its appeal, Key Energy asserts the following assignments of error:
1. The WCJ erred in granting plaintiff's motion to enforce this Court's judgment of April 24, 2019.
2. The WCJ erred in failing to consider the tender of funds calculated to be due under this Court's judgment of April 24, 2019 sent to plaintiff through his lawyer on October 1, 2019.
3. The WCJ erred in failing to follow this Court's judgment that granted Key Energy Services, LLC a $12,500 credit against all indemnity due between August 4, 2015 and June 21, 2016.
4. The WCJ erred in failing to follow this Court's judgment of April 24, 2019 that granted Key Energy Services, LLC a dollar-for-dollar credit for any compensation benefits that may be owed after June 21, 2016.
5. The WCJ erred in failing to give Key Energy Services, LLC credit for medical expenses paid by plaintiff's health insurer.
6. The WCJ erred in awarding $561.20 in medical expenses to plaintiff.
7. The WCJ erred in awarding costs of $3233.35 to plaintiff.
8. The WCJ erred in awarding penalties under La. R.S. 23:1201 (F) in the amount of $4000 and attorney[ ] fees in the amount of $12,000.
DISCUSSION
Plaintiff's Motion to Enforce
Key Energy's first two assignments of error assert its belief that Plaintiff's Motion to Enforce was granted in error because the judgment in question had already been honored. In McCallon v. Key Energy Services, LLC , 18-880, pp. 19-20 (La.App.3 Cir. 4/24/19), 271 So.3d 249 , 262-63, writ denied , 19-850 (La. 9/17/19), 279 So.3d 381 , this court ruled on the question of whether Plaintiff forfeited his right to benefits because of his settlement with a third-party tort-feasor, issuing the following disposition:
For the reasons discussed herein, the WCJ's judgment is reversed to the extent that it holds that Michael McCallon forfeited compensation benefits before June 21, 2016; it is amended to provide that Michael McCallon is entitled to reserve his right to future compensation as provided by La.R.S. 23:1102(B) ; it is also amended to award Michael McCallon
343 So.3d 848
$4,000 in penalties and $12,000 in attorney fees; and the matter is remanded to the trial court for calculation of the offset due Key Energy Services, LLC. for medical expenses paid on behalf of Michael McCallon by his health insurer. The judgment is affirmed in all other respects. All costs are assessed to Key Energy Services, LLC.
After the denial of writs from the supreme court, the judgment in this matter became final and definitive on October 1, 2019.La.Code Civ.P. art. 2167. Key Energy then tendered to Plaintiff $28,079.67, as follows: $11,619.42 representing weekly indemnity benefits plus interest owed from August 4, 2015 to April 16, 2016 less a credit of $12,500; and $16,460.27 representing the penalties and attorney fees awarded by this court. Key Energy contends this represents the entirety of its obligations under the judgment of this court, and thus, the WCJ erred in granting Plaintiff's motion to enforce judgment.
However, this court ruled that Plaintiff was entitled to indemnity benefits from the period of August 4, 2015 to June 21, 2016. McCallon , 271 So.3d 249 . Key Energy does not deny that indemnity benefits were only paid for the period between August 4, 2015 to April 16, 2016, the date of Plaintiff's subsequent automobile accident. Rather, it argues its belief that the June 21, 2016 date was chosen in error, stating, "There is still a question as to where the June 21, 2016 date came from[.]"We disagree.
In McCallon , 271 So.3d 249 , this court noted the testimony of Plaintiff's doctor that, before the April 2016 accident, he anticipated being able to release Plaintiff in June 2016. The forfeiture clause of La.R.S. 23:1102(B) relied upon by Key Energy, states, in pertinent part:
If the employee or his dependent fails to notify the employer or insurer of the suit against the third person or fails to obtain written approval of the compromise from the employer and insurer at the time of or prior to such compromise, the employee or his dependent shall forfeit the right to future compensation, including medical expenses.
The future compensation that an injured claimant forfeits for failing to obtain the consent or approval of his employer prior to settling his claim with a third party means any workers’ compensation benefits that became payable after the compromise. Bolton v. Tulane Univ. , 99-970 (La.App.4 Cir. 3/1/00), 755 So.2d 1003 , writ granted , 00-922 (La. 5/26/00), 762 So.2d 626 , and writ granted , 00-932 (La. 5/26/00), 762 So.2d 627 . This court found that Plaintiff was entitled to benefits, at minimum, through June 21, 2016. McCallon , 271 So.3d 249 . We also found Plaintiff was entitled to reserve his right to future compensation past that date pursuant to provisions of La.R.S.23:1102(B). Id.
This court issued a final judgment...
Lonesome Dev., LLC v. Town of Abita Springs, DOCKET NUMBER 2021 CA 1463 United States Court of Appeal of Louisiana (US) June 29, 2022 ...record evidence factually demonstrates that Ms. Chatelain, Mr. Thibodeaux, the Planning and Zoning Commission, and the Board of Aldermen 343 So.3d 844 approved the grading plan during the preliminary plat approval process and no further documentation by Lonesome would be required. We agree ......
| https://case-law.vlex.com/vid/mccallon-v-key-energy-917008181 |
(PDF) Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) adnexectomy for benign pathology compared with laparoscopic excision (NOTABLE): A protocol for a randomised controlled trial
PDF | Introduction Natural orifice transluminal endoscopic surgery (NOTES) uses natural orifices to access the cavities of the human body to perform... | Find, read and cite all the research you need on ResearchGate
Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) adnexectomy for benign pathology compared with laparoscopic excision (NOTABLE): A protocol for a randomised controlled trial
DOI: 10.1136/bmjopen-2017-018059
Peter De Mulder
Abstract
Introduction
Natural orifice transluminal endoscopic surgery (NOTES) uses natural orifices to access the cavities of the human body to perform surgical interventions. NOTES limits the magnitude of surgical trauma and potentially reduces postoperative pain. Our group published a protocol on a randomised study comparing transvaginal NOTES (vNOTES) versus laparoscopy for hysterectomy (HALON). We simultaneously designed a similar randomised controlled trial (RCT) comparing vNOTES with laparoscopy for adnexectomy. To the best of our knowledge, this is the first RCT comparing vNOTES with laparoscopy for adnexal surgery.
Methods and analysis
The methodology of the Notes Adnexectomy for Benign Indication versus Laparoscopic Excision (NOTABLE) study is similar to that of the HALON trial. Women aged 18–70 years with an indication for benign adnexal surgery will be eligible. We will use stratification according to adnexal size. Entrants will be randomised to the laparoscopic treatment (control) or vNOTES (intervention). Participants will be evaluated on days 0–7 and at 3 and 6 months. The primary outcome will be the proportion of women successfully treated by removing an adnexa by the allocated technique without conversion. We will collect the following data (secondary outcomes): proportion of women hospitalised on the day of surgery, postoperative pain scores measured two times per day from day 1 to 7, total dosage of pain killers used from day 1 to 7, hospital readmission during the first 6 weeks, dyspareunia and sexual well-being at baseline, 3 and 6 months using a validated questionnaire (Short Sexual Functioning Scale), health-related quality of life at baseline, 3 and 6 months after surgery using a validated questionnaire (EQ-5D-3L), duration of surgical intervention, infection or other surgical complications and direct costs up to 6 weeks following surgery. For the primary outcome measure, a one-sided 95% CI of the difference in the proportions of women with a successful removal of the uterus by the randomised technique will be estimated. Non-inferiority will be concluded when 15% lies above the upper limit of this 95% CI.
Ethics and dissemination
The study was approved on 1 December 2015 by the EthicsCommitteeof the Imelda Hospital (registration no: 689), Bonheiden, Belgium. We aim to present the final results of the NOTABLE trial in peer-reviewed journals and at scientific meetings within 4 years after the start of the recruitment.
Trial registration number
NCT02630329.
160+ million publication pages
1
BaekelandtJF , etal . BMJ Open 2018; 8 :e018059. doi:10.1136/bmjopen-2017-018059
Open Access
Transvaginal natural orice
transluminal endoscopic surgery
(vNOTES) adnexectomy for benign
pathology compared with laparoscopic
excision (NOTABLE): a protocol for a
randomised controlled trial
Jan Filip Baekelandt, 1 Peter A De Mulder , 2 Ilse Le Roy , 2 Chantal Mathieu, 3,4
Annouschka Laenen, 5 Paul Enzlin, 6 Steven Weyers, 7 Ben W J Mol, 8,9
Jan J A Bosteels 1,12,7,10
To cite: BaekelandtJF , De
MulderPA, Le RoyI, etal .
Transvaginal natural orice
transluminal endoscopic
surgery (vNOTES) adnexectomy
for benign pathology
compared with laparoscopic
excision (NOTABLE): a
protocol for a randomised
controlled trial. BMJ Open
2018; 8 :e018059. doi:10.1136/
bmjopen-2017-018059
► Prepublication history and
additional material for this
paper are available online. T o
view these les, please visit
the journal online (http:// dx. doi.
org/ 10. 1136/ bmjopen- 2017-
018059).
Received 2 June 2017
Revised 14 November 2017
Accepted 24 November 2017
For numbered afliations see
end of article.
Correspondence to
DrJan FilipBaekelandt;
jan. baekelandt@ imelda. be
Protocol
ABSTRACT
Introduction Natural orice transluminal endoscopic
surgery (NOTES) uses natural orices to access
the cavities of the human body to perform surgical
interventions. NOTES limits the magnitude of surgical
trauma and potentially reduces postoperative pain.
Our group published a protocol on a randomised
study comparing transvaginal NOTES (vNOTES) versus
laparoscopy for hysterectomy (HALON). We simultaneously
designed a similar randomised controlled trial (RCT)
comparing vNOTES with laparoscopy for adnexectomy. T o
the best of our knowledge, this is the rst RCT comparing
vNOTES with laparoscopy for adnexal surgery.
Methods and analysis The methodology of the Notes
Adnexectomy for Benign Indication versus Laparoscopic
Excision (NOTABLE) study is similar to that of the HALON
trial. W omen aged 18–70 years with an indication for benign
adnexal surgery will be eligible. We will use stratication
according to adnexal size. Entrants will be randomised to the
laparoscopic treatment (control) or vNOTES (intervention).
Participants will be evaluated on days 0–7 and at 3 and
6 months. The primary outcome will be the proportion of
women successfully treated by removing an adnexa by the
allocated technique without conversion. We will collect the
following data (secondary outcomes): proportion of women
hospitalised on the day of surgery, postoperative pain scores
measured two times per day from day 1 to 7, total dosage
of pain killers used from day 1 to 7, hospital readmission
during the rst 6 weeks, dyspareunia and sexual well-being
at baseline, 3 and 6 months using a validated questionnaire
(Short Sexual Functioning Scale), health-related quality
of life at baseline, 3 and 6 months after surgery using a
validated questionnaire (EQ-5D-3L), duration of surgical
intervention, infection or other surgical complications and
direct costs up to 6 weeks following surgery. F or the primary
outcome measure, a one-sided 95% CI of the difference in
the proportions of women with a successful removal of the
uterus by the randomised technique will be estimated. Non-
inferiority will be concluded when 15% lies above the upper
limit of this 95% CI.
Ethics and dissemination The study was approved on
1 December 2015 by the EthicsCommitteeof the Imelda
Hospital (registration no: 689), Bonheiden, Belgium. W e
aim to present the nal results of the NOTABLE trial in
peer-reviewed journals and at scientic meetings within 4
years after the start of the recruitment.
Trial registration number NCT02630329.
BACKGROUND
Laparoscopic surgery has reduced surgical
morbidity and mortality. ‘Minimally invasive
surgery’ has moved even further forward with
newer techniques such as single incision lapa-
roscopic surgery and natural orifice translu-
minal endoscopy (NOTES) with or without
robot assistance.
The NOTES technique uses any natural
orifice (mouth, vagina, urethra or rectum) as
a possible access route facilitating a surgical
intervention in a cavity of the human body.
Clinical researchers at Johns Hopkins Univer-
sity first reported its use in 2004 in a preclin-
ical trial using an animal model. 1 Ever since
the clinical application of NOTES has been
Strengths and limitations of this study
► This study is a randomised controlled trial.
► The patients, the outcome assessors and the
personnel are blinded in this trial.
► This is a single-centre study.
► The generalisability of this study to a ‘real-life’
setting is limited due to the experimental setting of
the study.
► The use of non-therapeutic incisions for blinding
may confound the outcome pain.
2 BaekelandtJF , etal . BMJ Open 2018; 8 :e018059. doi:10.1136/bmjopen-2017-018059
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reported in many surgical procedures in ways that seem
to defy human imagination, appendectomy and chole-
cystectomy have been performed using the mouth and
the stomach as the access route. 2 3 The technique seems
feasible and safe in the hands of experienced surgeons
beyond their surgical learning curve. Observational
evidence (mostly case reports) has reported, moreover ,
that NOTES may cause less postoperative pain, a shorter
length of hospital stay, less complications and last but
not least, for female patients, improved cosmetic results.
The feasibility of scar-free surgery in combination with
reduced wound (trocar) complications may be tempting
for patients and their care providers. This may be a strong
facilitator for the widespread implementation of this new
surgical approach.
NOTES has gained popularity among general surgeons,
urologists and gastroenterologists over the past few years,
and its feasibility and safety in these domains have been
reported. 4 Although NOTES may be performed using
various entries including the stomach, oesophagus,
bladder and rectum, the majority of NOTES procedures
in women have been performed through the vagina. 5
This is not surprising because the colpotomy technique
has been used widely in vaginal prolapse surgery and for
benign adnexal surgery involving the extraction of large
specimens. Its use has been reported as a safe access. 6 7 T wo
variants of NOTES have been described in the present
literature. Hybrid NOTES combines the access through
the vagina with transabdominal assistance; pure NOTES
refers to procedures that involve only transluminal access.
The removal of one or both adnexa using a transvag-
inal NOTES (vNOTES) approach was described for
the first time by Lee and coworkers in 2012. 8 vNOTES
adnexectomy for benign pathology was introduced at
our department by the first author (JFB) in 2013. Our
group published three small case series on adnexal
removal (n=20), 9 salpingectomy (n=5) 10 and hysterec-
tomy (n=10) 11 by vNOTES during the period between
November 2013 and February 2015. We also published the
protocol of the laparoscopy for hysterectomy (HALON)
study randomly comparing NOTES and laparoscopy for
doing hysterectomy in women with benign gynaecolog-
ical disease. 12 The recruitment of the HALON study was
finished recently (24 February 2017). The final data anal-
ysis of the HALON study is foreseen for September 2017.
Objectives and hypotheses
We started our research by doing a systematic review (SR)
of the literature. We searched MEDLINE, EMBASE and
the Cochrane Library from inception to 1 August 2015
using a combination of MeSH terms and key words for
‘colpotomy’ and ‘adnexal diseases’ or ‘adnexal mass’. We
aim to publish the results of this systematic search of the
literature and a critical appraisal of the retrieved evidence
in a separate SR: we will adhere to the Preferred Reporting
Items for Systematic Review and Meta-Analysis Protocols
guidelines 13 for the protocol of this SR. The protocol of
the SR has been registered in the International Prospective
Register of Systematic Reviews (PROSPERO) at the
Centre for Reviews and Dissemination (CRD), Univer-
sity of York, UK 14 as CRD42016033670. T o the best of our
knowledge, no randomised controlled studies comparing
vNOTES with the transabdominal laparoscopic approach
for removal of one or both adnexa have been published
in the literature. The main objective of the NOTABLE
study is to study the effectiveness of vNOTES for success-
fully removing one or both adnexa for benign gynaeco-
logical disease using the classical laparoscopic approach
as the established effective technique. The rationale and
the objectives of NOTABLE are in accordance with the
principles outlined by the Idea Development Exploration
Assessment Long term study (IDEAL) collaboration. 15–17
Our primary study hypothesis is that vNOTES is not
inferior to transabdominal laparoscopy for removing one
or both adnexa for a benign gynaecological indication
without having to convert to another technique. vNOTES
may offer several advantages including the avoidance of
abdominal scars, less need for hospital admission and
possibly less postoperative pain.
METHODS
Trial design and study analysis
The NOTABLE study should be considered as a pilot
study. It is a single-centre parallel-group double-blinded
(patient and outcome assessor) randomised trial
conducted at the Department of Gynaecology of the
Imelda Hospital in Bonheiden. This is a general hospital
in Belgium serving an estimated population of 150 000
people. All women aged 18–70 years bound to undergo
removal of one or both adnexa for benign gynaecological
disease will be informed about the NOTABLE study , and
they will be invited to participate in the study, if eligible.
The baseline characteristics of eligible women not wishing
to give informed consent for participating in the study will
be recorded as well as the reason for declining to partici-
pate. All surgical procedures (vNOTES and laparoscopy)
will be done by one surgeon (JFB) who is equally skilled
in both techniques. The surgeon has been using the
vNOTES approach for various interventions (salpingec-
tomy for Extra-Uterine Gravidity (EUG), adnexectomy
and hysterectomy) since November 2013. JFB is also the
surgeon performing the hysterectomies in the HALON
trial. The surgeon cannot be blinded, but the allocated
treatment will be concealed. We will use a non-inferi-
ority study design to test the effectiveness of vNOTES
compared with laparoscopy. The protocol adheres to the
Standard Protocol Items: Recommendations for Inter-
ventional T rials standards (http://www. spirit- statement.
org/). The study protocol of the NOTABLE trial is very
similar to that of the earlier published HALON study. 12
Study dates
The first patient was included on 15 January 2016. On
22 May 2017, 38 of the targeted 70 participants were
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recruited. Anticipated date of study completion is esti-
mated in May 2018.
Participants
NOTABLE will recruit eligible women aged 18–70 years,
regardless of parity, who need the removal of one or both
adnexa for a benign adnexal disease and who provide
informed consent prior to surgery.
Exclusion criteria are as follows:
► history of rectal surgery
► suspected rectovaginal endometriosis
► suspected malignancy
► history of pelvic inflammatory disease
► active lower genital tract infection
► virginity
► pregnancy
► failure to provide written informed consent.
Intervention, procedures and standard care
On the day of the surgery, all patients are admitted to the
day care unit. A nurse administers clindamycin vaginal
cream on admission.
Under general anaesthesia, the patient is positioned in
a vacuum mattress in the classical lithotomy. An alcoholic
Betadine solution is used for disinfection of the vagina,
vulva and abdomen before draping. A Foley catheter is
inserted into the bladder . In accordance with hospital
protocol, the anaesthesiologist will administer cefazolin
2 g and metronidazole 1.5 g intravenous prior to incision
for prophylaxis against infection to all women of both
treatment arms. In both groups, a 30° rigid endoscope
is used.
Control group: laparoscopic technique
The surgeon will start the procedure by making a small
vertical intraumbilical skin incision. A Veress needle is
introduced into the peritoneal cavity; the tip position
is checked with a Semm test before insufflating carbon
dioxide (CO 2 ) until a maximal intraperitoneal pressure
of 15 mm Hg. A 10 mm trocar is inserted through the
umbilicus after removal of the Veress needle. An optic is
inserted to inspect the peritoneal cavity. The operating
table is tilted in the T rendelenburg position. T wo 5 mm
trocars are placed under direct vision in the suprapubic
region and in the left iliac fossa lateral of the epigastric
vessels. The small intestine is lifted out of the pelvis.
The ureter is identified, but no retroperitoneal dissec-
tion is performed unless indicated. The proximal end of
the Fallopian tube is coagulated at its origin in the uterus
using a reusable bipolar grasping forceps before being
cut with cold microscissors. The ovarian and infundibu-
lopelvic ligament are coagulated and cut. After resection,
the adnexa is placed in an endobag (Memobag; T eleflex,
Wayne, Pennsylvania, USA). When indicated, the same
procedure is repeated for the contralateral side.
After confirmation of haemostasis, the peritoneal cavity
is rinsed. No drains are left in the peritoneal cavity unless
necessary, for example, problematic haemostasis. The
5 mm trocars are be removed under direct vision. The
purse string of the endobag is pulled through the 10 mm
trocar on removal of the optic. The umbilical incision
is extended vertically in caudal direction, but not more
than 2.5 cm. The fascia and peritoneum are opened, and
the proximal end of the endobag is pulled through the
incision without causing any rupture if possible. If not
possible, the endobag will be opened, and the content
of the cyst will be aspirated to reduce the volume of the
adnexa. The aspirated fluid will be sent for cytological
evaluation. The endobag will then be removed with the
adnexa inside it.
The fascia is closed using a Vicryl-1 running suture. The
umbilicus and other incisions are disinfected with Beta-
dine solution. All skin incisions are closed with a Monocryl
3/0 intradermal suture and approximated using steris-
trips. The wound sites are covered with a wound dressing.
A vaginal plug (Betadine gauze 10 cm×5 m) is inserted
into the vagina. After 3 hours, the Foley catheter and the
vaginal plug are removed.
Intervention group: vNOTES
The surgeon makes three non-therapeutic superficial
skin incisions on exactly the same location as in the clas-
sical laparoscopic approach in all women allocated to
the vNOTES group to blind study participants and the
outcome assessor to the allocated technique. A 2.5 cm
posterior colpotomy is made using a cold knife. The
pouch of Douglas is opened using scissors. A Gelpoint
Mini (Applied Medical), used as vNOTES port, is inserted
into the pouch of Douglas. CO 2 is insufflated until a
maximal intraperitoneal pressure of 15 mm Hg. An optic
is inserted to inspect the peritoneal cavity. The operating
table is tilted in the T rendelenburg position. The small
intestine is lifted out of the pelvis.
The ureter is identified, but no retroperitoneal dissec-
tion is performed unless indicated. The proximal end
of the Fallopian tube is coagulated at its origin into the
uterus using a reusable bipolar grasping forceps and cut
using microscissors. The ovarian and infundibulopelvic
ligament are coagulated and cut. The adnexa is removed.
When indicated, the procedure is repeated for the contra-
lateral side. After confirmation of haemostasis, the perito-
neal cavity is rinsed.
Small benign-looking adnexa is removed directly
through the wound protector part of the vNOTES port.
Large adnexa or adnexa that appears macroscopically
suspicious is placed in an endobag (Memobag; T eleflex).
The purse string of the endobag is pulled through the
wound protector , and the purse string released. The
content of the cyst is aspirated to reduce the volume
of the adnexa. The endobag is then removed with the
adnexa inside it. The vNOTES port is removed.
The colpotomy is closed using three interrupted
figure-of-eight Vicryl 2/0 sutures. A vaginal plug (Beta -
dine gauze 10 cm×5 m) is inserted into the vagina. After
3 hours, the Foley catheter and the vaginal plug are
removed.
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In the majority of patients, it is feasible to perform a
successful vNOTES or laparoscopic adnexectomy. W omen
in whom the intended approach has to be abandoned
for an alternative intervention will not be excluded or
withdrawn from the NOTABLE trial but will be followed
up further . It is anticipated that most included patients
with a normal cancer antigen 125 value, and benign
features of the ovary on ultrasound will not require other
interventions besides the removal of the adnexa. If the
responsible clinician judges that additional treatment is
necessary at the time of the surgery or afterwards, this
will be recorded and the patient will not be withdrawn
from the study. However , if there is a preoperative indi-
cation for additional surgery during the same procedure,
these patients will be excluded from recruitment to the
NOTABLE trial.
The anaesthesiologists involved in the clinical trial have
developed a standardised protocol to insure that the pain
management is identical for both groups. The outcome
assessor (JJAB) and the patient are both blinded to the
surgical approach used. The patient makes the decision
to be discharged from the day care unit on the evening of
the procedure or to be admitted to an in-hospital nursing
ward for the night. The outcome assessor can only over-
rule the patient’s decision in the interest of her health,
for example, when surgical complications were recorded
in the surgical report or when vital parameters indicate a
life-threatening condition. Before discharge, all patients
are given a standard list of instructions to avoid physical
work, exercise and sexual intercourse for 4 weeks after the
intervention.
All participants, regardless of being at home or in
hospital, are requested to use a Visual Analogue Scale
(VAS) two times per day to measure postoperative pain
from day 1 to day 7 following surgery. Adequate instruc-
tions on how to use the VAS measuring tool are given on
an individual basis by a dedicated nurse of the day care
unit. One measurement is made in the evening before
going to bed after physical activity (active), and another
is made in the morning after bed rest at night (rest). All
patients are asked to note the name, dosage and route of
administration of any analgesic drug taken from day 1 to
7 in a pain log book.
Outcome measure
We searched the COMET 18 database for a core outcome
set for adnexectomy (general settings) in gynaecology
(health area-disease category) in women (target popula-
tion: sex) aged 18 to 70 years (target population: age):
no core outcome set relevant to laparoscopic removal of
adnexa was identified. 19
Primary outcome measure
The proportion of women successfully treated by
removing one or both adnexa without spill by the allo-
cated technique as randomised will be measured as the
primary outcome of effectiveness.
Secondary outcome measures
The secondary outcomes are as follows:
► The proportion of women hospitalised on the day of
surgery based on their own preference.
► Postoperative pain scores measured using V AS 20 two
times per day from day 1 to 7.
► The total dosage of pain killers taken during the first
week following surgery.
► Postoperative infection defined by lower abdominal
pain with fever >38°C and positive clinical signs or
laboratory findings detected during the first 6 weeks
of surgery.
► Intraoperative or postoperative complications classi-
fied according to the Clavien-Dindo classification 21
detected during the first 6 weeks of surger y.
► Readmission to hospital during the first 6 weeks of
surgery.
► Occurrence and severity of pain on sexual intercourse
self-reported by the study participants at baseline, 3
and 6 months by using a simple questionnaire and
VAS.
► Sexual well-being at baseline, 3 and 6 months by
self-reporting the Short Sexual Functioning Scale
(SSFS). 22
► Health-related quality of life (QoL) at baseline, 3 and
6 months after surgery by self-reporting using a vali-
dated questionnaire (EQ-5D-3L).
► The duration of the surgical intervention measured in
minutes from the insertion of the bladder catheter to
the end of vaginal/abdominal wound closure.
► Direct costs for both techniques up to 6 weeks
following surgery.
The SSFS and the EQ-5D-3L questionnaires were vali-
dated in Dutch and presented to the participants in their
mother tongue.
Randomisation and blinding
Participants will be randomly allocated to one of both
treatment arms (vNOTES vs laparoscopy). We will use
a computer-generated randomisation schedule gener-
ated by the management assistant of our department.
We will use a stratification into three categories (A, B
or C) according to the size of the cyst on transvaginal
ultrasound (0 to 5 cm, 5 to 10 cm and larger than 10 cm).
Sequentially numbered, opaque, sealed envelopes will be
used to ensure allocation concealment for the surgeon
and the outcome assessor . The management assistant will
safeguard the allocation code until the last visit of the last
patient. The management assistant will not be involved in
the outcome assessment or the data collection.
All participating women and the outcome assessor will
be blinded to the allocation by the use of non-therapeutic
skin incisions. It is impossible to blind the surgeon. In case
of life-threatening adverse events, the outcome assessor
will notify the surgeon to enable further treatment
without the need for non-blinding the patient. The use of
the vNOTES technique avoids the use of abdominal inci-
sions. Participants allocated to the vNOTES arm will have
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three superficial non-therapeutic skin incisions similar
to those routinely done with the laparoscopic technique.
This enables blinding all study participants, personnel
and the outcome assessor . The wound dressings of all
women will be left untouched until the postoperative visit
on day 7. The practice of using non-therapeutic skin inci-
sions has been reported in some surgical trials to minimise
performance and detection bias when measuring subjec-
tive outcomes (eg, pain). 23 The decision to use non-thera-
peutic skin incisions is justified by the risk to benefit ratio
of the two interventions under comparison. 24 Its use in
the HALON and NOTABLE trials has been intensively
discussed among the investigators. The written approval
with the Belgian unique study identifier B689201526268
was sent to the Federal Agency for Medicines and Health
Products (FAMHP) in Brussels.
Statistical methods
Sample size calculation
A sample size calculation was done for the primary
outcome only. An appropriate level of statistical power was
applied to preclude any clinically important inferiority of
vNOTES compared with laparoscopy. The assumptions for
the sample size calculation are based on evidence retrieved
from two sources: a randomised study comparing the exci -
sion of mature dermoid cysts using colpotomy with laparo -
scopic assistance versus colpotomy without laparoscopy 25
and an SR with meta-analysis comparing single port lapa -
roscopy versus conventional laparoscopy in benign adnexal
disease. 26 An important consideration in any adnexal mass
surgery is the inadvertent opening of the ovarian capsule
of an unsuspected malignancy resulting in the spill of
malignant cells into the abdominal cavity. Based on a
2.4% failure rate to remove dermoid cysts by colpotomy
using laparoscopic assistance 25 and a 0% conversion rate
from laparoscopy to laparotomy, 26 we assumed that the
successful removal of adnexal cysts without spill would be
feasible in 95% of all cases. The sample size was calculated
with a one-sided test for non-inferiority for the primary
outcome. The vNOTES approach may be the treatment of
choice for women because it avoids scars. We assume that
vNOTES would be the preferred technique even when
15% less women had in the end a successful removal of
a benign adnexal mass by using vNOTES compared with
laparoscopy with its unavoidable scars. Non-inferiority will
be concluded when 15% lies above the upper limit of the
95% CI calculated for the difference in the proportion
of women successfully treated with either technique. T o
achieve 80% power to demonstrate non-inferiority under
the assumption of similar success rates of 95% in both
groups, a sample size of 54 participants (27 women per
group) will be required. We increased the target sample
size to 64 participants (32 women per group) to account
for a dropout rate of 15%. Based on the power calcula -
tions for the primary outcome, the use of three strata for
the randomisation and assuming a loss-to-follow-up rate
of 15%, we decided to include 66 study participants in the
NOTABLE trial.
Statistical analyses
General principles
For all baseline and outcome variables, the number
of available measurements and the number of missing
values will be given. A probability (P) less than 0.05
will be considered to be significant. Analysis will be
performed by intention-to-treat, as recommended
in the Consolidated Standards of Reporting T rials
(CONSORT) statement. 27 Since the study compares two
regular interventions and is expected to recruit during
a reasonably limited period, interim analyses will not be
performed.
Categorical data will be reported as absolute numbers
and percentages. Normally distributed continuous vari-
ables will be summarised as means with SDs, and non-nor-
mally distributed continuous variables will be reported as
medians with IQR. Main analyses will not impute missing
values.
All analyses will be performed using SAS software (V.9.4
of the SAS System for Windows).
DESCRIPTIVE ANAL YSES
Study population—baseline characteristics
► Mean age (±SD),
► Mean body mass index (BMI) (±SD),
► Mean number of natural vaginal births (±SD),
► Mean number of abdominal/pelvic surgical interven-
tions (±SD),
► Mean weight of the uterus (±SD).
STUDY ENDPOINTS
Main study parameter/endpoint
Differences in the proportions of women successfully
treated by removing the uterus by the intended technique
without conversion to another approach.
Secondary study parameters/endpoints
► Proportions of women hospitalised on the day of
surgery;
► Postoperative pain scores, measured using V AS two
times per day from day 1 to 7 self-reported by the
study participants;
► T otal dose analgesics used during the first week
following surgery;
► Incidence of postoperative infection during the first
6 weeks of surger y;
► Incidence of intraoperative complications;
► Incidence of postoperative complications during the
first 6 weeks following surgery;
► Incidence of readmission during the first 6 weeks of
surgery;
► Incidence of dyspareunia recorded by the participants
at baseline, 3 and 6 months by self-reporting using a
simple questionnaire;
► Severity of dyspareunia recorded by the participants at
baseline, 3 and 6 months by self-reporting using VAS;
6 BaekelandtJF , etal . BMJ Open 2018; 8 :e018059. doi:10.1136/bmjopen-2017-018059
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► Sexual well-being at baseline, 3 and 6 months by self-re-
porting the SSFS QoL at baseline, 3 and 6 months by
self-reporting the EQ-5D-3L questionnaire;
► Duration of surgery;
► T otal costs of both intervention surgeries.
STA TISTICAL ANAL YSIS
For the primary outcome measure, a one-sided 95% CI
of the difference in the proportions of women with a
successful removal of the uterus by the intended tech-
nique as randomised will be estimated. Non-inferiority
will be concluded when 15% lies above the upper limit
of this 95% CI.
For the manuscript, all above listed secondary outcomes
will be compared between the two groups. These data will
be reported as vNOTES versus laparoscopy.
For dichotomous secondary outcome measures,
comparisons between the two arms will be performed by
applying Fisher’s exact test or Χ 2 test, as appropriate.
Cross-sectionally measured continuous secondary
outcomes will be analysed using an independent t-test or
Mann–Whitney U test, as appropriate.
Longitudinally measured continuous secondary
outcomes will be analysed using multilevel modelling.
Differences in evolution between both treatment groups
will be compared by means of a time by group interaction.
In absence of such an interaction, mean differences will
be compared over all time points. Outcome scores will be
transformed if required to meet model assumptions.
All statistical analyses will be done by an experi-
enced biostatistician (AL) who is a coinvestigator . After
data cleaning, the management secretary will send the
non-blinded data to the biostatistician after the last visit of
the last patient. The biostatistician will do all the analyses
without any assistance of the other investigators who will
remain blinded until all data have been analysed.
The following strategy will be used in case of missing
data. In case of a single item response missing, the data
will be imputed from given values. In cases where more
than one item is missing or an entire form is missing,
imputation will not be attempted. We will assess whether
the obtained results are robust to the methods used to
handle missing data, by performing a sensitivity analysis.
MONITORING
NOTABLE is a small trial; therefore, a data monitoring
All adverse events reported spontaneously by the partic-
ipant or observed by the investigator or his staff will be
recorded. Infection and perioperative or postoperative
complications will be assessed as secondary outcomes
until 6 weeks after surgery. W e will inform the family physi-
cian of all participants in order to assess all possible unin-
tended effects of the trial intervention and promote to
report all possible adverse events anonymously using the
participant’s unique study number to an email address (
NOTES@ imelda. be). We will use descriptive statistics for
data analysis although the trial is not adequately powered
to detect important differences in rates of uncommon
adverse events. Given the limited resources and the single-
centre design, there will be no auditing of the conduct of
the trial. We will review patient enrolment, consent and
eligibility on a regular basis to promote data quality and
to preserve trial integrity. The distribution of the alloca-
tion to the study groups will be blindly checked by the
study secretary at 30%, 60% and 90% of the recruitment
and discussed with the study statistician and the principal
investigators.
RESULTS
Figure 1 shows the study flow reported as outlined by the
CONSORT ( figure 1 ).
Recruitment time frame
All potentially eligible women aged 18 to 70 years, regard-
less of parity, in need of adnexal surgery for benign
gynaecological disease without exclusion criteria will be
invited to participate in the trial. Only eligible women
with written informed consent obtained before randomi-
sation will be finally included in the NOTABLE trial.
We perform 36 interventions for adnexal surgery by lapa-
roscopy for benign gynaecological disease at our Depart-
ment of Gynaecology per year . The recruitment period of
NOTABLE to meet the sample size will be approximately
2 years. Including the follow-up period of 6 months after
the last patient last visit and the time required to perform
data analysis and reporting (6 months to 1 year), we esti-
mate that the total study period will be at least 3 years.
Data collection
We will record the following patient characteristics at
baseline: age, BMI, the number of vaginal births, previous
abdominal or pelvic surgery (C sections included),
adnexal size, concomitant medication, dyspareunia ques-
On the day of surgical intervention (day 0), we will
record the following data: the duration of the surgical
intervention, the successful removal of the adnexa by
the technique as allocated without conversion to another
technique with or without spilling (into the peritoneal
cavity or the endobag), hospitalisation of the participant
on the day of the surgical intervention based on her own
preference, the total dosage of analgesics used at the
recovery and day care unit and the maximum VAS pain
score on the day 0.
After 1 week at visit day 7, the outcome assessor will
collect the pain scores as self-reported by the study partic-
ipants two times per day from day 1 to day 7 using VAS.
The outcome assessor will also collect data on the total
dosage of pain killers used during the first postoperative
week.
At visit day 7 and day 42, the outcome assessor will
record the following data: pelvic infection defined by
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lower abdominal pain with fever >38°C and positive clin-
ical signs or laboratory findings, readmission to hospital
and the occurrence of other postoperative complications
classified according to the Clavien-Dindo classification.
On months 3 and 6 following surgery, the dyspareunia
questionnaires, the EQ-5D-3L and the SSFS question-
naires will be filled in by the study participants and
collected by regular mail. The management assistant will
oversee this process and send reminders until all ques-
tionnaires have been received. We refer to table 1 for an
overview of the data collection process ( table 1 ).
DISCUSSION
Interpretation, limitations and generalisability
The NOTABLE trial is a randomised pilot study on the
efficacy of the vNOTES technique. All surgical proce-
dures in the NOTABLE study are done by one single
surgeon (JFB) who is equally skilled in using both tech-
niques under comparison. The surgeon has been using
the vNOTES approach since November 2013. During
this 2-year period, the new technique and suitable instru-
ments used were pilot-tested and subsequently fine-tuned
by the usual ‘trial and error’ method used for centuries in
surgical practice. 17 The feasibility and preliminary safety
of the new technique were reported in three observational
studies performed at our department 9–11 in accordance
with the principles outlined in the three article series on
the IDEAL statement. 15–17 According to the terminology
used by the IDEAL collaboration, 17 this study should be
classified as an IDEAL stage 2b trial. The full Patient Inter-
vention Control Outcome (PICO) research question is as
follows: will a surgeon who is equally skilled at performing
both techniques, and beyond his learning curve for the
new technique (vNOTES), succeed in removing one
or both adnexa in women with benign gynaecological
disease at least as often with the new pilot-tested vNOTES
approach compared with the standard transabdominal
laparoscopic approach without having to convert to any
other technique. An intraoperative decision to remove
an adnexa via laparoscopy and not via vNOTES due to,
for example, a large specimen or an atrophic vagina may
better be defined as a pre-emptive conversion, as it has
less clinical implications than a conversion from laparos-
copy to laparotomy. However , for the sake of unambiguity
in this trial, we decided to count as a conversion every case
that was not treated by the allocated technique, whether
the conversion was pre-emptive or not.
NOTABLE aims to measure efficacy of vNOTES for
removing one or both adnexa (Can vNOTES work under
ideal experimental conditions?). The NOTABLE trial
Figure 1 CONSORT (Consolidated Standards of Reporting T rials) 2010 ow diagram. vNOTES, transvaginal natural orice
transluminal endoscopic surgery .
8 BaekelandtJF , etal . BMJ Open 2018; 8 :e018059. doi:10.1136/bmjopen-2017-018059
Open Access
does not address the effectiveness of the new interven-
tion at this moment (Does vNOTES work in a real-life
setting?). The conditions in NOTABLE are truly exper -
imental and in many instances opposed to ‘real life’
practice: all women are always treated by the most expe-
rienced surgeon equally skilled in using both techniques,
all women receive more attention during this trial than
the routine care given during standard clinical practice,
the dosage of anaesthetic drugs is calculated to limit any
side effect (nausea and vomiting) that may cause women
to be hospitalised on the day of the surgical interven-
tion, all outcomes measured are very relevant for women
in general and participants with adverse outcomes (eg,
dyspareunia and sexual dysfunction) will be recalled after
the end of the study for counselling and therapy. The
results of the NOTABLE trial will therefore have a limited
generalisability, and their interpretation will be done
cautiously. The testing of the safety and the cost-effective-
ness will be needed in the longer term using pragmatic
multicentre randomised controlled trials or a prospective
register .
As suggested by the IDEAL collaboration, more research
(large multicentre trials performed by adequately trained
surgeons in centres of clinical excellence and large
prospective registries cumulating data on the safety of the
new technique over many years) and adequate surgical
training will be needed before vNOTES can be offered
as a standard daily care surgical practice by a majority of
gynaecological surgeons for all women bound to undergo
removal of one or both adnexa for benign gynaecological
disease.
ETHICS AND DISSEMINATION
The NOTABLE trial will be conducted in accordance with
the ethical principles outlined in the latest version of the
‘Declaration of Helsinki’, the ‘Guideline for Good Clin-
ical Practice’ and the Belgian Law of 7 May 2004 related
to experiments on humans.
All eligible women wishing to participate in the study
will receive a detailed patient information document
about the study protocol, the aims of the research and
the possible adverse events related to the surgical tech-
University of Leuven, Leuven, Belgium
6 Department of Neurosciences, Interfaculty Institute for Family and Sexuality
Studies, KU Leuven-University of Leuven, Leuven, Belgium
7 Universitaire Vrouwenkliniek, Ghent University Hospital, Ghent, Belgium
8 The Robinson Institute, The University of Adelaide, Adelaide, South Australia,
Australia
9 School of Paediatrics & Reproductive Health, The University of Adelaide, Adelaide,
South Australia, Australia
10 CEBAM, The Centre for Evidence-based Medicine, Cochrane Belgium, KU Leuven-
University of Leuven, Leuven, Belgium
12 Academic Centre for General Practice, KU Leuven-University of Leuven, Leuven,
Belgium
Acknowledgements We thank the vNOTES investigators’ team for taking care of
the study participants. We also thank Amanda McPhail for language correction and
editing of the manuscript.
Contributors JFB is the surgeon responsible for all interventions in all study
participants. JJAB is the outcome assessor . JFB and JJAB conceived the study.
PADM and ILR are responsible for the draft of the pain protocol and the anaesthesia
for all trial participants. JJAB, JFB, PADM and ILR will be responsible for data
collection, quality analysis and storage. PE provided expertise for the sexuality
research involved in this clinical trial design. SW provided external review as a
content expert. CM provided external peer review on the scientic conduct of the
study. AL is responsible for the biostatistics involved in the design and conduct of
the trial, reviewed the SAP (Statistical Analysis Plan) of both HALON and NOT ABLE
and will perform all data analysis for both studies without any involvement of the
surgeon (JFB) and the outcome assessor (JJAB). BWJM provided external peer
review as a methodology expert. All authors contributed to the renement of the
study protocol and approved the nal manuscript. For the economic analyses, we
will seek assistance from a Health Economist at the University of Ghent or at the
Belgian Health Care Knowledge Centre.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Committee of Imelda Hospital Bonheiden, protocol no
B689201526268, 01/12/2015.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The study protocol can be found at ClinicalTrials. gov
study reference: NCT02630329.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY -NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http:// creativecommons. org/
licenses/ by- nc/ 4. 0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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Jan Baekelandt · Peter De Mulder · Ilse Le Roy · Chantal Mathieu · Jan Bosteels
... 14 The NOTABLE randomized controlled trial did not show any difference in sexual-function outcomes 6 months following surgery as measured by a sexual-function index.
15
Postoperative dyspareunia was seen in 5% of patients (n = 36) in an interventional nonrandomized trial by Tanaka et al.; however, this had completely resolved at the 2-month follow-up visit. 16 ...
... There is a learning curve associated with adoption of this technique. 17 Given extrapolated data showing potential increased complications in cases performed via vNOTES, as opposed to laparoscopy, for adnexal procedures in the NOTABLE trial,
15
adoption of this technique should only occur with care and appropriate training. 18 Further outcome data are required and will become available as more cases are added into the prospective complications registry that has been implemented by the international Natural Orifice Transluminal Endoscopic Surgery society (iNOTESs) registry. ...
Standardized Step-by-Step Approach to Ovarian Cystectomy via Vaginal Natural Orifice Transluminal Endoscopic Surgery
... (5) The anesthesia depth required for this procedure is shallow, which reduces the anesthesia risk. Combined with the advantages of V-NOTES in less pain, patients can get out of bed earlier, indirectly reducing the incidence of postoperative pulmonary atelectasis and lung infection and shortening the postoperative hospital stay and recovery time
[19]
. However, our study also showed that the shortcomings of V-NOTES surgery largely lay in the longer operation duration, the larger HB decline, etc. ...
Feasibility and Safety of Transvaginal Natural Orifice Transluminal Endoscopic Surgery (V-NOTES) Panhysterectomy: A Polycentric Retrospective Study
Objective
To investigate the feasibility and safety of Transvaginal Natural Orifice Transluminal Endoscopic Surgery (V-NOTES) panhysterectomy.
Method
A retrospective analysis was conducted on the data of 75 patients who underwent panhysterectomy for hysteromyoma in the Department of Obstetrics and Gynecology of Tongxiang Maternal and Child Health Hospital; Department of Gynecology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University and Department of Gynecology, The First Affiliated Hospital of USTC from June 2019 to June 2020. According to the operation mode, the patients were divided into two groups: the traditional Multi-Port Laparoscopic Surgery (MPLS) group (n = 45) and the Transvaginal Natural Orifice Transluminal Endoscopic Surgery (V-NOTES) group (n = 30). The operation duration, intraoperative blood loss, postoperative exsufflation time, postoperative activity time, hospital stay, treatment cost, 6h activities of daily living (ADL) score after the operation, cosmetic score, visual analog score, and complications were observed in the two groups.
Results
Perioperative period related indicators: Compared with the MPLS group, the total treatment cost and cosmetic score of the V-NOTES group were significantly better than those of the MPLS group, but the operation duration was longer, and the HB decreased more significantly (P < 0.05). However, there was no significant difference in intraoperative blood loss, postoperative exsufflation time, postoperative activity time, 6h ADL score after the operation, and hospital stay between the two groups (P > 0.05). Postoperative pain: The VAS score 1h, 6h, 12h, and 24h after the operation was lower in the V-NOTES group than in the MPLS group (P < 0.05). Postoperative complications: The complication rate of the V-NOTES group was significantly lower than that of the MPLS group (P < 0.05).
Conclusion
In treating panhysterectomy patients, both V-NOTES and MPLS can achieve satisfactory efficacy and prognosis, and both have advantages and disadvantages. Specifically, the V-NOTES surgery has significant advantages such as a lower treatment cost, lower incidence of postoperative complications, less pain, and more beautiful wounds.
... TSPLS completes all surgical operations through the natural cavity of the human umbilicus, holding almost the same surgical effect that traditional laparoscopic surgery does in current stage [7]. Transvaginal natural endoscopic surgery (TNES) (V-NOTES) is also a surgical method that has gradually emerged in the field of gynecology in recent years, in which vagina was served as an approach to avoid abdominal skin scars
[8]
. ...
Comparison of clinical efficacy and safety of transvaginal natural endoscopic surgery and transumbilical single port laparoscopy surgery for endometrial cancer
Objective:
To explore the difference in clinical efficacy and safety of transvaginal and transumbilical single port laparoscopy for endometrial cancer.
Methods:
We retrospectively included 100 endometrial cancer patients who were admitted to the Fuzhou Second Hospital for surgical treatment from September 2020 to September 2021 and divided them into two groups according to different surgical treatment options. Patients in Group A (48 cases) were treated with transvaginal natural endoscopic surgery (TNES), and those in Group B (52 cases) were with transumbilical single port laparoscopic surgery (TSPLS). The operation time, intraoperative blood loss, time to postoperative exhaust, length of hospital stay, pelvic lymph node dissection, and incision infection rate of two groups were compared. The white blood cell count (WBC), hemoglobin (Hb), hematocrit (Hct) of the two groups of patients before and after the surgery were compared between the two groups, as well as th VAS score of 24 hours after the operation, rate of complications during hospitalization, satisfaction with surgery and quality of life 3 months after surgery.
Results:
Compared with Group B, the operation time and intraoperative blood loss of Group A patients were markedly increased. The time to postoperative exhaust, length of hospital stay, incision infection rate, VAS score at postoperative 24 h, and complication rate of Group A were significantly lower than that of Group B. In addition, Group A had higher performance on the number of pelvic lymph node dissections, surgical satisfaction and quality of life 3 months after surgery.
Conclusion:
Transvaginal natural cavity endoscopy had better surgical results with faster postoperative recovery and higher safety compared with TSPLS, making it valuable in clinical application and worthy of further popularization.
Could the Trustworthiness in RAndomized Controlled Trials (TRACT) checklist be trusted?
Randomized controlled trials (RCTs) are considered the gold standard study design in clinical effectiveness research, albeit some RCTs have been found to be fraudulent post-publication. The Trustworthiness in RAndomized Controlled Trials (TRACT) checklist examines RCT integrity through an assessment covering seven domains. While the authors claim that it can identify problematic trials, it has never been validated. A critical appraisal of the checklist highlights major failures in terms of health measurement methodology, including the arbitrary nature of items chosen. We applied the checklist to 16 RCTs coauthored by the checklist developer, and identified potential violations related to retrospective registration, ethical implications, authorship, methodology, implausible timeframes, zero participants to follow-up, implausible baseline characteristics, and excessive inter-group within trial as well as inter-trial similarities. In addition, we identified inconsistencies between the trials’ registration and data in the final published manuscripts. If we uncritically assume that the checklist is valid, then a formal institutional investigation into the trial portfolio its developer is warranted; especially targeting these 16 trials objectively shown to be problematic. The checklist should be considered as neither investigative nor conclusive of potential problems with RCTs until it is further refined and validated.
Could the Trustworthiness in RAndomized Controlled Trials (TRACT) checklist be trusted?
Randomized controlled trials (RCTs) are considered the gold standard study design in clinical effectiveness research, albeit some RCTs have been found to be fraudulent post-publication. The Trustworthiness in RAndomized Controlled Trials (TRACT) checklist examines RCT integrity through an assessment covering seven domains. While the authors claim that it can identify problematic trials, it has never been validated. A critical appraisal of the checklist highlights major failures in terms of health measurement methodology, including the arbitrary nature of items chosen. We applied the checklist to 16 RCTs coauthored by the checklist developer, and identified potential violations related to retrospective registration, ethical implications, authorship, methodology, implausible timeframes, zero participants to follow-up, implausible baseline characteristics, and excessive inter-group within trial as well as inter-trial similarities. In addition, we identified inconsistencies between the trials’ registration and data in the final published manuscripts. If we uncritically assume that the checklist is valid, then a formal institutional investigation into the trial portfolio its developer is warranted; especially targeting these 16 trials objectively shown to be problematic. The checklist should be considered as neither investigative nor conclusive of potential problems with RCTs until it is further refined and validated.
Could the Trustworthiness in RAndomized Controlled Trials (TRACT) checklist be trusted?
Randomized controlled trials (RCTs) are considered the gold standard study design in clinical effectiveness research, albeit some RCTs have been found to be fraudulent post-publication. The Trustworthiness in RAndomized Controlled Trials (TRACT) checklist examines RCT integrity through an assessment covering seven domains. While the authors claim that it can identify problematic trials, it has never been validated. A critical appraisal of the checklist highlights major failures in terms of health measurement methodology, including the arbitrary nature of items chosen. We applied the checklist to 16 RCTs coauthored by the checklist developer, and identified potential violations related to retrospective registration, ethical implications, authorship, methodology, implausible timeframes, zero participants to follow-up, implausible baseline characteristics, and excessive inter-group within trial as well as inter-trial similarities. In addition, we identified inconsistencies between the trials’ registration and data in the final published manuscripts. If we uncritically assume that the checklist is valid, then a formal institutional investigation into the trial portfolio its developer is warranted; especially targeting these 16 trials objectively shown to be problematic. The checklist should be considered as neither investigative nor conclusive of potential problems with RCTs until it is further refined and validated.
Could the Trustworthiness in RAndomized Controlled Trials (TRACT) checklist be trusted?
Randomized controlled trials (RCTs) are considered the gold standard study design in clinical effectiveness research, albeit some RCTs have been found to be fraudulent post-publication. The Trustworthiness in RAndomized Controlled Trials (TRACT) checklist examines RCT integrity through an assessment covering seven domains. While the authors claim that it can identify problematic trials, it has never been validated. A critical appraisal of the checklist highlights major failures in terms of health measurement methodology, including the arbitrary nature of items chosen. We applied the checklist to 16 RCTs coauthored by the checklist developer, and identified potential violations related to retrospective registration, ethical implications, authorship, methodology, implausible timeframes, zero participants to follow-up, implausible baseline characteristics, and excessive inter-group within trial as well as inter-trial similarities. In addition, we identified inconsistencies between the trials’ registration and data in the final published manuscripts. If we uncritically assume that the checklist is valid, then a formal institutional investigation into the trial portfolio its developer is warranted; especially targeting these 16 trials objectively shown to be problematic. The checklist should be considered as neither investigative nor conclusive of potential problems with RCTs until it is further refined and validated.
Initial experience of hysterectomy by transvaginal natural orifice transluminal endoscopic surgery in our hospitalTransvaginal natural orifice transluminal endoscopic surgery （vNOTES）による子宮全摘術の初期経験
Objective: After the increasing number of recent reports of hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (vNOTES), we have introduced a novel procedure called vaginally-assisted NOTES hysterectomy (VANH). The objective of this study was to describe the VANH technique step-by-step, assess the technical feasibility of the procedure, and evaluate its initial surgical outcomes.
Methods: We retrospectively reviewed the perioperative outcomes in 20 patients with benign gynecologic disease who underwent VANH (n=10) or total laparoscopic hysterectomy (TLH; n=10) between February and November 2019 at our institution. Patient characteristics, operation time, blood loss, perioperative complications, and postoperative pain scores were compared between the two groups, as well as the amount of oral analgesia used in the first three postoperative days.
Results: There was no significant between-group difference in operation time or length of postoperative hospital stay. Mean estimated blood loss was significantly greater (198 mL vs. 18 mL, p=0.02) and the mean postoperative pain score was significantly lower in the VANH group than in the TLH group. The mean number of oral analgesics used was significantly lower in the VANH group (1.9 vs 3.5, p=0.01).
Conclusion: VANH could be safely introduced at our institution as an alternative approach for hysterectomy and have several benefits, including less postoperative pain and no visible scars. We anticipate that accumulation of more cases will allow us to improve our technique, consider expansion of the surgical indications for VANH, and introduce other vNOTES procedures.
Transvaginal natural orifice endoscopic surgery for myomectomy: Can it be a conventional surgery?
Introduction
As a new minimally invasive surgery, transvaginal natural orifice transluminal endoscopic surgery (vNOTES) has been proved to be suitable for the treatment of a variety of gynecological benign diseases. However, compared with other minimally invasive surgeries that have been widely used, such as conventional multiport laparoscopy and transumbilical laparoendoscopic single-site surgery (LESS), their advantages and disadvantages and how to choose are still unknown. The purpose of our study is to compare the advantages and disadvantages of the three minimally invasive surgeries in myomectomy and to provide theoretical basis for the wider development of vNOTES surgery.
Material and methods
This retrospective study included 282 patients at our hospital who underwent laparoscopic myomectomy from May 2021 to March 2022. Based on the surgical approach, patients were classified into multiport, transumbilical LESS, and vNOTES groups. The patients’ demographic characteristics and follow-up data were collected during the perioperative period and at 1 month postoperatively.
Results
Among the three procedures, vNOTES had the shortest anal exhaust time but also the highest postoperative infection rate. Multiple linear regression analysis showed that the operative time increased by 3.5 min for each 1 cm increase in myoma, and intraoperative bleeding increased by approximately 12 ml. The average duration of single pores increased by 25 min compared to that of multiports, and the operative duration increased by 10.48 min for each degree of adhesion.
Conclusions
For gynecologists who have mastered vNOTES, this procedure has the same efficacy and safety as the two existing minimally invasive surgeries in myomectomy, but it shows obvious advantages in postoperative recovery.
Soft robotic systems for endoscopic interventions
The field of soft robotics has established itself as an important research topic within robotics, offering several advantages over traditional rigid robots. This paradigm shift introduced by advances in material science and manufacturing methods has enabled new capabilities. These emerging soft robotic systems can squeeze and move through narrow openings, elongate, navigate around obstacles, and are considered inherently safe. In particular, the healthcare domain has been identified as one of the areas that might benefit from applying soft robotic systems.
This chapter focuses on the application of soft robotic systems for endoscopic interventions. At the outset, we provide an overview of endoscopic procedures and commercially available technologies and tools highlighting current challenges and how soft robotics might benefit. As soft robotic systems for healthcare application are a relatively young research area, we compiled a list of recommendations for creating soft robotic medical devices. Relevant topics include dimension requirements, biocompatibility as well as reliability of materials, durability specification, and ergonomics. Finally, a discussion of current soft robotic medical devices concerning the aforementioned endoscopic procedures will identify shortcomings and future research challenges.
HALON—hysterectomy by transabdominal laparoscopy or natural orifice transluminal endoscopic surgery: a randomised controlled trial (study protocol)
Introduction
Natural orifice transluminal endoscopic surgery (NOTES) uses natural body orifices to access the cavities of the human body to perform surgery. NOTES limits the magnitude of surgical trauma and has the potential to reduce postoperative pain. This is the first randomised study in women bound to undergo hysterectomy for benign gynaecological disease comparing NOTES with classical laparoscopy.
Methods and analysis
All women aged 18–70 years, regardless of parity, consulting at our practice with an indication for hysterectomy due to benign gynaecological disease will be eligible. After stratification according to uterine size on clinical examination, participants will be randomised to be treated by laparoscopy or by transvaginal NOTES. Participants will be evaluated on day 0, days 1–7 and at 3 and 6 months. The following data will be collected: the proportion of women successfully treated by removing the uterus by the intended approach as randomised; the proportion of women admitted to the inpatient hospital; postoperative pain scores measured twice daily by the women from day 1 to 7; the total amount of analgesics used from day 1 to 7; readmission during the first 6 weeks; presence and intensity of dyspareunia and sexual well-being at baseline, 3 and 6 months (Short Sexual Functioning Scale (SSFS) scale); duration of surgery; postoperative infection or other surgical complications; direct and indirect costs incurred up to 6 weeks following surgery. The primary outcome will be the proportion of women successfully treated by the intended technique; all other outcomes are secondary.
Ethics and dissemination
The study was approved on 1 December 2015 by the Ethics Committee of the Imelda Hospital, Bonheiden, Belgium. The first patient was randomised on 17 December 2015. The last participant randomised should be treated before 30 November 2017. The results will be presented in peer-reviewed journals and at scientific meetings within 4 years after starting recruitment.
Trial registration number
NCT02631837; Pre-results.
Adnexectomy by poor man’s transvaginal NOTES
Abstract The purpose of this study was to demonstrate the
feasibility and safety of adnexectomy by transvaginal natural
orifice transluminal endoscopic surgery (vNOTES) for benign
adnexal masses. Conventional, reusable laparoscopic instruments
were used, inserted through aninexpensive, selfconstructed
single port device. Between November 2013 and
November 2014, 20 adnexectomies by vNOTES were performed
by a single surgeon (BJ). Only conventional, reusable
laparoscopic instruments were used. The self-constructed single
port device was made by assembling a surgical glove, a
wound protector, one reusable 10-mm trocar, and four reusable
5-mm trocars. The adnexectomy was performed according
to the technique for standard laparoscopic surgery, and the
specimen was removed through the colpotomy incision. Patient
and perioperative data were analysed. Twenty patients
underwent adnexectomy by vNOTES, and no conversion to
standard laparoscopy or laparotomy was necessary. Mean operation
time was 32 min (20–50 min); mean drop in hemoglobin
level was 0.9 g/dl (0–2.1 g/dl). There were no operative
complications. Post-operative pain scores were very low. The
mean size of the removed adnexal mass was 51.8 mm (35–
110 mm). Adnexectomy by vNOTES is feasible even for
masses up to 110 mm and even when performed with reusable,
conventional laparoscopic instruments. The main advantages
of vNOTES are better cosmetics, low postoperative pain
scores and easy removal of the specimen without spillage.
This frugally innovative technique also enables surgeons to
perform adnexectomies by vNOTES in low resource settings.
| https://www.researchgate.net/publication/322388264_Transvaginal_natural_orifice_transluminal_endoscopic_surgery_vNOTES_adnexectomy_for_benign_pathology_compared_with_laparoscopic_excision_NOTABLE_A_protocol_for_a_randomised_controlled_trial |
(PDF) Special Issue on “Recent Trends on Convergence Personal Wireless System”: Selected Topics from the ICITCS Conference on December 5–7 2012 in Pyeongchang, Korea
PDF | Welcome to the special issue of Wireless Personal Communications. This special issue contains a collection of the best papers from the 2nd... | Find, read and cite all the research you need on ResearchGate
Special Issue on “Recent Trends on Convergence Personal Wireless System”: Selected Topics from the ICITCS Conference on December 5–7 2012 in Pyeongchang, Korea
November 2013
Wireless Personal Communications 73(2)
DOI: 10.1007/s11277-013-1227-4
Authors:
Jung-Soo Han
Sang Yeob Oh
Abstract
Welcome to the special issue of Wireless Personal Communications. This special issue contains a collection of the best papers from the 2nd International Conference on IT convergence and Security which was held in Pyeongchang, Korea from December 5th to 7th, 2012.The main goal of International Conference on IT convergence and Security is to bring together researchers from academia and practitioners from different industries to share ideas, problems , as well as solutions. This conference also aimed to meet the demands of the academia and practitioners from related industries, where we believe it is one of the most comprehensive conferences focused on solving problems occurring in industrial computing environments and providing high-demand technology.
Wireless Pers Commun
DOI 10.1007/s11277-013-1227-4
EDITORIAL
Special Issue on “Recent T rends on Con vergence
Personal Wireless System”
Selected T opics from the ICITCS Conference on December 5–7 2012
in Pyeongchang, Korea
Joong-Kyung Ryu · Junseok Y oo · Jung-Soo Han ·
Sang Y eob Oh · Kui nam J. Kim
© Springer Science+Business Media New Y ork 2013
W elcome to the special issue of Wireless Personal Communications. This special issue con-
tains a collection of the best papers from the 2nd International Conference on IT convergence
and Security which was held in Pyeongchang, Korea from December 5th to 7th, 2012.The
main goal of International Conference on IT convergence and Security is to bring together
researchers from academia and practitioners from different industries to share ideas, prob-
lems, as well as solutions. This conference also aimed to meet the demands of the academia
and practitioners from related industries, where we believe it is one of the most comprehensiv e
conferences focused on solving problems occurring in industrial computing environments
and providing high-demand technology .
J.-K. Ryu
Department of Computer Software, Daelim University, 29, Imgok-ro, Dongan-gu,
Anyang-si, Gyeonggi-do, Republic of Korea
e-mail: [email protected]
J. Y oo ( B
)
Institute for Creative and Advanced T echnologies, 154-42, Gwanggyosan-ro,
Y eongtong-gu, Suwon-si, Gyeonggi-do, Republic of Korea
e-mail: [email protected]
J.-S. Han
Division of Information & Communication, Baekseok University, 115 Anseo-dong,
Cheonan-si, Chungnam-do 330-704, Korea
e-mail: [email protected]
S. Y . Oh
Department of Interactive Media, Gachon University, Bokjeong-dong, Sujeong-gu,
Seongnam-si, Gyeonggi-do 461-701, Korea
e-mail: [email protected]
K. J. Kim
Department of Industrial Security, Kyonggi University, 154-42, Gwanggyosan-ro,
Y eongtong-gu, Suwon-si, Gyeonggi-do, Korea
e-mail: [email protected]
123
J.-K. Ryu et al.
This special issue presents the recent researches in convergence wireless personal system
for better performance and availability as well as for av oiding vulnerabilities, whose topics
are certainly the hottest topics in Convergence Personal W ireless System. W e believe that
this special issue will have a high citation in the areas of wireless personal communications.
• Personal and Content Protection
• Audio, Video, Image Processing for Con vergence
• Digital Signal Processing for Personal Communications
• Wireless Communications and Networking
• Information System for Personal Computing
• Digital Management for Personal Communications
• Wireless Personal Communications and Appliances
• Personal Information Extraction Algorithm
• Indexing, Searching, and Visualization
• Wireless Communications and Computing
The first paper by Kim et al. presented a convergence security system for pre venting
leakage of internal information. This is a convergence security system that is capable of
preventing the leakage of internal information as well as tracing the information leaker by
blocking the used ports such as FTP , messenger, cloud, etc. The proposed system detects
abnormal symptoms such as the leakage of information inside and operating a mail backup
server. The TCP packet monitoring method is capable of detection of abnormal symptoms,
grasping the destination, and prompt post-action, and it shows the weakness for grasping the
leaker and leaked contents as well as securing safety against internal attack.
The second paper by Lee et al. introduced a wireless IP camera that is used to expand
monitoring ranges in existing physical spaces in order to propose a security service structure
that can support instantaneous detection and responses to disasters. Using this method, it is
possible to provide flexibility in determining threatening factors dynamically and responding
to them in a physical security region that uses labor and equipment under the formal security
policy . Further, the information obtained from external environments is defined through
determining problems, which can be generated by providing physical security services,
figuring solutions in a procedural manner, and analyzing the causal relationship between
varia ble s.
The third paper by Y oo et al. showed the novel secure scheme for a wireless Ad hoc
network. The proposed method is a cache management technique to manage that removes
the threat of malicious nodes through authentication of reliable nodes as well as reduces
the delay time of cache search. The structure has an advantage in finding desired data by
utilizing limited resources and bandwidth. Fairness of the trust evaluation for mobile nodes
is improved, and the accuracy of trust ev aluation can be increased using the reliability value
received from neighboring nodes.
The fourth paper by Jung et al. presented home health gateway-based healthcare ser-
vices through The U-health platform. For this, they proposed a home health gateway-based
healthcare service through the U-Health platform. The proposed U-health platform allows
users to enjoy the contents of various special service providers in a multi-device en viron-
ment. The service distributors provide information on diets, workouts, and health, and the
users are given the most appropriate contents through the intellectual information provision
service.
The fifth paper by Kim et al. showed the numerical analysis of airflows in a traditional
Korean house. This inv estigation examined the thermal behaviors of airflows inside a tradi-
123
Recent Trends on Conver gence Personal Wireless System
tional Korean house made of construction materials. For this purpose, they conducted numer -
ical predictions of airflows depending on the temperature distribution inside the house. The
thermal properties for the calculation were procured by parallel measurements. The transient
numerical experiments were performed according to house type, weather conditions, and
operating time of heating. The details of airflows and temperature in the houses illustrated
that the thermal design of traditional Korean houses satisfy living requirements.
The sixth paper by Suh et al. introduced a perceived quality measurement model supporting
full session mobility in multimedia service delivery . The purpose of this system focuses on
video quality measurement in a seamless video service delivery process considering the
mobility patterns of users. Further, the optimal video deliv ery switching point to enable a
user mobility-based video service is studied through the quality analysis of host mobility
services at varying distances among the hosts. The results of simulation of their proposed
system showed that the quality model has a high correlation with assessed quality and is
useful to enable adequate seamless mobility for multimedia service delivery .
The seventh paper by Chung et al. introduced an interactive design recommendation
system using sensor-based smart wear and the weather W ebBot. The purpose of this system
is to increase the efficiency of merchandising for human-oriented sensibility product designs.
A user interface and collaborative filtering of textile and fashion designs are used to satisfy a
user’s needs. The feedback information gi ven by users is stored in the database, and when a
given user logs into the system again, the system provides more accurate recommendations
using the altered preference information. Te xtile and fashion merchandising may meet a
customer’s needs more precisely and easily using this system. This will result in quicker
responses and stimulate the fashion industry nationwide.
The eighth paper by Sung et al. proposed a Q-learning reward propagation method for
reducing the transmission power of sensor nodes in wireless sensor networks. This is a
reward propagation method (RPM), i.e., a method that integrates various updating algo-
rithms to propagate the reward of the goal state to more Q-values, thus reducing the learning
time required for Q-learning. For this purpose, they compared RPM with conventional Q-
learning in three experiments based on a hunter–prey game mapped to a WSN en vironment.
This experiment showed that obstacles affected the success rate of both methods and nar -
rowed the difference in performance between RPM and con ventional Q-learning. This result
was due to a decrease in the number of propagated rewards caused by the obstacles. Over -
all, the results of these experiments verified that RPM can reduce the learning time of Q-
learning.
The ninth paper by Hong et al. introduced an effective personalized service pro vision
scheme based on virtual spaces for a ubiquitous computing environment. The purpose of
this research was to propose an efficient management scheme for the virtual personal world,
which is a model focused on service continuity of the personal world. When they regulated
the number of spaces, pre-defined service, and VOs, they observed steady increases at the
beginning that later closed at a conver gent level. This means that user-generated services
satisfy users with time.
The tenth paper, an efficient gaming user -oriented load balancing scheme for MMORPGs
authored by Kim et al., proposed two schemes: taking care of neighboring gaming users
in one server by searching for nearby gaming users when one logs in and lessening the
load that occurs by server relocation by using gradients between servers to relocate the
servers, resulting in a common critical section. This scheme is more effectiv e at dealing
with hot-spots and other gatherings of gaming users at specific servers compared to previous
methods.
123
J.-K. Ryu et al.
The eleventh paper by Lee et al. presented an efficient sport tar get scene extracting method-
ology for a P2P-based personal mobile beaming broadcasting service using a smartphone.
The proposed method extracts and displays a specific context of the target scene from whole
scenes by considering optimal viewer visual sight on devices. They used P2P manner for
mobile personal beaming broadcast through the UDP protocol. Due to packet loss in commu-
nication, the UDP protocol method was used to provide a seamless service. The simulations
show that the proposed method is useful to enable an adequate seamless multimedia service
for a wireless environment.
The twelfth paper by Baek et al. showed dynamic reconfiguration based on a goal-scenario
by an adaptation strategy . They provided rapid dynamic reconfiguration using workflow based
on a goal-scenario as the basis to set up strategies in accordance with adaptive judgment.
Their approach uses estimates based on a goal-scenario to determine which remaining parts
of running workflows are affected by the external en vironment as well as to perform suitable
adaptation. This helps ensure that necessary adaptations are performed in time with minimal
user interaction, which is especially valuable in an external en vironment.
The thirteenth paper by Lim et al. introduced the detection and trace back of illegal
users based on an anonymous network in a bit-torrent environment. They suggested three
methodologies for prohibiting the sharing of illegal digital contents through torrents. The
first step is to block the torrent site, the second is to block the tracker, and the third is to block
Exit nodes. The second case is problematic since some trackers operate for normal purposes.
As a result, they verified that the technology attacking the new vulnerability can paralyze the
functions of a windows system PC and smartphones using Android OS. Further, the routing
packets are discarded before they reach the destination, and the connection to the destination
host cannot be established.
The fourteenth paper by Sohn presented a constraint satisfaction approach to the reader
collision problem in dense mode environments for static RFID networks. This method assigns
available channels and time slots to RFID readers to increase the read rate while also sat-
isfying all interference constraints. For the purpose of finding good heuristics, a problem-
classifying rule is applied to improve the quality of the variable orderings. These algorithms
are a combination of dynamic and static variable orderings, which are the most suitable for
DS-type problems.
The final paper by Kang et al. proposed a bio-interactive healthcare service system
using lifelog-based context computing. V arious noise signals were grouped into six cate-
gories by context estimation and effectively reconfigured into noise reduction filters by a
neural network and genetic algorithm. This system uses a distributed self-growing frame-
work that can be applied to adaptive systems under dynamic en vironments by taking advan-
tage of lifelog-based context-awareness, self-growing architecture, and conte xt knowledge
base.
This fine collection of papers was achieved by fruitful collaborations. W e gratefully
acknowledge and express heartfelt thanks to all the authors for their worthy contribution
to this special issue. We also w ould like to thank all the members of the Program Com-
mittee and anonymous reviewers for their help in identifying the no vel papers and for their
careful reading of earlier drafts. Furthermore, we would like to thank Professor Ramjee
Prasad, editor-in-chief of the international journal Wireless Personal Communications, for
his valuable remarks and his undeterred help throughout the publication process of this special
issue.
123
Recent Trends on Conver gence Personal Wireless System
Author Biographies
Joong-Kyung Ryu received the B.S degree from Department of
Computer Science and Engineering, Korea National Open University ,
Korea, in 1988 and the M.S. degree from the Department of Informa-
tion Engineering, Inha University , Korea in 1991. He got Ph.D. degree
from the Department of Computer Information Engineering, Inha Uni-
versity, K orea in 2012. From 1983 to 1992, he has been researcher of
Department of Computer Center, Daelim Industrial Co., Ltd. He is cur-
rently a professor in the Department of Computer Software, Daelim
University , Korea. His research interests include computer architecture,
u-healthcare, data mining, and HCI.
Junseok Y oo is the executive secretary of Institute of Creati ve and
Advanced T echnologies, Korea. He supervised and managed five con-
ferences including ICISA and ICITCS. Furthermore, He has obtained
and controlled sixteen special issues of prestigious international jour-
nals indexed in Science Citation Index Expanded (SciSerach) including
Personal Wireless Communications, Personal Ubiquitous Computing,
and Multimedia Tools and Applications and so on.
Jung-Soo Han received the B.S. degree, the M.S. degree and the Ph.D.
degree in computer engineering from KyungHee University , Korea.
Since 2001, he has been a professor in Division of Information and
Communication, BaekSeok University , Korea. His main research inter-
ests include Content Design, 3D Modeling, and CBD.
123
J.-K. Ryu et al.
Sang Y eob Oh received the B.S. degree in Computer Science from
Kyungwon University in 1989 and M.S., and Ph.D. degrees from
the Kwangwoon University , Korea, respectively in 1991, 1999 by the
Department of Computer Science. He is currently a professor in the
Division of Computer Media, Gachon University , Korea. His research
interests include Speech Recognition, V ehicle Safety Communications.
Kuinam J. Kim received the B.S. degree from Mathematics, Uni-
versity of Kansas in 1989. He received the M.S. degree of Statistics
and Ph.D. degree of Industrial Engineering from Colorado State Uni-
versity. He is currently professor of Industrial Security Department,
Kyonggi University , Korea. His research interests include industrial
security, con vergence, and advanced technology .
123
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| https://www.researchgate.net/publication/263331391_Special_Issue_on_Recent_Trends_on_Convergence_Personal_Wireless_System_Selected_Topics_from_the_ICITCS_Conference_on_December_5-7_2012_in_Pyeongchang_Korea |
Towards the Linguistic Gender Differentiation in Dictionaries: A Perspective of Human Interaction in Languages | Request PDF
Request PDF | Towards the Linguistic Gender Differentiation in Dictionaries: A Perspective of Human Interaction in Languages | There’s an intimate link between language and ideology, and social relations are mediated through language. The lexicographical treatment of... | Find, read and cite all the research you need on ResearchGate
Chapter
Towards the Linguistic Gender Differentiation in Dictionaries: A Perspective of Human Interaction in Languages
January 2020
DOI: 10.1007/978-3-030-25629-6_33
In book: Human Interaction and Emerging Technologies (pp.207-212)
Authors:
<here is a image b0dbb73edb9445d9-600106a5468525a5>
Pingfang Yu
Guandong University of Foreign Studies, China
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Jiali Du
Guangdong University of Foreign Studies
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Xinguang Li
Xinguang Li
Abstract
There’s an intimate link between language and ideology, and social relations are mediated through language. The lexicographical treatment of cultural loaded lexical item has a direct influence on the dictionary users’ perception of the world, the conceptualization of categories in that world and how the user will act in future. This paper seeks to analyze how gender differences are presented in learners’ dictionaries from a society-oriented cross-linguistic perspective, and finally we find there is an observable “anthropological turn” in the treatment of the example sentences in some distinguished English learners’ dictionaries.
Language and Gender: A Prosodic Study of Iranian Speakers’ Talks
Article
Full-text available
Jan 2013
<here is a image f9d97cf28887e151-f99bb0f4358bbe69> Laya Heidari Darani
Hourieh Heidari Darani
The current study is an attempt to explore the influence of gender on the prosodic behavior of Iranian male and female speakers in same-sex and cross-sex situations. In this research, it is hypothesized that the gender of the speakers is an influential factor to create a difference in their linguistic behavior rather than other factors such as formality of the context. Talks made by pairs of Iranian male and female speakers whose speech were totally formal were examined from an acoustical point of view by measuring the fundamental frequency of the speakers’ speech. One-way ANOVA was run on the data and the results indicated that women had lower pitch in their cross-sex talks compared with their talks in same-sex situations. However, men showed to have higher pitch when their talk occurred in a cross-sex situation, compared with the situations where they talked with other men. This proves that men and women do not react linguistically similarly in the same situations; and thus, they endeavor to insist on linguistic differences resulted from gender differences.
Gender in Language and Gender in Employment
Article
Full-text available
<here is a image f2ca7ffb6c88361c-70caa94579dad209> Astghik Mavisakalyan
Women lag behind men in many domains. Feminists have proposed that sex-based grammatical gender systems in languages reinforce traditional conceptions of gender roles, which in turn contribute to disadvantaging women. This article evaluates the empirical plausibility of this claim in the context of the labour market outcomes of women. Based on a sample of over 100 countries, the analysis shows that places where the majority language is gender-intensive have lower participation rates of women in the labour force. Individual level estimates further underscore this finding and indicate a higher prevalence of genderdiscriminatory attitudes among speakers of gender-intensive languages.
Think Practically and Look Locally:Language and Gender as Community-Based Practice
Article
Full-text available
ANNU REV ANTHROPOL
<here is a image 0b24c06a7c3bf917-7418c4dcfb60c3ea> Penelope Eckert
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Sally McConnell-Ginet
What role do race, ethnicity, language and gender play in the teaching profession?
Article
Full-text available
Race Ethn Educ
Critical race theory and standard language ideology are employed as theoretical and analytical frames for conceptualizing and understanding the entry perspectives and experiences of some Vietnamese American pre-service teachers in U.S. schools. Study findings from a qualitative case study approach suggest that race, ethnicity, language, and gender influence these teachers’ construction of self vis-à-vis others and their social milieu. Specifically, manifestations of these social constructs inform the ways in which others perceive them and measure their potential for success as future teachers. The heritage backgrounds and practicum accounts of these Vietnamese American women help to illuminate their individual and collective struggles and the mechanisms they each adopted in coping with their particular cases in the local school context.
LANGUAGE AND GENDER IN ENGLISH LANGUAGE TEACHING
<here is a image ec75d4d6469ab5a3-1dde325586cc5bdd> Murni Mahmud
Abstract: This paper highlights the impact of gender differences in English Language Teaching. It explores students’ learning styles as affected by the notions about men and women differences in communication. The data collected in 2008 from 20 males and 20 females’ English students of the State University of Makassar. It is to reveal their attitudes towards speaking to different sex, strategy to express opinion, group work preferences, activeness/passiveness, and their perception to increase English skills dealing with sex difference. It is revealed that female than male students were reluctant to speak to different sex; females preferred the direct way to express opinions (writing), work with the same sex, and tended to be passive in class. In addition, females saw the high possibility to increase their English skills by working with the same sex but the reverse is true for males. These different styles of female and male students in learning English were affected by the notions of women’s language.
Language and Gender Classification of Speech Files Using Supervised Machine Learning Methods
<here is a image 8bf09fefef474547-199f6822d400ce22> Yaakov HaCohen-Kerner
Ruben Hagege
Many language identification (LID) systems are based on language models using techniques that consider the fluctuation of speech over time. Considering these fluctuations necessitates longer recording intervals to obtain reasonable accuracy. Our research extracts features from short recording intervals to enable successful classification of spoken language. The feature extraction process is based on frames of 20 ms, whereas most previous LIDs presented results based on much longer frames (3 s or longer). We defined and implemented 200 features divided into four feature sets: cepstrum features, RASTA features, spectrum features, and waveform features. We applied eight machine learning (ML) methods on the features that were extracted from a corpus containing speech files in 10 languages from the Oregon Graduate Institute (OGI) telephone speech database and compared their performances using extensive experimental evaluation. The best optimized classification results were achieved by random forest (RF): from 76.29% on 10 languages to 89.18% on 2 languages. These results are better or comparable to the state-of-the-art results for the OGI database. Another set of experiments that was performed was gender classification from 2 to 10 languages. The accuracy and the F measure values for the RF method for all the language experiments were greater than or equal to 90.05%.
Controlling Interaction in Multilingual Conversation Revisited: A Perspective for Services and Interviews in Mandarin Chinese
May 2017
Lect Notes Comput Sci
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jiali Du
<here is a image b51d076a9ae90a96-e52f441063f18d93> Christina Alexandris
<here is a image 3d000aa39149909e-c9f3d103600173b8> Dimitrios Mourouzidis
Antonios Iliakis
The present approach targets to provide a framework for facilitating multilingual interaction in online business meetings with an agenda as well as in similar applications in the service sector where there is a less task-oriented form of interaction. A basic problem to be addressed is the control of the topics covered during the interaction and the expression of opinion. In the proposed template-based approach, the System acts as a mediator to control the dialog flow, within the modeled framework of the sublanguage-specific design.
The Lenses of Gender: Transforming the Debate on Sexual Inequality
Nov 1993
Leanne Lamke
Sandra Lipsitz Bem
Feb 2012
J PIDGIN CREOLE LANG
Jack Sidnell
Gender and discourse, gender and categorization: Current developments in language and gender research
Jan 2004
Qual Res Psychol
<here is a image d595f8ad8ef068b9-6774da6b102aeb1a> Elizabeth Stokoe
In this paper, I review recent developments in the study of language and gender. During the past decade, many researchers have abandoned a ‘gender differences’ agenda in pursuit of constructionist and, increasingly, ethnomethodological analyses of gender's production, performance and occasioning in discourse. I consider these developments in the light of other recent work that focuses on and analyses gender categories and their sequential trajectories in talk, using Membership Categorization Analysis (Sacks, 1992). I argue that the ‘doing’ of gender in our society is constituted in people's situated and reflexively organized categorization practices, and that these practices are fruitfully explored using this explicitly articulated machinery for understanding how the gender order is constituted as an ongoing reality.
The Lenses of Gender: Transforming the Debate on Sexual Inequality
May 1994
MICH LAW REV
Sandra Lipsitz Bem
In this book a leading theorist on sex and gender discusses how hidden assumptions embedded in our cultural discourses, social institutions, and individual psyches perpetuate male power and oppress women and sexual minorities. Sandra Lipsitz Bem argues that these assumptions, which she calls the lenses of gender, shape not only perceptions of social reality but also the more material things—like unequal pay and inadequate daycare—that constitute social reality itself. Her . . . examination of these hidden cultural lenses enables us to look at them rather than through them and to better understand recent debates on gender and sexuality. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Politeness and Postmodernism -- An Appropriate Approach to the Analysis of Language and Gender?
Feb 2005
J SOCIOLING
<here is a image 5ed73dacde416e81-7ab28156d16b95d2> Janet Holmes
The abstract for this document is available on CSA Illumina.To view the Abstract, click the Abstract button above the document title.
The Handbook of Language and Gender
Chapter
Jan 2008
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Deborah Cameron
IntroductionRepresenting Language and Gender: Uniformity and DiversityShifting Ideological Landscapes: The Fall and Rise of “Women's Language”“Communication”: The Language Ideology of Late Modernity?Representations and RealitiesNotesReferences
Language and gender in Congressional speech
Jan 2013
2986-3004
Yu. B.: Language and gender in Congressional speech. Lit. & Linguist. Comput. 156(15),
2986-3004 (2013)
| https://www.researchgate.net/publication/334681393_Towards_the_Linguistic_Gender_Differentiation_in_Dictionaries_A_Perspective_of_Human_Interaction_in_Languages |
HOTEL LOBSANN : Hotels near Lobsann 67250 France
HOTEL LOBSANN : Find the best hotel among all the hotels near Lobsann and BOOK NOW for your trip in France ! 67250 Bas-Rhin
Here is the list of the hotels near Lobsann. Book your hotel near Lobsann today, Saturday 03 June for the best price, reservation and cancellation free of charge thanks to our partner Booking.com, leader in on-line hotels reservation. To help you find available hotels, you can follow these links to check the list of hotels in nearby towns of Lobsann : - Hotel Memmelshoffen (67250) : town located at 1.58 km - Hotel Lampertsloch (67250) : town located at 2.35 km - Hotel Keffenach (67250) : town located at 2.51 km - Hotel Retschwiller (67250) : town located at 2.89 km - Hotel Drachenbronn-Birlenbach (67160) : town located at 2.97 km - Hotel Merkwiller-Pechelbronn (67250) : town located at 3.16 km - Hotel Kutzenhausen (67250) : town located at 3.39 km - Hotel Soultz-sous-Forêts (67250) : town located at 3.92 km - Hotel Preuschdorf (67250) : town located at 4.23 km - Hotel Schœnenbourg (67250) : town located at 4.95 km - Hotel Cleebourg (67160) : town located at 5.32 km To help you choose your destination as well as the place of the hotel here is: - pictures of Lobsann : photo Lobsann - the map of Lobsann : map Lobsann - the road map of Lobsann : road map Lobsann Below here is the list the 50 closest hotels of Lobsann, sortable according your criteria. You will find the position of these accommodations on the Lobsann hotels map . Share the hotels list of Lobsann ! Search Hotels Book now, Best Price Guaranteed ! Where ? Lobsann Check-in date 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 May 2023 June 2023 July 2023 August 2023 September 2023 October 2023 November 2023 December 2023 January 2024 February 2024 March 2024 April 2024 _link_ Check-out date 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 May 2023 June 2023 July 2023 August 2023 September 2023 October 2023 November 2023 December 2023 January 2024 February 2024 March 2024 April 2024 _link_ on I have no specific dates Search
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Ferme Auberge du Moulin des Sept Fontaines Bed and Breakfast Drachenbronn
Housed in a renovated oil mill, Ferme Auberge du Moulin des Sept Fontaines is located in Drachenbronn-Birlenbach. It offers a garden, a terrace and soundproofed rooms with free Wi-Fi access. Rooms at Ferme Auberge du Moulin des Sept Fontaines feature a wardrobe and a private bathroom with a shower. Some of them have a TV. Guests are invited to enjoy a continental breakfast in the dining room. They can enjoy French dishes on the restaurant’s terrace. This property is 15 km from Château de Fleckenstein. There is a farm with cows, geese and rabbits at the property. Free private parking is available on site.
Price :
from
68.00 €
to
110.00 €
Bed and Breakfast of Lobsann or nearby towns :
Address :
1 rue Moulin des Sept Fontaines 67160 Drachenbronn
Distance on map, Hotel - Lobsann : 2.33 kilometers
Number of room :
10
Holiday home Rue du Herrenberg Guest accommodation Birlenbach
Situated in Birlenbach in the Alsace region, Holiday home Rue du Herrenberg is a 4-star property featuring free WiFi. The accommodation is 49 km from Karlsruhe. The holiday home is fitted with a TV and 2 bedrooms. The accommodation is equipped with a kitchen. Haguenau is 23 km from the holiday home. Strasbourg International Airport is 71 km away.
Guest accommodation of Lobsann or nearby municipalities :
Location :
67160 Birlenbach
Route on map, Hotel - Lobsann : 2.75 kilometer
Number of rooms :
Gîte L'Alsace à Coeurs Apartment Drachenbronn
Set in the Northern Vosges Regional Natural Park, Gîte L'Alsace à Coeurs is a self-catering apartment located in Drachenbronn, just 200 metres from the Wine Route. It offers board games for children, free Wi-Fi and a shaded courtyard with table, chairs and barbecue. Accessible by a staircase, the apartment is located on tge first floor and features a TV, a seating area and a DVD player. The private bathroom comes with free toiletries and a bathtub, and a washing machine is provided. The apartment’s kitchen is equipped with a dishwasher and a microwave. Guests can also sit on the deck chairs in the sunny orchard overlooking the property and the village. Several walking paths start from the property. Quad hiking and paintball activities are available in a forest located 23 km from the property.
Rate :
from
85.00 €
to
115.00 €
Apartment of Lobsann or nearby towns :
Address :
18, Rue Louis Philippe Kamm 67160 Drachenbronn
Distance on map between hotel and center of Lobsann : 3.04 km
Room in hotel :
Hôtel Restaurant À L'Etoile Hotel Merkwiller-Pechelbronn
Hôtel Restaurant À L'étoile is located in Merkwiller-Pechelbronn in the Alsace region, 40 minutes from Strasbourg. It offers free Wi-Fi and a large garden with terrace. Each comfortable guest room at L'étoile has a TV and a private bathroom. The restaurant serves traditional and regional cuisine and guests are invited to relax in the bar with a drink. Nearby guests can visit the typical villages of Hunspach and Seebach, and Haguenau is a 15-minute drive from the Hôtel Restaurant À L'étoile. For guests discovering the region by car, free private parking is available.
Price :
from
53.00 €
to
73.00 €
Hotel Lobsann :
Location :
1 Route De Woerth 67250 Merkwiller-Pechelbronn
Distance between hotel and center of Lobsann : 3.19 kms
Rooms in hotel :
40
Maison OTTO Guest accommodation Lembach
Situated in Lembach in the Alsace region, Maison OTTO has a terrace. Guests staying at this holiday home have access to a fully equipped kitchen. The holiday home consists of 1 separate bedroom, 1 bathroom, and a seating area. A TV is featured. Kirrwiller is 38 km from the holiday home, while Haguenau is 26 km from the property. Strasbourg International Airport is 75 km away.
Guest accommodation of Lobsann or nearby towns :
Address :
45, Place des Châtaigniers 67510 Lembach
Distance on map, Hotel - Lobsann : 3.46 kilometers
Number of room :
maison Apartment Kutzenhausen
Maison is situated in Kutzenhausen and offers barbecue facilities, a garden and a shared lounge. Housed in a building dating from 1987, this apartment features free WiFi. This apartment is equipped with a living room and a fully equipped kitchen with an oven. The property also has 1 bathroom with a shower. A continental or buffet breakfast can be enjoyed at the property. Speaking German and French, staff will be happy to provide guests with practical guidance on the area at the reception. The apartment offers a sun terrace. Hiking can be enjoyed nearby. Baden-Baden is 46 km from maison. The nearest airport is Strasbourg International Airport, 67 km from the accommodation.
Rate :
from
60.00 €
to
100.00 €
Apartment Lobsann :
Location :
Rue du Cure Knauer 67250 Kutzenhausen
Route on map, Hotel - Lobsann : 3.47 kilometer
Number of rooms :
1
Ferienidyll Cleebourg Guest accommodation Cleebourg
Ferienidyll Cleebourg is situated in Cleebourg. It provides free WiFi and barbecue facilities. The 4-bedroom holiday home is fitted with a living room with satellite flat-screen TV and DVD player, and a fully equipped kitchen. The accommodation also offers 1 bathroom with a shower. Guests at the holiday home can enjoy hiking nearby, or make the most of the garden. Karlsruhe is 46 km from Ferienidyll Cleebourg. The nearest airport is Strasbourg International Airport, 76 km from the property.
Price :
from
117.00 €
to
207.00 €
Guest accommodation of Lobsann or nearby towns :
Address :
1 Rue des Prés 67160 Cleebourg
Distance on map between hotel and center of Lobsann : 5.18 km
Room in hotel :
Hôtel au Heimbach Hotel Lembach
Situated within the Vosges regional park, this hotel is in the scenic village of Lembach. It offers en suite rooms with satellite TV in a traditional half-timbered building. All of the guest rooms at Hôtel au Heimbach are accessible by lift and have a private bathroom and a flat-screen TV. Some also have a balcony. A buffet breakfast is served daily in the hotel. Popular regional eateries can be found within 500 metres of the hotel. Chateau du Fleckenstein is 7.2 km from Hôtel au Heimbach. Haguenau Train Station is 25 km away. Free private parking is available on site.
Prices :
from
78.00 €
to
88.00 €
Hotel of Lobsann or nearby municipalities :
Location :
15, Route de Wissembourg 67510 Lembach
Distance between hotel and center of Lobsann : 5.97 kms
Rooms in hotel :
Château du Liebfrauenberg Hotel Goersdorf
Château Du Liebfrauenberg is located in the Natural Park of the North Vosges region in Goersdorf. Southfacing, it offers panoramic views over the Black forest and the Vosges mountain range. Château Du Liebfrauenberg offers lodging for individuals or groups. Guests have the choice of staying in the main residence, the youth house or the pavilion. The rooms are authentic with wooden furnishings. Alsatian specialities are served in the restaurant. A range of tourist excursions are offered to discover the region, the castle and the church. The Chateau is ideally located for exploring the Natural Park as hiking trails surround the residence. Free private parking is available onsite.
Rate :
from
56.00 €
to
95.00 €
Hotel of Lobsann or nearby towns :
Address :
220 Rue du Château 67360 Goersdorf
Distance on map, Hotel - Lobsann : 6.00 kilometers
Number of room :
40
L'auberge Du Cheval Blanc is located in the Alsatian village of Lembach. It offers a gourmet restaurant and offers spacious en suite guest rooms with free Wi-Fi. Guests can enjoy a traditional or an innovative menu in the Cheval Blanc’s restaurant. Apéritifs and tea are available in the more intimate dining room. Some of the Auberge Du Cheval Blanc’s guest rooms have an individual spa, with a balneo bath, sauna and Feng-Shui design. Other rooms are traditionally designed with a TV and seating area. Château de Fleckenstein is just a 5-minute drive from the Auberge and guests can enjoy hiking and cycling in the scenic Alsatian countryside.
Price :
from
240.00 €
to
300.00 €
Hotel of Lobsann or nearby municipalities :
Location :
4 Rue De Wissembourg 67510 Lembach
Route on map, Hotel - Lobsann : 6.05 kilometer
Number of rooms :
21
Hotel Restaurant A l'Ange Hotel Climbach
Located in a typical Alsacian town, this 2-star hotel is a 10-minute drive from the German border. It is set in the heart of Vosges du Nord Regional Park and offers an on-site restaurant, 9 km from Wissembourg. The rooms at Hotel Restaurant A l'Ange are individually decorated and have satellite TV. They also have a private bathroom complete with free toiletries and a hairdryer. The hotel serves a buffet-style breakfast every morning or continental-style in the comfort of your room. You can also sample traditional, regional cuisine in the restaurant. Free private parking is available on site and the centre of Strasbourg is a 1-hour drive away. You may also choose to visit more local towns such as Lembach, 5 km away or go walking in the regional park.
Prices :
from
59.50 €
to
105.00 €
Hotel of Lobsann or nearby towns :
Address :
10 Route de Wissembourg 67510 Climbach
Distance on map between hotel and center of Lobsann : 6.05 km
Room in hotel :
13
Located in Rott, Hotel Restaurant Le Cleebourg has a garden, terrace and bar. The 3-star hotel has air-conditioned rooms with a private bathroom and free WiFi. The hotel has a children's playground and a sauna. At the hotel, rooms include a desk. The rooms are equipped with a flat-screen TV, and certain units at Hotel Restaurant Le Cleebourg have a garden view. The rooms have a wardrobe. The accommodation offers a continental or buffet breakfast. Guests at Hotel Restaurant Le Cleebourg will be able to enjoy activities in and around Rott, like cycling. Karlsruhe is 43 km from the hotel, while Kirrwiller is 44 km from the property. Strasbourg International Airport is 77 km away.
Rate :
from
100.00 €
to
105.00 €
Hotel of Lobsann or nearby municipalities :
Location :
route du Vin 67160 Rott
Distance between hotel and center of Lobsann : 6.25 kms
Rooms in hotel :
22
Set in Hunspach, 44 km from Strasbourg, Meublé dans Village Typique features a barbecue and views of the garden. Baden-Baden is 31 km from the property. Free private parking is available on site. Featuring a terrace, the accommodation is equipped with a seating and dining area. All units include a kitchen equipped with a dishwasher and oven. A microwave and coffee machine are also featured. Meublé dans Village Typique features free WiFi . Towels and bed linen are provided. The property also offers grocery delivery. Free use of bicycles is available at the property and the area is popular for cycling. Karlsruhe is 34 km from Meublé dans Village Typique, while Kirrwiller is 34 km away. The nearest airport is Strasbourg International Airport, 51 km from Meublé dans Village Typique. There are Christmas markets in the surrounding villages during the Christmas season.
Apartment Lobsann :
Address :
9, rue des Vosges 67250 Hunspach
Distance on map, Hotel - Lobsann : 6.61 kilometers
Number of room :
1
la maison de Lucie Guest accommodation Surbourg
La maison de Lucie is located in Surbourg. This holiday home features accommodation with free WiFi. The holiday home comes with 3 bedrooms and a fully fitted kitchen with a dishwasher. A flat-screen TV is provided. Strasbourg is 45 km from the holiday home. The nearest airport is Strasbourg International Airport, 61 km from the property.
Guest accommodation Lobsann :
Location :
32 Rue Jeanne d'Arc 67250 Surbourg
Route on map, Hotel - Lobsann : 6.61 kilometer
Number of rooms :
chez salome et fritz Guest accommodation Ingolsheim
Preferred hotel !
Set in Ingolsheim in the Alsace region, chez salome et fritz has a terrace. The holiday home, set in a building dating from 18th century, offers free WiFi. The holiday home features 2 bedrooms, a kitchen with a dishwasher and an oven, a washing machine, and 1 bathroom. A flat-screen TV with satellite channels is featured. A continental breakfast is available each morning at chez salome et fritz. The accommodation offers a children's playground. Guests can also relax in the garden or on the shared lounge area. Baden-Baden is 48 km from chez salome et fritz, while Karlsruhe is 46 km from the property. Strasbourg International Airport is 71 km away.
Rate :
from
71.25 €
to
75.00 €
Guest accommodation Lobsann :
Address :
0388941171 15 Rue de Bessines 67250 Ingolsheim
Distance on map between hotel and center of Lobsann : 6.64 km
Room in hotel :
GÎte rue de l'Ange Apartment Hunspach
Set in Hunspach in the Alsace region, GÎte rue de l'Ange features a garden. Guests staying at this apartment have access to free WiFi. The apartment is fitted with 2 bedrooms and a fully fitted kitchen with a dishwasher and an oven. A flat-screen TV is featured. A buffet breakfast is served daily at the property. The apartment offers a barbecue. A terrace is available for guests at GÎte rue de l'Ange to use. Baden-Baden is 44 km from the accommodation. The nearest airport is Strasbourg International Airport, 73 km from the property.
Apartment Lobsann :
Location :
7 rue de l'Ange 67250 Hunspach
Distance between hotel and center of Lobsann : 6.91 kms
Rooms in hotel :
Chambres d'hôtes Sabine Billmann Bed and Breakfast Hunspach
Chambres d'hôtes Sabine Billmann is located in Hunspach in the Alsace Region, 44 km from Strasbourg. Free private parking is available on site. It features a barbecue and views of the garden. Some units feature a seating area for your convenience. Every room is equipped with a private bathroom fitted with a shower. Chambres d'hôtes Sabine Billmann features free WiFi throughout the property. A flat-screen TV is available. You will find a shared kitchen at the property. You can engage in various activities, such as cycling and hiking. Baden-Baden is 31 km from Chambres d'hôtes Sabine Billmann, while Karlsruhe is 34 km away. The nearest airport is Strasbourg International Airport, 51 km from Chambres d'hôtes Sabine Billmann.
Bed and Breakfast Lobsann :
Address :
7 rue de l'Ange 67250 Hunspach
Distance on map, Hotel - Lobsann : 6.92 kilometers
Number of room :
2
Quartier vert Apartment Hunspach
Featuring accommodation with a terrace, Quartier vert is located in Hunspach. This apartment provides free bikes as well as free WiFi. This apartment is equipped with a living room and a fully equipped kitchen with a dishwasher. The apartment also provides guests with a seating area as well as 1 bathroom with a bath and a shower. Guests at the apartment can enjoy table tennis on site, or cycling in the surroundings. Baden-Baden is 44 km from Quartier vert, while Karlsruhe is 48 km away. The nearest airport is Strasbourg International Airport, 73 km from the property.
Rate :
from
49.84 €
to
129.00 €
Apartment Lobsann :
Location :
3 rue des vergers 67250 Hunspach
Route on map, Hotel - Lobsann : 7.04 kilometer
Number of rooms :
1
Chambres d'Hôtes Guest accommodation Wingen
Chambres d'Hôtes features free WiFi and views of pool in Wingen. Featuring a shared kitchen, this property also provides guests with an outdoor pool. The guest house provides a shared lounge. All units at the guest house are equipped with a flat-screen TV with cable channels, a kitchen and a dining area. The private bathroom is fitted with free toiletries. All guest rooms include a desk. Chambres d'Hôtes offers a continental or buffet breakfast. The accommodation offers a barbecue. Cycling and hiking are among the activities that guests of Chambres d'Hôtes can find nearby. Kirrwiller is 38 km from the guest house. The nearest airport is Strasbourg International Airport, 76 km from Chambres d'Hôtes.
Price :
from
120.00 €
to
130.00 €
Guest accommodation of Lobsann or nearby towns :
Address :
7 rue des Vosges 67510 Wingen
Distance on map between hotel and center of Lobsann : 7.31 km
Room in hotel :
2
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Gîte Découverte Alsace Guest accommodation Kuhlendorf
Preferred hotel !
Providing barbecue facilities and free WiFi, Gîte Découverte Alsace offers accommodation in Kuhlendorf. The units have a fully equipped kitchen with dining area, a microwave, coffee machine, and a toaster. A terrace with garden views is offered in all units. Guests can go skiing or relax in the garden. Baden-Baden is 40 km from the holiday home. Strasbourg International Airport is 68 km away.
Guest accommodation of Lobsann or nearby municipalities :
Location :
6 RUE DU VILLAGE 67660 Kuhlendorf
Distance between hotel and center of Lobsann : 7.80 kms
Rooms in hotel :
Chambres d'hôtes "La Bouill'hôte" Bed and Breakfast Langensoultzbach
Located in Langensoultzbach, Chambres d'hôtes "La Bouill'hôte" is a bed and breakfast accommodation. It is set in a traditional Alsatian house dating back from 1830, offering a garden and terrace with outdoor furniture. It features rooms with free WiFi, a CD player and private bathrooms with free toiletries. The shared kitchen is equipped with a microwave and a refrigerator. A continental breakfast is served daily in the shared dining area. Barbecue facilities are also offered. Free parking is also available at the property. The city of Hagenau is located only 16 km from this bed and breakfast. Fleckenstein Chateau Fort is situated 15 km away. Strasbourg Airport is 68 km away.
Bed and Breakfast of Lobsann or nearby towns :
Address :
6 rue des Vignes 67360 Langensoultzbach
Distance on map, Hotel - Lobsann : 8.06 kilometers
Number of room :
Hotel Restaurant Beau Séjour Hotel Morsbronn-les-Bains
Hotel Restaurant Beau Séjour features a garden, terrace, a shared lounge and bar in Morsbronn-les-Bains. This hotel offers free WiFi. The rooms are fitted with a terrace. At the hotel, the rooms include a desk. Featuring a private bathroom with a shower and free toiletries, certain units at Hotel Restaurant Beau Séjour also provide guests with a mountain view. The units have a wardrobe. A continental breakfast is available every morning at the property. Guests at the accommodation will be able to enjoy activities in and around Morsbronn-les-Bains, like cycling. Didiland Attraction Park is a 15-minute walk away and a thermal spa is located 100 metres from the property. Strasbourg is 36 km from Hotel Restaurant Beau Séjour. The nearest airport is Strasbourg International Airport, 41 km from the hotel.
Price :
from
79.00 €
Hotel of Lobsann or nearby municipalities :
Location :
3 Route de Haguenau 67360 Morsbronn-les-Bains
Route on map, Hotel - Lobsann : 9.56 kilometer
Number of rooms :
9
Logis La Source Des Sens Adult only Hotel Morsbronn-les-Bains
Logis La Source Des Sens Adult only welcomes you in a warm, friendly and contemporary environment, only 10 minutes by car from Haguenau and a 35-minute drive from Strasbourg. It offers a 2000 m² spa with sauna. This non smoking establishment offers comfortable and fully-equipped rooms, fresh and creative cuisine in a bright, cosy and modern decor. The restaurant room has a capacity of 100 seats. In the summer time you can enjoy your meals on a terrace on stilts that overlooks the garden. The seminar rooms can accommodate between 15 and 60 people and feature all necessary facilities for successful meetings.
Prices :
from
255.00 €
to
265.00 €
Hotel of Lobsann or nearby towns :
Address :
19, Rte De Haguenau 67360 Morsbronn-les-Bains
Distance on map between hotel and center of Lobsann : 9.97 km
Room in hotel :
30
Villa Alfredshöhe Apartment Wissembourg
Villa Alfredshöhe is a detached holiday home situated in Wissembourg in the Alsace Region and is 39 km from Baden-Baden. It provides free private parking. Free WiFi is featured throughout the property. This holiday home features a sun terrace with a barbecue and a garden. The kitchen is fitted with a dishwasher and an oven, as well as a coffee machine. The living room has a fireplace and a flat-screen TV is provided. There is a private bathroom with a bath. Bike hire is available at the property and the area is popular for cycling. Karlsruhe is 35 km from Villa Alfredshöhe, while Speyer is 48 km away. Strasbourg International Airport is 59 km from the property. This property is 1 km from the German border.
Apartment of Lobsann or nearby municipalities :
Location :
40 Route de Weiler 67160 Wissembourg
Distance between hotel and center of Lobsann : 10.28 kms
Rooms in hotel :
1
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Le Moulin de la Walk Hotel Wissembourg
Located in the grounds of a watermill and next to a forest, this hotel is a 10-minute walk from the historical centre of Wissembourg. It features a garden and a restaurant serving traditional French dishes and regional specialities. Rooms at Le Moulin de la Walk are decorated in warm wooden and cream colours. Each room offers views of the garden, a flat-screen TV and a work space. Guests have a private bathroom with a bath or shower and free toiletries. Guests can enjoy free Wi-Fi access from their rooms or the hotel terrace. Continental breakfast is available daily. Vosgien Club hiking and cycling trails pass through the area and into the Northern Vosges Regional Natural Park. Guests can also discover Fleckenstein Castle, a 30-minute drive away. Le Moulin de la Walk provides free private parking on site.
Price :
from
88.00 €
to
106.00 €
Hotel of Lobsann or nearby towns :
Address :
2, rue de la Walk 67160 Wissembourg
Distance on map, Hotel - Lobsann : 10.33 kilometers
Number of room :
25
Chambre d'hôtes Du côté des remparts Guest accommodation Wissembourg
Located in the historic centre of Wissembourg, Chambre d'hôtes Du côté des remparts features free WiFi access and a free private parking. Situated on the banks of the river, this property offers views of the river and the nearby landmarks as well as a garden and a terrace. Housed in a 19th-century building, every room includes a flat-screen TV and a coffee machine. All rooms has a private bathroom fitted with a walk-in shower, free toiletries and a hairdryer. You will find a shared lounge at the property. You can engage in various activities, such as cycling and hiking. The guest house also offers free use of bicycles. Karlsruhe is 34 km from Chambre d'hôtes Du côté des remparts, while Baden-Baden is 38 km from the property. Strasbourg International Airport is 59 km away.
Prices :
from
78.00 €
to
150.00 €
Guest accommodation of Lobsann or nearby municipalities :
Location :
10 Fossé des Tilleuls 67160 Wissembourg
Route on map, Hotel - Lobsann : 10.47 kilometer
Number of rooms :
3
Les Tilleuls Apartment Wissembourg
Boasting accommodation with a terrace, Les Tilleuls is situated in Wissembourg. Guests staying at this apartment have access to a fully equipped kitchenette. This apartment with river views features 1 bathroom with a shower. A flat-screen TV with satellite channels is offered. The apartment offers a barbecue. Karlsruhe is 39 km from Les Tilleuls, while Haguenau is 32 km from the property. The nearest airport is Strasbourg International Airport, 81 km from the accommodation.
Apartment of Lobsann or nearby towns :
Address :
9 Fossé des Tilleuls 67160 Wissembourg
Distance on map between hotel and center of Lobsann : 10.47 km
Room in hotel :
1
Hôtel Restaurant Ritter'hoft Hotel Morsbronn-les-Bains
The hotel enjoys a quiet location in the centre of Morsbronn-les-Bains. It offers recently renovated en suite rooms with free Wi-Fi access. Each room at Hôtel Restaurant Ritter'hoft is simply decorated and has its own bathroom and a TV. All rooms are accessible by lift. The hotel’s restaurant and bar are open every day for breakfast, lunch and dinner. It serves a wide choice of regional cuisine. Bikes and motorcycles can be left in the indoor private courtyard overnight. The hotel is 35 km from the German border.
Price :
from
60.00 €
to
84.00 €
Hotel of Lobsann or nearby municipalities :
Location :
23, rue Principale 67360 Morsbronn-les-Bains
Distance between hotel and center of Lobsann : 10.49 kms
Rooms in hotel :
16
Appartement Wissembourg Apartment Wissembourg
Appartement Wissembourg is set in Wissembourg. Guests staying at this apartment have access to free WiFi. This apartment comes with 3 bedrooms, a living room and a fully equipped kitchen with a dishwasher. A flat-screen TV is available. Cycling can be enjoyed nearby. Karlsruhe is 38 km from the apartment, while Haguenau is 32 km away. Strasbourg International Airport is 81 km from the property.
Apartment of Lobsann or nearby towns :
Address :
12 Rue des Bouchers 67160 Wissembourg
Distance on map, Hotel - Lobsann : 10.61 kilometers
Number of room :
1
Hotel Weiss Hotel Wissembourg
Hotel Weiss is located in Wissembourg in the Alsace region, close to the Northern Vosges Mountains and the German border. The hotel has a bistro serving French and Alsatian cuisine. Each room at Hotel Weiss is equipped with a TV, telephone and an en suite bathroom with either a bath or shower. Some rooms have a view of the garden. Free Wi-Fi is available throughout the hotel. A Continental breakfast is served daily. For guests wishing to explore the area by car Hotel Weiss offers free on-site parking and storage for bicycles and motorcycles. Wissembourg train station is located behind the hotel and Strasbourg train station is 60 km away. Karlsruhe Baden-Baden Airport is situated 30 km from the hotel, which has free private parking for cars, motorbikes and bikes.
Rate :
from
70.00 €
to
100.00 €
Hotel of Lobsann or nearby municipalities :
Location :
23 avenue de la Gare 67160 Wissembourg
Route on map, Hotel - Lobsann : 10.63 kilometer
| https://www.map-france.com/Lobsann-67250/hotel-Lobsann.html |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Journal Paper
Themes
Assistive & Accessible Technology
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Jamie Danemayer,Cathy Holloway,Youngjun Cho, Nadia Berthouze, Aneesha Singh, William Bhot, Ollie Dixon, Marko Grobelnik, John Shawe-Taylor
Paper highlights: Assistive technology (AT) information networks are insular among stakeholder groups, causing unequal access to information. Participants often cited fragmented international marketplaces as a barrier and valued info-sharing across industries. Current searches produce biased results in marketplaces influenced by commercial interests and high-income contexts. Smart features could facilitate searching, update centralised data sources, and disseminate information more inclusively.
International Journal of Human-Computer Studies; 2023
Abstract
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain.
Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems
Type
Journal Paper
Themes
Assistive & Accessible Technology
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Cite
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Type
Journal Paper
Themes
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Cite
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Emma M Smith, Maria Luisa Toro Hernandez, Ikenna D Ebuenyi, Elena V Syurina,Giulia Barbareschi, Krista L Best,Jamie Danemayer,Ben Oldfrey, Nuha Ibrahim,Catherine Holloway, Malcolm MacLachlan
The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
International Journal of Health Policy and Management; 2020
Abstract
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Abstract
Background:The coronavirus disease 2019 (COVID-19) pandemic has impacted all segments of society, but it has posed particular challenges for the inclusion of persons with disabilities, those with chronic illness and older people regarding their participation in daily life. These groups often benefit from assistive technology (AT) and so it is important to understand how use of AT may be affected by or may help to mitigate the impacts of COVID-19.Objective:The objectives of this study were to explore the how AT use and provision have been affected during the initial stages of the COVID-19 pandemic, and how AT policies and systems may be made more resilient based on lessons learned during this global crisis.
Methods:This study was a rapid, international online qualitative survey in the 6 United Nations (UN) languages (English, French, Spanish, Russian, Arabic, Mandarin Chinese) facilitated by extant World Health Organization (WHO) and International Disability Alliance networks. Themes and subthemes of the qualitative responses were identified using Braun and Clarke's 6-phase analysis.
Results:Four primary themes were identified in in the data: Disruption of Services, Insufficient Emergency Preparedness, Limitations in Existing Technology, and Inadequate Policies and Systems. Subthemes were identified within each theme, including subthemes related to developing resilience in AT systems, based on learning from the pandemic.
Conclusion:COVID-19 has disrupted the delivery of AT services, primarily due to infection control measures resulting in lack of provider availability and diminished one-to-one services. This study identified a need for stronger user-centred development of funding policies and infrastructures that are more sustainable and resilient, best practices for remote service delivery, robust and accessible tools and systems, and increased capacity of clients, caregivers, and clinicians to respond to pandemic and other crisis situations.
Cite
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Smith EM, Toro Hernandez ML, Ebuenyi ID, Syurina EV, Barbareschi G, Best KL, Danemayer J, Oldfrey B, Ibrahim N, Holloway C, MacLachlan M. Assistive Technology Use and Provision During COVID-19: Results From a Rapid Global Survey. Int J Health Policy Manag. 2022 Jun 1;11(6):747-756. doi: 10.34172/ijhpm.2020.210. PMID: 33201656;
Assistive Technology Use and Provision During COVID19: Results From a Rapid Global Survey
Type
Journal Paper
Themes
Assistive & Accessible Technology
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Katte, Cynthia Liao, Mathilde Chaudron, Novia Afdhila
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle- income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of a market and sector analysis that was conducted under the UK aid funded AT2030 programme and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Development outcomes are inextricably linked to the health of the marketplace that delivers products and services to people in low- and middle-income countries (LMIC). Shortcomings in the market for assistive technology (AT) contribute to low access in LMIC. Market shaping is aimed at improving a market’s specific outcomes, such as access to high quality, affordable AT, by targeting the root causes of these shortcomings. The paper summarizes the findings of market analyses conducted under the UK aid funded AT2030 programme in support of ATscale and aims to discuss how market shaping can help more people gain access to the AT that they need and what are the best mechanisms to unlock markets and commercial opportunity in LMICs. The paper also explores how market shaping for AT markets could be part of a mission-oriented approach AT policy. A mission-oriented approach can help accelerate progress toward a common objective among stakeholders, at country or global level. While market-shaping activities direct the outcomes of the market toward a specific end goal, such as access to quality, affordable products and services, missions are more comprehensive and include other policy interventions and stakeholder collaborations in order to create a robust and sustainable structure.
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Margaret Savage, Sarah Albala, Frederic Seghers, Rainer Kattel, Cynthia Liao, Mathilde Chaudron & Novia Afdhila (2021) Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries, Assistive Technology, 33:sup1, 124-135, DOI: 10.1080/10400435.2021.1991050
Applying market shaping approaches to increase access to assistive technology in low- and middle-income countries
Type
Journal Paper
Themes
Assistive & Accessible Technology
Assistive technology access in longitudinal datasets: a global review
Jamie Danemayer, Sophie Mitra,Cathy Holloway, Shereen Hussein
A person’s access to assistive products such as hearing aids, wheelchairs, and glasses, is an essential part of their ability to age in a healthy way. But, according to the World Health Organization, a staggering 90% of people who need assistive products worldwide, do not have access to them. In many instances access is limited or simply non-existent. This is often due to assistive products being too expensive, demand outweighing supply, not always being suitable to use in different environments, or even the lack of availability of trained providers. In such circumstances, people are more likely to age ‘unhealthily’ if they do not have access to assistive products that are designed to support their day to day functioning and independence.
International Journal of Population Data Science; 2023
Abstract
Assistive technology access in longitudinal datasets: a global review
Functional limitations become more prevalent as populations age, emphasising an increasingly urgent need for assistive technology (AT). Critical to meeting this need trajectory is understanding AT access in older ages. Yet few publications examine this from a longitudinal perspective.
This review aims to identify and collate what data exist globally, seeking all population-based cohorts and repeated cross-sectional surveys through the Maelstrom Research Catalogue (searched May 10, 2022) and the Disability Data Report (published 2022), respectively. Datasets incorporating functional limitations modules and question(s) dedicated to AT, with a wave of data collection since 2009, were included.
Of 81 cohorts and 202 surveys identified, 47 and 62 meet inclusion criteria, respectively. Over 40% of cohorts were drawn from high-income countries which have already experienced significant population ageing. Cohorts often exclude participants based on pre-existing support needs. For surveys, Africa is the most represented region (40%). Globally, 73% of waves were conducted since 2016. 'Use' is the most collected AT access indicator (69% of cohorts and 85% of surveys). Glasses (78%) and hearing aids (77%) are the most represented AT. While gaps in data coverage and representation are significant, collating existing datasets highlights current opportunities for analyses and methods for improving data collection across the sector.
Cite
Assistive technology access in longitudinal datasets: a global review
Danemayer, J., Mitra, S., Holloway, C. and Hussein, S. (2023) “Assistive technology access in longitudinal datasets: a global review”, International Journal of Population Data Science, 8(1). doi: 10.23889/ijpds.v8i1.1901.
Assistive technology access in longitudinal datasets: a global review
Type
Journal Paper
Themes
Assistive & Accessible Technology
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Jamie Danemayer, Dorothy Boggs, Vinicius Delgado Ramos, Emma M. Smith, Ariana Kular, William Bhot, Felipe Ramos Barajas, Sarah Polack,Catherine Holloway
Assistive technology (AT) includes assistive products (APs) and related services that can improve health and well-being, enable increased independence and foster participation for people with functional difficulties, including older adults and people with impairments or chronic health conditions. 1This paper uses the umbrella term ‘functional difficulty’ (FD) to refer to all of these groups. This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
BMJ Global Health; 2021
Abstract
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Introduction:To improve access to assistive products (APs) globally, data must be available to inform evidence based decision-making, policy development and evaluation, and market-shaping interventions.
Methods:This systematic review was undertaken to identify studies presenting population-based estimates of need and coverage for five APs (hearing aids, limb prostheses, wheelchairs, glasses and personal digital assistants) grouped by four functional domains (hearing, mobility, vision and cognition).
Results:Data including 656 AP access indicators were extracted from 207 studies, most of which (n=199, 96%) were cross-sectional, either collecting primary (n=167) or using secondary (n=32) data. There was considerable heterogeneity in assessment approaches used and how AP indicators were reported; over half (n=110) used a combination of clinical and self-reported assessment data. Of 35 studies reporting AP use out of all people with functional difficulty in the corresponding functional domains, the proportions ranged from 4.5% to 47.0% for hearing aids, from 0.9% to 17.6% for mobility devices, and from 0.1% to 86.6% for near and distance glasses. Studies reporting AP need indicators demonstrated >60% unmet need for each of the five APs in most settings.
Conclusion:Variation in definitions of indicators of AP access have likely led to overestimates/underestimates of need and coverage, particularly, where the relationship between functioning difficulty and the need for an AP is complex. This review demonstrates high unmet need for APs globally, due in part to disparate data across this sector, and emphasises the need to standardise AP data collection and reporting strategies to provide a comparable evidence base to improve access to APs.
Cite
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Danemayer J, Boggs D, Delgado Ramos V, et al. Estimating need and coverage for five priority assistive products: a systematic review of global population-based research. BMJ Global Health 2022;7:e007662. doi:10.1136/bmjgh-2021-007662
Estimating need and coverage for five priority assistive products: A systematic review of global population based research
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor
This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies.
Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021
Abstract
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers.
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Type
Workshop
Themes
Assistive & Accessible Technology
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Tabish Ahmed, Sahan Bulathwela
The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need.
Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022
Abstract
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval.
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Type
Journal Paper
Themes
Assistive & Accessible Technology
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick,Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga,Catherine Holloway
An estimated 1.5 million people undergo limb amputation each year [1]. Low- and middle-income countries (LMICs) are projected to have a rapid increase in people living with an amputation in the coming years due to prevalence of non-communicable dis-ease, trauma and conflict [1–3]. This paper explores the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Disability and Rehabilitation; 2022
Abstract
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
PurposeTo explore the personal and system factors that motivate and enhance outcomes for patients accessing a prosthetic service and using a lower-limb prosthesis within a low resource setting.
Materials and methodsThis study employed a qualitative approach to explore the motivations and satisfaction of individuals with lower limb loss engaging with a prosthetic service in Mombasa, Kenya. In-depth interviews were conducted over Microsoft Teams with 10 lower limb prosthesis users and thematic analysis was applied.
ResultsFive key themes emerged: acceptance, self-determination, hope, clinician relationship and perception. These findings demonstrate the importance of hopeful thinking and a supportive community in overcoming physical and stigmatising challenges. The findings further highlight the value of the service provider relationship beyond just prescribing an assistive device.
ConclusionThese results have relevance in developing patient-centred services, assistive devices and personnel training that are responsive, motivating, and cognisant of the service user. This is of particular interest as assistive technology services are newly developed in low resource settings.
Cite
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Kate Mattick, Ben Oldfrey, Maggie Donovan-Hall, Grace Magomere, Joseph Gakunga & Catherine Holloway (2022) Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes, Disability and Rehabilitation, DOI:10.1080/09638288.2022.2152875
Experiences of lower limb prosthesis users in Kenya: a qualitative study to understand motivation to use and satisfaction with prosthetic outcomes
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Victoria Austin,Catherine Holloway, Ignacia Ossul Vermehren, Abs Dumbuya,Giulia Barbareschiand Julian Walker
The World Health Organisation (WHO) estimates that there are currently one billion people in the world who need access to assistive technology (AT). Yet over 90% currently do not have access to assistive products (AP)—such as wheelchairs, hearing aids, walking sticks and eyeglasses—they need, nor and the systems and services necessary to support their appropriate provision [1]. This shocking deficit is set to double by 2050, with about two billion of us likely to require AT but no anticipated reduction in lack of access. The World Health Organisation defines AT as the “the umbrella term covering the systems and services related to the delivery of assistive products and services”, which are products that “maintain or improve an individual’s functioning and independence, thereby promoting their well-being” [2], and the importance of AT provision is strongly highlighted in the Convention on the Rights of Persons with Disabilities (CRPD) [3]. AT has also been shown to be essential to achieving many of the United Nation’s Sustainable Development Goals (SDG) [4]. Without access to AT, many persons with disabilities are unable to go to school, be active in their communities, earn an income, or play a full role in their families [5]. As a recent study found, “AT can make the impossible possible for people living with a wide range of impairments, but a lack of access to basic AT …excludes individuals and reduces their ability to live full, enjoyable, and independent lives” [6].
International Journal of Environmental Research and Public Health; 2021
Abstract
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
The importance of assistive technology (AT) is gaining recognition, with the World Health Organisation (WHO) set to publish a Global Report in 2022. Yet little is understood about access for the poorest, or the potential of AT to enable this group to participate in the activities of citizenship; both formal and informal. The aim of this qualitative study was to explore AT as mediator of participation in citizenship for persons with disabilities who live in two informal settlements in Freetown, Sierra Leone (SL). The paper presents evidence from 16 participant and 5 stakeholder interviews; 5 focus groups and 4 events; combining this with the findings of a house-to-house AT survey; and two national studies—a country capacity assessment and an informal markets deep-dive. Despite citizenship activities being valued, a lack of AT was consistently reported and hindered participation. Stigma was also found to be a major barrier. AT access for the poorest must be addressed if citizenship participation for persons with disabilities is a genuine global intention and disability justice is to become a reality.
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Austin, V.; Holloway, C.; Ossul Vermehren, I.; Dumbuya, A.; Barbareschi, G.; Walker, J. “Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone. Int. J. Environ. Res. Public Health2021, 18, 5547.https://doi.org/10.3390/ijerph...
“Give Us the Chance to Be Part of You, We Want Our Voices to Be Heard”: Assistive Technology as a Mediator of Participation in (Formal and Informal) Citizenship Activities for Persons with Disabilities Who Are Slum Dwellers in Freetown, Sierra Leone
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Additive manufacturing techniques for smart prosthetic liners
B Oldfrey, A Tchorzewska, R Jackson, M Croysdale, R Loureiro,C Holloway, M Miodownik
Elastomeric liners are commonly worn between socket and limb by prosthetic wearers. This is due to their superior skin adhesion, load distribution and their ability to form a seal. Laboratory tests suggest that elastomeric liners allow reduced shear stress on the skin and give a higher cushioning effect on bony prominences, since they are soft in compression, and similar to biological tissues [1]. However, they also increase perspiration reducing hygiene and increasing skin irritations. Prosthetic users in general face a myriad of dermatological problems associated with lower limb prosthesis such as ulcers, cysts, and contact dermatitis, which are exacerbated by the closed environment of a fitted socket where perspiration is trapped and bacteria can proliferate [2].
Medical Engineering & Physics; 2021
Abstract
Additive manufacturing techniques for smart prosthetic liners
Elastomeric liners are commonly worn between the prosthetic socket and the limb. A number of improvements to the state of the art of liner technology are required to address outstanding problems. A liner that conforms to the residuum more accurately, may improve the skin health at the stump-socket interface. Previous work has shown that for effective thermal management of the socket environment, an active heat removal system is required, yet this is not available. Volume tracking of the stump could be used as a diagnostic tool for looking at the changes that occur across the day for all users, which depend on activity level, position, and the interaction forces of the prosthetic socket with the limb. We believe that it would be advantageous to embed these devices into a smart liner, which could be replaced and repaired more easily than the highly costly and labour-intensive custom-made socket. This paper presents the work to develop these capabilities in soft material technology, with: the development of a printable nanocomposite stretch sensor system; a low-cost digital method for casting bespoke prosthetic liners; a liner with an embedded stretch sensor for growth / volume tracking; a model liner with an embedded active cooling system.
Additive manufacturing techniques for smart prosthetic liners
, Additive manufacturing techniques for smart prosthetic liners, Medical Engineering & Physics, Volume 87, 2021, Pages 45-55, ISSN 1350-4533,https://doi.org/10.1016/j.mede....
Additive manufacturing techniques for smart prosthetic liners
Type
Journal Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Disability Interactions
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Giulia Barbareschi, Mark T. Carew, Elizabeth Aderonke Johnson, Norah Kopi,Catherine Holloway
Stigmatizing attitudes and beliefs towards disability represent one of the most pervasive and complex barriers that limits access to health care, education, employment, civic rights and opportunities for socialization for people with disabilities [1,2,3]. The damaging impact of disability stigma is widely acknowledged and, according to article 8 of the UN Convention on the Rights of Persons with disabilities, developing strategies, campaigns, policies and other initiatives to combat disability stigma and ensure that all people with disabilities are treated with dignity and respect is also a duty of the 182 countries who ratified the treaty [4]. Although the majority of literature focused on understanding disability stigma has been carried out in high-income settings [5,6,7], in the last decade, an increasing number of scholars have conducted studies looking at the negative stereotypes, prejudices and inaccurate beliefs that shape disability stigma in the Global South [3,8,9,10]. Most of these studies have described how these stigmatizing beliefs are often driven by a combination of personal and societal factors, ranging from misconceptions concerning the causes of different impairments (e.g., disability to be seen as a form of curse or punishment); assumptions about the lack of capabilities of people with disabilities; or discriminatory practices that actively endorse separation between people with and without disabilities [3,9,11,12]. Yet, there is a dearth of comparative studies that examine the perspectives of both people with and without disabilities of disability stigma and discrimination, including how the use of assistive technology may shape stigmatizing interactions.
International Journal of Environmental Research and Public Health; 2021
Abstract
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Disability stigma in many low- and middle-income countries represents one of the most pervasive barriers preventing people with disabilities from accessing equal rights and opportunities, including the uptake of available assistive technology (AT). Previous studies have rarely examined how disability stigma may be shaped through factors endemic to social interactions, including how the use of assistive technology itself may precipitate or alleviate disability stigma. Through two strands of work, we address this gap. Via a series of focus groups with Kenyans without disabilities (Study 1) and secondary data analysis of consultations with Kenyans with disabilities and their allies (Study 2), we identify shared and divergent understandings of what shapes disability stigma and discrimination. Specifically, Kenyans with and without disabilities were cognizant of how religious/spiritual interpretations of disability, conceptions of impairments as “different” from the norm, and social stereotypes about (dis)ability shaped the experience of stigma and discrimination. Moreover, both groups highlighted assistive technology as an influential factor that served to identify or “mark” someone as having a disability. However, whereas participants without disabilities saw assistive technology purely as an enabler to overcome stigma, participants with disabilities also noted that, in some cases, use of assistive technologies would attract stigma from others.
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Barbareschi G, Carew MT, Johnson EA, Kopi N, Holloway C. “When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya. International Journal of Environmental Research and Public Health. 2021; 18(8):4272.https://doi.org/10.3390/ijerph...
“When They See a Wheelchair, They’ve Not Even Seen Me”—Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya
Type
Journal Paper
Themes
Inclusive Design
Culture and Participation
Research Group
Disability Interactions
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi,Ben Oldfrey, Long Xin, Grace N. Magomere, Wyclife A. Wetende, Carol Wanjira, Joyce Olenja,Victoria Austin, andCatherine Holloway
The World Health Organisation estimate that there are approximately a billion people with disabilities who require access to appropriate assistive technology and this number is set to double by 2050 [82]. Assistive technologies (ATs) play a crucial role in the lives of people with disabilities and are necessary to be able to access essential services and participate in family and community life according to one’s aspirations [40, 62, 68, 81]. Although this is not often specifcally mentioned, the large majority of people with disabilities will routinely use more than one assistive device in their everyday lives [25, 26]. For example a person with a visual impairment is likely to use a white cane to navigate from their house to the office where they work and have a screen-reader, or an equivalent accessibility software, on their computer to be able to do their work once in the office [17].
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Living in informality is challenging. It is even harder when you have a mobility impairment. Traditional assistive products such as wheelchairs are essential to enable people to travel. Wheelchairs are considered a Human Right. However, they are difficult to access. On the other hand, mobile phones are becoming ubiquitous and are increasingly seen as an assistive technology. Should therefore a mobile phone be considered a Human Right? To help understand the role of the mobile phone in contrast of a more traditional assistive technology – the wheelchair, we conducted contextual interviews with eight mobility impaired people who live in Kibera, a large informal settlement in Nairobi. Our findings show mobile phones act as an accessibility bridge when physical accessibility becomes too challenging. We explore our findings from two perspective – human infrastructure and interdependence, contributing an understanding of the role supported interactions play in enabling both the wheelchair and the mobile phone to be used. This further demonstrates the critical nature of designing for context and understanding the social fabric that characterizes informal settlements. It is this social fabric which enables the technology to be useable.
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Giulia Barbareschi, Ben Oldfrey, Long Xin, Grace Nyachomba Magomere, Wycliffe Ambeyi Wetende, Carol Wanjira, Joyce Olenja, Victoria Austin, and Catherine Holloway. 2020. Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal settlement. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 50, 1–13.https://doi.org/10.1145/337362...
Bridging the Divide: Exploring the use of digital and physical technology to aid mobility impaired people living in an informal setlement
Type
Journal Paper
Themes
Assistive & Accessible Technology
Climate & Crisis Resilience
Research Group
Disability Interactions
Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer,Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella,Cathy Holloway,and Sarah Polack
An assistive product (AP) is defined as a product used exter-nally to the human body, whose primary purpose is to main-tain or improve an individual’s functioning and independence and thereby promote his or her well-being (WHO, 2016). Global population aging forecasts a rise in the need for solu-tions that support participation and independence, including APs. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Measuring assistive technology supply and demand: A scoping review
The supply of and market demand for assistive products (APs) are complex and influenced by diverse stakeholders. The methods used to collect AP population-level market data are similarly varied. In this paper, we review current population-level AP supply and demand estimation methods for five priority APs and provide recommendations for improving national and global AP market evaluation. Abstracts resulting from a systematic search were double-screened. Extracted data include WHO world region, publication year, age-groups, AP domain(s), study method, and individual assessment approach.497 records were identified. Vision-related APs comprised 65% (n = 321 studies) of the body of literature; hearing (n = 59), mobility (n = 24), cognitive (n = 2), and studies measuring multiple domains (n = 92) were proportionately underrepresented. To assess individual AP need, 4 unique approaches were identified among 392 abstracts; 45% (n = 177) used self-report and 84% (n = 334) used clinical evaluation. Study methods were categorized among 431 abstracts; Cross-sectional studies (n = 312, 72%) and secondary analyses of cross-sectional data (n = 61, 14%) were most common. Case studies illustrating all methods are provided. Employing approaches and methods in the contexts where they are most well-suited to generate standardized AP indicators will be critical to further develop comparable population-level research informing supply and demand, ultimately expanding sustainable access to APs.
Measuring assistive technology supply and demand: A scoping review
Jamie Danemayer, Dorothy Boggs, Emma M. Smith, Vinicius Delgado Ramos, Linamara Rizzo Battistella, Cathy Holloway & Sarah Polack (2021) Measuring assistive technology supply and demand: A scoping review, Assistive Technology, 33:sup1, S35-S49, DOI: 10.1080/10400435.2021.1957039
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Humanitarian & Disasters
Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero,Maria Kett, Kirstin Lange
This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020.
Assistive Technology The Official Journal of RESNA; 2021
Abstract
Meeting AT needs in humanitarian crises: The current state of provision
Humanitarian coordination systems increasingly recognize and aim to respond to the needs of people with disabilities within populations affected by crises, spurred on by the UN Convention on the Rights of Persons with Disabilities (CRPD) which was adopted in 2006. Many agencies state their aim to meet the requirements of the CRPD using a “twin track” approach: ensuring the inclusion of people with disabilities in mainstream provision, alongside targeted support for their needs, which may include the need for Assistive Technology (AT). However, there is very little evidence of AT provision in humanitarian settings, which is a specific and urgent need for many people including the elderly and people with disabilities, and an implicit requirement of Article 11 of the CRPD and World Health Assembly resolution on improving access to assistive technology. There is also little evidence of effective mechanisms for AT provision in humanitarian settings. This is despite high and growing levels of unmet AT need in crises, and despite the legally binding requirement in the CRPD to provide AT for those who need it. AT provision faces unique challenges in humanitarian settings. This paper discusses the evidence available in the literature for the scale and quality of AT provision interventions in crises, and what is known about the challenges and facilitators of provision. We conducted a search of the academic literature and retained literature that reported on any form of AT provision following crisis, where international humanitarian response was in place, published in English between January 2010 and June 2020. We found very few examples in that academic literature of systematic and coordinated AT provision at the acute stage of crisis, and even less in the preparedness and post-acute stages. However, it is difficult to assess whether this is the result of insufficient academic attention or reflects a lack of provision. The small body of academic literature that describes AT provision in humanitarian settings paints a picture of small-scale provision, specialized to single types of impairments, and delivered by predominantly by NGOs. We also conducted a search of the gray literature, using the same inclusion criteria, in two countries: Afghanistan and South Sudan (case studies forthcoming). This gray literature provided supplementary evidence of the types of AT providers and AT provision available in those protracted crises. There are very few examples of how AT services can be scaled up (from a very low baseline) and maintained sustainably within a strengthened health system. The literature also describes more examples of provision of assistive products for mobility over assistive products for other impairments. If the paucity of literature on AT provision in humanitarian settings is a reflection of the scale of provision, this implies a deficiency in humanitarian response when it comes to providing people with AT needs with the essential products and services to which they have a right, and which will enable their access to basic, life-saving assistance. We conclude by providing recommendations for urgent actions that the AT and humanitarian community must take to fill this critical gap in the provision of essential products and services for a potentially marginalized and excluded group.
Meeting AT needs in humanitarian crises: The current state of provision
Golnaz Whittaker, Gavin Adam Wood, Giulia Oggero, Maria Kett & Kirstin Lange (2021) Meeting AT needs in humanitarian crises: The current state of provision, Assistive Technology, 33:sup1, S3-S16, DOI: 10.1080/10400435.2021.1934612
Meeting AT needs in humanitarian crises: The current state of provision
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Ben Oldfrey,Giulia Barbareschi, Priya Morjaria, Tamara Giltsoff, Jessica Massie, Mark Miodownik andCatherine Holloway
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have.
Sustainability
Abstract
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
From multiple studies conducted through the FCDO AT2030 Programme, as well as key literature, we examine whether Assistive Technology (AT) provision models could look towards more sustainable approaches, and by doing this benefit not only the environment, but also address the problems that the current provision systems have. We show the intrinsic links between disability inclusion and the climate crisis, and the particular vulnerability people with disabilities face in its wake. In particular, we discuss how localised circular models of production could be beneficial, facilitating context driven solutions and much needed service elements such as repair and maintenance. Key discussion areas include systems approaches, digital fabrication, repair and reuse, and material recovery. Finally, we look at what needs be done in order to enable these approaches to be implemented. In conclusion, we find that there are distinct parallels between what AT provision models require to improve equitable reliable access, and strategies that could reduce environmental impact and bring economic benefit to local communities. This could allow future AT ecosystems to be key demonstrators of circular models, however further exploration of these ideas is required to make sense of the correct next steps. What is key in all respects, moving forward, is aligning AT provision with sustainability interventions.
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Oldfrey, B.; Barbareschi, G.; Morjaria, P.; Giltsoff, T.; Massie, J.; Miodownik, M.; Holloway, C. Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World? Sustainability2021, 13, 10867.https://doi.org/10.3390/su1319...
Could Assistive Technology Provision Models Help Pave the Way for More Environmentally Sustainable Models of Product Design, Manufacture and Service in a Post-COVID World?
Type
Journal Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez,Tigmanshu Bhatnagar,Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi,Giulia Barbareschi,Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan,Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally.
Assistive Technology The Official Journal of RESNA
Abstract
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
It is essential to understand the strategies and processes which are deployed currently across the Assistive Technology (AT) space toward measuring innovation. The main aim of this paper is to identify functional innovation strategies and processes which are being or can be deployed in the AT space to increase access to AT globally. We conducted a scoping review of innovation strategies and processes in peer-reviewed literature databases and complemented this by identifying case studies demonstrating innovation strategies. The review includes WHO world region, publication year, AT type and a sector analysis against the Systems-Market for Assistive and Related Technologies Framework. We analyzed the case studies and interviews using thematic analysis. We included 91 papers out of 3,127 after review along with 72 case studies. Our results showed that product innovations were more prevalent than provision or supply innovations across papers and case studies. Case studies yielded two themes: open innovation (OI); radical and disruptive innovation. Financial instruments which encourage OI are needed and we recommend pursuing OI for AT innovation. Embedding AT within larger societal missions will be key to success governments and investors need to understand what AT is and their translational socioeconomic value.
A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems
Catherine Holloway, Dafne Zuleima Morgado Ramirez, Tigmanshu Bhatnagar, Ben Oldfrey, Priya Morjaria, Soikat Ghosh Moulic, Ikenna D. Ebuenyi, Giulia Barbareschi, Fiona Meeks, Jessica Massie, Felipe Ramos-Barajas, Joanne McVeigh, Kyle Keane, George Torrens, P. V.M. Rao, Malcolm MacLachlan, Victoria Austin, Rainer Kattel, Cheryl D Metcalf & Srinivasan Sujatha (2021) A review of innovation strategies and processes to improve access to AT: Looking ahead to open innovation ecosystems, Assistive Technology, 33:sup1, 68-86, DOI:10.1080/10400435.2021.1970653
Type
Journal Paper
Themes
Inclusive Design
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Mikaela Patrick,Iain McKinnon
Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments. Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya.
The Journal of Public Space
Abstract
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
This paper presents some of the findings from a global research study on inclusive infrastructure and city design and will focus on inclusive public spaces. Persons with disabilities can experience multi-dimensional exclusion from urban life, including but not limited to physical, attitudinal and social barriers. Public spaces, including recreational and social spaces, are often not prioritised. Inclusive public spaces are fundamental to participation and inclusive in society. Including persons with disabilities in the design and planning of the built environment supports equal rights and helps identify people’s aspirations for inclusive environments.Four city case studies will be discussed in this paper: Ulaanbaatar, Mongolia; Varanasi, India; Surakarta, Indonesia; and Nairobi, Kenya. Research participants and objectives are organised by three stakeholder groups:
People - first-hand experiences of persons with disabilities living in the city and their aspirations for a more inclusive city
Policy - the awareness and understanding of inclusive design among policy-makers
Practice - the awareness and understanding of inclusive design among practitioners including barriers to implementation, opportunities and the relationship with assistive technology
Methods include document reviews, interviews, photo diaries and co-design workshops with participatory and inclusive engagement of persons with disabilities throughout. Findings on public spaces are discussed in three ways:
The types of public spaces valued by participants in each of the four cities.
The barriers and challenges experienced by persons with disabilities in the public realm.
Aspirations for more inclusive public spaces and opportunities for inclusive design
The paper concludes by discussing how the targeted stakeholder groups of people, policy and practice also help represent three essential dimensions of inclusive city design and forming a framework for successful implementation and delivery and supporting targets set out through the UNCRPD and Sustainable Development Goals (SDGs).
Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities
Patrick, M. and McKinnon, I. (2022) “Co-creating Inclusive Public Spaces: Learnings from Four Global Case Studies on inclusive Cities”, The Journal of Public Space, 7(2), pp. 93–116. doi: 10.32891/jps.v7i2.1500.
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Jessica Noske-Turner, Emma Pullen, Mufunanji Magalasi, Damian Haslett, Jo Tacchi
Communication & Sport
Abstract
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
The purpose of this commentary is to discuss how Paralympic coverage in sub-Saharan Africa can be effectively mobilised to stimulate discursive and structural change around disability. Paralympic coverage has demonstrated its pedagogical power to engage public(s) and challenge stigma toward disability. Yet, the Global picture of Paralympic broadcasting is deeply uneven, with audiences in parts of the Global South afforded limited opportunities to watch the Games. Considering this, the International Paralympic Committee has begun to broadcast Paralympic coverage across sub-Saharan Africa with an explicit aim to challenge stigma toward disability. In this article, we draw on examples from research to argue that ideas from the field of Communication for Social Change (CfSC) can add value towards this aim. We begin by providing a brief overview of CfSC before critically examining one of the field’s key concepts – Communicative (E)ecologies. Following this, we critically reflect on the potential of Paralympic broadcasting as a vehicle for social change and disability rights agendas in sub-Saharan Africa. We argue that thinking with CfSC concepts show the importance of a ‘decentred’ media approach that engages with disability community advocacy groups, localised communication activities and practices, and culturally specific disability narratives.
Cite
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Noske-Turner, J., Pullen, E., Magalasi, M., Haslett, D., & Tacchi, J. (2022). Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change. Communication & Sport, 10(5), 1001–1015.https://doi.org/10.1177/216747...
Paralympic Broadcasting in Sub-Saharan Africa: Sport, Media and Communication for Social Change
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Troy Bodkin
Doctoral Thesis. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process.
Loughborough University
Abstract
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
For many years, the biggest issue that causes discomfort and hygiene issues for patients with lower limb amputations have been the interface between body and prosthetic, the socket. Often made of an inflexible, solid polymer that does not allow the residual limb to breathe or perspire and with no consideration for the changes in size and shape of the human body caused by changes in temperature or environment, inflammation, irritation and discomfort often cause reduced usage or outright rejection of the prosthetic by the patient in their day to day lives. To address these issues and move towards a future of improved quality of life for patients who suffer amputations, Loughborough University formed the Next Generation Prosthetics research cluster. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. The research presented in this thesis is based on three primary studies. The first study involved the conception of a CAD criteria, deciding what features are needed to represent the various properties the future socket outlined by the research cluster needs. These criteria were then used for testing three CAD systems, one each from the Parametric, Non Uniform Rational Basis Spline (NURBS) and Polygon archetypes respectively. The result of these tests led to the creation of a hybrid control workflow, used as the basis for finding improvements. The second study explored emerging CAD solutions, various new systems or plug-ins that had opportunities to improve the control model. These solutions were tested individually in areas where they could improve the workflow, and the successful solutions were added to the hybrid workflow to improve and reduce the workflow further. The final study involved taking the knowledge gained from the literature and the first two studies in order to theorise how an ideal CAD system for producing future prosthetic sockets would work, with considerations for user interface issues as well as background CAD applications. The third study was then used to inform the final deliverable of this research, a software design specification that defines how the system would work. This specification was written as a challenge to the CAD community, hoping to inform and aid future advancements in CAD software. As a final stage of research validation, a number of members of the CAD community were contacted and interviewed about their feelings of the work produced and their feedback was taken in order to inform future research in this area.
Cite
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Bodkin, Troy L. (2017): Specifying a hybrid, multiple material CAD system for next-generation prosthetic design. Loughborough University. Thesis.https://hdl.handle.net/2134/25...;
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Giulia Barbareschi
Doctoral Thesis. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs.
UCL (University College London)
Abstract
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Transferring independently to and from their wheelchair is an essential routine task for many wheelchair users but it can be physically demanding and can lead to falls and upper limb injuries that reduce the person’s independence. New assistive technologies (ATs) that facilitate the performance of wheelchair transfers have the potential to allow wheelchair users to gain further independence. To ensure that users’ needs are addressed by ATs, the active involvement of wheelchair users in the process of design and development is critical. However, participation can be burdensome for many wheelchair users as design processes where users are directly involved often require prolonged engagement. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. A related outcome based on these contributions is a framing document to share knowledge between wheelchair users and designers to provide focus and promote an equal collaboration among participants.
Cite
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Barbareschi, Giulia. “YouTransfer, YouDesign : a Participatory Approach to Design Assistive Technology for Wheelchair Transfers / Giulia Barbareschi.” Thesis (Ph.D.)--University College London, 2018., 2018. Print.
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Understanding wrist splint user needs and personalisation through codesign
Charlotte Pyatt
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy at Loughborough University.
Loughborough University
Abstract
Understanding wrist splint user needs and personalisation through codesign
Wrist splints are a common treatment for rheumatoid arthritis, however their effectiveness is compromised by patients not wearing splints as often as prescribed. Previous research has identified a number of reasons for non-compliance, but typically lacks insights that could lead to improved splint design.
This thesis investigates the motivators for patients to wear and not wear their wrist splints and, the impact of personalisation of splint appearance on patient wear. The work is based on the premise that digital design and manufacturing processes, such as Computer-Aided Design (CAD) and 3D Printing, can produce bespoke splints on demand.
The research begins with a literature review across the core areas of: splinting, additive manufacture, product appearance and personalisation. This literature review identifies gaps in knowledge from which research questions are established for the work.
The research employs a qualitative, generative design research approach and, follows a codesign framework employing telling, making and enacting tools. The thesis is made up of three studies. The first study is a sensitisation study and uses design probes to prepare the participants for the research and begin exploring the problem space. The second is a comprehensive study into participants splint wear behaviour and uses context mapping and scenario picture card tools to investigate the motivators for participants to wear and not wear wrist splints, along with positive and negative outcomes or wearing/not wearing splints. The final study uses a personalisation toolkit to elicit patient needs for a future wrist splint design and investigate self-reported expectations regarding compliance of patients who used the toolkit.
The research finds that patient compliance is affected by practical and aesthetic limitations of current splints. It identifies 4 motivating factors to wear a splint and 10 motivating factors to not wear a splint. Additionally, it identifies 6 positive outcomes of wearing splints, 6 negative outcomes of wearing splints, 3 positive outcomes of not wearing splints and 3 negative outcomes of not wearing splints. Requirements for an improved splint design are established and form the basis of the design for a prototype personalisation toolkit. Testing of this toolkit reveals that patients are keen to own more than one splint and personalise splints to match the scenario in which it is to be worn. Patients reported that they expected to be more compliant with a personalised splint when compared to their current splint.
Cite
Understanding wrist splint user needs and personalisation through codesign
Pyatt, Charlotte (2018): Understanding wrist splint user needs and personalisation through codesign. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
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Understanding wrist splint user needs and personalisation through codesign
Type
PhD
Themes
Assistive & Accessible Technology
Shared Control for Wheelchair Interfaces
Dr Chinemelu Ejiamatu Muoma Ezeh
Doctoral Thesis. Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch.
UCL (University College London)
Abstract
Shared Control for Wheelchair Interfaces
Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. Control is shared between a powered wheelchair user, using an alternative interface and a pow- ered wheelchair fitted with sensors. This shared control then produces a resulting motion that is close to what the user desires to do but a motion that is also safe. A path planning algorithm on the wheelchair is implemented using techniques in mo- bile robotics. Afterwards, the output of the path planning algorithm and the user’s com- mand are both modelled as random variables. These random variables are then blended in a joint probability distribution where the final velocity to the wheelchair is the one that maximises the joint probability distribution. The performance of the probabilistic approach to blending the user’s inputs with the output of a path planner, is benchmarked against the most common form of shared control called linear blending. The benchmarking consists of several experiments with end users both in a simulated world and in the real-world. The thesis concludes that probabilistic shared control provides safer motion compared with the traditional shared control for difficult tasks and hard-to-use interfaces.
Ezeh, Chinemelu Ejiamatu Muoma. Shared Control for Wheelchair Interfaces. UCL (University College London), 2018. Print.
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Materials For Facial Prostheses In Resource Limited Countries
Sophia Esther Liiba Tetteh
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University
Loughborough University
Abstract
Materials For Facial Prostheses In Resource Limited Countries
Facial prostheses are artificial devices that replace a missing body part in the facial and neck regions of the body. Defects or deformities in these regions can lead to functional deficiencies; social and psychological effects in addition to cosmetic defects. Restoration or rehabilitation in resource limited countries is usually provided by charities and organisations volunteering assistance overseas, with some training of local staff in the fabrication of these prostheses. Furthermore, these countries typically lack technical knowhow and trained personnel. In industrialised nations maxillofacial prosthetics has developed into a sophisticated medical speciality requiring highly skilled staff and expensive facilities. In resource limited countries surgical procedures may be an option for rehabilitation of these deformities/defects however, they tend to be unavailable or unaffordable and donated prostheses are not suitable. Hence, this research explores, from first principles, the appropriate and affordable local provision of maxillofacial prostheses in resource constrained regions. The investigation provides knowledge on identifying requirements for resource limited areas, resulting in the creation of a guideline constituting priorities, requirements and specifications. It further explores the viability of potentially cheaper, locally available candidate materials via weathering and antimicrobial methods in ascertaining material longevity.
Materials For Facial Prostheses In Resource Limited Countries
Tetteh, Sophia (2019): Materials for facial prostheses in resource-limited countries. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Materials For Facial Prostheses In Resource Limited Countries
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Rhys James Williams
Thesis: Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
UCL, ProQuest Dissertations Publishing
Abstract
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Amongst lower-limb prosthesis wearers, thermal discomfort is a common problem with an estimated prevalence of more than 50%. Overheating does not just create discomfort to the user, but it has been linked to excessive sweating, skin damage caused by a moist environment and friction. Due to impermeable prosthetic components and a warm moist environment, minor skin damage can result in skin infections that can lead to prosthesis cessation, increased social anxiety, isolation and depression. Despite the seriousness of thermal discomfort, few studies explore the issue, with research predominantly constrained to controlled laboratory scenarios, with only one out of laboratory study. In this thesis, studies investigate how thermal discomfort arises and what are the consequences of thermal discomfort for lower-limb prosthesis wearers. Research studies are designed around the principles of presenting lived experiences of the phenomenon and conducting research in the context of participants' real-life activities. A design exploration chapter investigates modifying liner materials and design to create a passive solution to thermal discomfort. However, this approach was found to be ineffective and unfeasible. Study 1 presents a qualitative study which investigates the user experience of a prosthesis, thermal discomfort and related consequences. Study 2 explores limb temperature of male amputees inside and outside the laboratory, with the latter also collecting perceived thermal comfort (PTC) data. Finally, Study 3 investigates thermal discomfort in the real-world and tracks limb temperature, ambient conditions, activities, and experience sampling of PTC. While there were no apparent relationships presented in sensor data, qualitative data revealed that in situations where prosthesis wearers perceived a lack of control, thermal discomfort seemed to be worse. When combined, the studies create two knowledge contributions. Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Williams, Rhys James. “Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers.” ProQuest Dissertations Publishing, 2020. Print.
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Design rules for additively-manufactured wrist splints
Sarah Kelly
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University.
Loughborough University
Abstract
Design rules for additively-manufactured wrist splints
Additive Manufacturing (AM) often known by the term three-dimensional printing (3DP) has been acknowledged as a potential manufacturing revolution. AM has many advantages over conventional manufacturing techniques; AM techniques manufacture through the addition of material - rather than traditional machining or moulding methods. AM negates the need for tooling, enabling cost-effective low-volume production in high-wage economies and the design & production of geometries that cannot be made by other means. In addition, the removal of tooling and the potential to grow components and products layer-by-layer means that we can produce more from less in terms of more efficient use of raw materials and energy or by making multifunctional components and products. The proposed Centre for Doctoral Training (CDT) in Additive Manufacturing and 3D Printing has the vision of training the next generation of leaders, scientists and engineers in this diverse and multi-disciplinary field. As AM is so new current training programmes are not aligned with the potential for manufacturing and generally concentrate on the teaching of Rapid Prototyping principles, and whilst this can be useful background knowledge, the skills and requirements of using this concept for manufacturing are very different. This CDT will be training cohorts of students in all of the basic aspects of AM, from design and materials through to processes and the implementation of these systems for manufacturing high value goods and services. The CDT will also offer specialist training on aspects at the forefront of AM research, for example metallic, medical and multi-functional AM considerations. This means that the cohorts graduating from the CDT will have the background knowledge to proliferate throughout industry and the specialist knowledge to become leaders in their fields, broadening out the reach and appeal of AM as a manufacturing technology and embedding this disruptive technology in company thinking. In order to give the cohorts the best view of AM, these students will be taken on study tours in Europe and the USA, the two main research powerhouses of AM, to learn from their international colleagues and see businesses that use AM on a daily basis. One of the aims of the CDT in AM is to educate and attract students from complementary basic science, whether this be chemistry, physics or biology. This is because AM is a fast moving area. The benefits of having a CDT in AM and coupling with students who have a more fundamental science base are essential to ensure innovation & timeliness to maintain the UK's leading position. AM is a disruptive technology to a number of industrial sectors, yet the CDTs industrial supporters, who represent a breadth of industrial end-users, welcome this disruption as the potential business benefits are significant. Growing on this industry foresight, the CDT will work in key markets with our supporters to ensure that AM is positioned to provide a real and lasting contribution & impact to UK manufacturing and provide economic stability and growth. This contribution will provide societal benefits to UK citizens through the generation of wealth and employment from high value manufacturing activities in the UK.
Cite
Design rules for additively-manufactured wrist splints
Kelly, Sarah (2020): Design rules for additively-manufactured wrist splints. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Design rules for additively-manufactured wrist splints
Type
PhD
Themes
Assistive & Accessible Technology
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Anna Vlachaki
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies.
Loughborough University
Abstract
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
The literature shows that research into the aesthetic aspects of prostheses is limited. Although there are suggestions that prostheses with high levels of emotionally-driven design may improve users’ well-being, they are based only on theoretical findings. Therefore, in this thesis, the effects of emotionally-driven prostheses on users’ lives and society’s attitudes were explored, with respect to culture and more specifically, the theories of individualism/ collectivism. In order to investigate the effects of culture, the research was conducted in two countries with different cultures; the UK (individualistic) and Greece (collectivistic). The thesis began with a literature review across three core areas: user, product and environment, and revealed the importance of investigating an additional area; that of prosthetists. The research employed a qualitative approach and consisted of four studies. Study I was an online questionnaire to explore users’ preferences towards prostheses, with respect to their culture. Study II consisted of semi-structured interviews and informational probes to comprehend the role of prostheses on users’ lives, with respect to prosthetic appearance. In Study III, the aim was to investigate prosthetists’ attitudes towards the needs of prosthetic users by conducting semi-structured interviews. Finally, Study IV was an online questionnaire to explore non-users’ attitudes towards the design of prostheses. The research showed that the use of prostheses for the completion of users’ body was not an adequate factor to improve their well-being, and a shift on users’ desires towards emotionally-driven prostheses has occurred. From the variables that were tested, sex, age, cause and area of limb-loss may affect people’s attitudes towards the design of prostheses. Furthermore, the results showed that prostheses with high emotionally-driven design evoked emotions, in both users and non-users, with higher levels of pleasantness and arousal than the emotions that were elicited by the prostheses of lower emotionally-driven designs and thus, they may trigger a greater behavioural reaction. This suggested that emotionally-driven prostheses may eliminate users’ stigmatisation by increasing their self-confidence and altering society’s attitudes. However, attention needs to be paid in collectivistic countries, as emotionally-driven prostheses may enhance users’ stigmatisation.
Cite
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Vlachaki, Anna (2020): Emotionally-driven prostheses: exploring the effects on users’ lives and societies’ attitudes in the UK and Greece. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Emotionally driven Prostheses: Exploring the Effects on Users’ Lives and Societies’ Attitudes in the UK and Greece
Type
Journal Paper
Themes
Culture and Participation
Research Group
Social Justice
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Victoria Austin,Kate Mattick, andCathy Holloway
Disability inclusion necessitates proactive efforts to ensure everybody has an independent and equitable opportunity to meaningfully participate in the activities of their choosing [1,2,3]. Furthermore, disability justice is not a minority concern. There are more than a billion disabled people worldwide, and impairment is something which affects most people’s family right now and will impact all of us over our lifetime. The United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enshrines human rights of all disabled people [4], and in 2015 the Sustainable Development Goals (SDG’s) recognised disability inclusion for the first time with the call to ‘leave no-one behind’. Increasingly, governments, non-governmental agencies and businesses alike are seeking to develop and implement policy and practice which enables greater social inclusion for disabled people (In this paper, Disabled People is used in line with the Social Model of Disability in the UK, though please note the UN uses ‘Persons with Disabilities’ as is common in North America) [5]. Eighty percent of the disabled people in the world live in low resource settings in the Global South [3] with a projected growth of this number due to an increase in population age, there is the ever-pressing need to critically evaluate how best to approach disability inclusion to build a societies where we all can flourish. Despite this, we lack case studies of how disability inclusion can be done well—in the literature and in practice. For this reason, we set out to undertake this research using one the most recognised cases of ‘disability inclusion done well’.
Sustainability
Abstract
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
The London 2012 Paralympic Games was called “the most successful Paralympic Games ever” (by the then-President of the IPC), and it saw more athletes from more countries than ever before compete and become global heroes for the first time in a redeveloped part of East London which also hosted “the most accessible Olympic Games ever” that summer. However, the model used to design and deliver disability inclusion for London 2012, and its legacy, has never been explicitly written up. This paper presents new primary evidence from first-hand research from those who were involved; retrospectively framing the London 2012 Disability Inclusion Model such that it might be usable and developed for other global disability challenges. We used an adapted Delphi methodology, through four rounds: beginning with an initial hypothesis and testing through semi-structured interviews with ten key players in the London 2012 disability inclusion approach. Using thematic analysis with consensus building surveys and workshops we came to a settled unanimous agreement on the 12-step London 2012 Disability Inclusion Modelcomprising three parts: (Get ready) community-led mission setting, (Get set) essential building blocksand (Go) enabling a culture of success. The model is presented here, alongside a narrative on its uniqueness and replicability to other major programs, as a public good. We welcome its active use, testing and adaption by others in service of disability innovation for a fairer world.
Cite
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Victoria Austin, Kate Mattick, and Cathy Holloway. 2021. "“This Is the Story of Community Leadership with Political Backing. (PM1)” Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges" Sustainability13, no. 16: 9253.https://doi.org/10.3390/su13169253
This Is the Story of Community Leadership with Political Backing. (PM1)" Critical Junctures in Paralympic Legacy: Framing the London 2012 Disability Inclusion Model for New Global Challenges ?"
Type
Workshop
Themes
Assistive & Accessible Technology
Culture and Participation
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh,Catherine Holloway,Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design.
CHI EA '21: Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems
Abstract
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. The aim is to better understand how we can re-think the senses in technology design for disability interactions and the dynamic self, constructed through continuously changing sensing capabilities either because of changing ability or because of the empowering technology. This workshop will: (i) bring together HCI researchers from different areas, (ii) discuss tools, frameworks and methods, and (iii) form a multidisciplinary community to build synergies for further collaboration.
Cite
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh, Catherine Holloway, Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme. 2021. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 118, 1–5. DOI:https://doi.org/10.1145/341176...
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
| https://www.disabilityinnovation.com/publications?page=5&subject=mobility&type=journal-paper+workshop+phd |
DICLOFENAC SODIUM tablet, film coated
Drug interactions, ingredients, warnings, and packaging details.
DICLOFENAC SODIUM tablet, film coated
Diclofenac sodium by
Drug Labeling and Warnings
Diclofenac sodium by is a Prescription medication manufactured, distributed, or labeled by Ingenus Pharmaceuticals, LLC, RiconPharma LLC, Ingenus Pharmaceuticals NJ, LLC. Drug facts, warnings, and ingredients follow.
Drug Details [ pdf ]
BOXED WARNING
(What is this?)
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS ).
Diclofenac sodium extended-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS , WARNINGS ).
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS ).
DESCRIPTION
Diclofenac sodium extended-release tablets, USP is a benzeneacetic acid derivative. Diclofenac sodium extended-release tablets are available as extended-release tablets of 100 mg (pink) for oral administration. Diclofenac sodium is a white to off-white, hygroscopic, crystalline powder and is sparingly soluble in water at 25°C. The chemical name is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14 g/mol. Its molecular formula is C 14H 10Cl 2NNaO 2, and it has the following structural formula
The inactive ingredients in diclofenac sodium extended-release tablets include: anhydrous lactose, hydroxyethyl cellulose, povidone, colloidal silicon dioxide, talc, magnesium stearate, hypromellose, titanium dioxide, macrogol, iron oxide red, polysorbate 80.
FDA approved dissolution test specifications differ from USP.
CLINICAL PHARMACOLOGY
Mechanism of Action
Diclofenac sodium extended-release tablets have analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of diclofenac sodium extended-release tablets, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivoeffects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues
Pharmacokinetics
Absorption
Diclofenac is 100% absorbed after oral administration compared to intravenous (IV) administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). When diclofenac sodium extended-release tablets are taken with food, there is a delay of 1 to 2 hours in the T maxand a 2-fold increase in C maxvalues. The extent of absorption of diclofenac, however, is not significantly affected by food intake.
Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (18 to 48 years) Mean Coefficient of Variation (%) Absolute bioavailability (%) [N = 7] 55 40 T max (hr) [N = 12] 5.3 28 Oral clearance (CL/F; mL/min) [N = 12] 895 56 Renal clearance (% unchanged drug in urine) [N = 7] < 1 - Apparent volume of distribution (V/F; L/kg) [N = 56] 1.4 58 Terminal half-life (hr) [N = 56] 2.3 48
Distribution
The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses.
Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.
Elimination
Metabolism
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy- diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acyl glucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patientswith renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.
Excretion
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.
Special Populations
Pediatric: The pharmacokinetics of diclofenac sodium extended-release tablets has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Impairment: Hepatic metabolism accounts for almost 100% of diclofenac sodium extended-release tablets elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium extended-release tablets compared to patients with normal hepatic function.
Renal Impairment: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and less than 30 mL/min; N = 6 in each group), area under the curve (AUC) values and elimination rate were comparable to those in healthy subjects.
Drug Interaction Studies
Voriconazole: When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the C maxand AUC of diclofenac increased by 114% and 78%, respectively (seePRECAUTIONS;Drug Interactions).
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (seePRECAUTIONS;Drug Interactions).
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of diclofenac sodium extended-release tablets and other treatment options before deciding to use diclofenac sodium extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (seeWARNINGS;Gastrointestinal Bleeding, Ulceration, and Perforation).
Diclofenac sodium extended-release tablets are indicated:
for relief of the signs and symptoms of osteoarthritis
for relief of the signs and symptoms of rheumatoid arthritis
CONTRAINDICATIONS
Diclofenac sodium extended-release tablets are contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product (see WARNINGS ; Anaphylactic Reactions , Serious Skin Reactions ).
History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS ; Anaphylactic Reactions , PRECAUTIONS ; Exacerbation of Asthma Related to Aspirin Sensitivity).
In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ; Cardiovascular Thrombotic Events ).
WARNINGS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the
first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events (seeWARNINGS;Gastrointestinal Bleeding, Ulceration, and Perforation).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (seeCONTRAINDICATIONS).
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of diclofenac sodium extended-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium extended-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients
Use the lowest effective dose for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium extended-release tablets until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS ; Drug Interactions ).
Hepatotoxicity
In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the upper limit of normal [ULN]) of aspartate aminotransferase (AST) (also known as SGOT) were observed in about 2% of approximately 5700 patients at some time during diclofenac treatment (ALT [alanine aminotransferase] was not measured in all studies).
In a large, open-label, controlled trial of 3700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium extended-release tablets should be discontinued immediately.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium extended-release tablets immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium extended-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium extended-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
Hypertension
NSAIDs, including diclofenac sodium extended-release tablets, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (seePRECAUTIONS;Drug Interactions).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalization for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (seePRECAUTIONS;Drug Interactions).
Avoid the use of diclofenac sodium extended-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium extended-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of diclofenac sodium extended-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium extended-release tablets may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium extended-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium extended-release tablets (seePRECAUTIONS;Drug Interactions). Avoid the use of diclofenac sodium extended-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium extended-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic Reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma (seeCONTRAINDICATIONS,WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium extended-release tablets are contraindicated in patients with this form of aspirin sensitivity (seeCONTRAINDICATIONS). When diclofenac sodium extended-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including diclofenac, can cause serious skin adverse events, such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of diclofenac sodium extended-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium extended-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (seeCONTRAINDICATIONS).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs, such as diclofenac sodium extended-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium extended-release tablets and evaluate the patient immediately.
Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (seePRECAUTIONS;Pregnancy).
Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium extended-release tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including diclofenac sodium extended-release tablets, may increase the risk of bleeding events. Comorbid conditions, such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (seePRECAUTIONS;Drug Interactions).
PRECAUTIONS
General
Diclofenac sodium extended-release tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
The pharmacological activity of diclofenac sodium extended-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium extended-release tablets and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (seeWARNINGS;Cardiovascular Thrombotic Events).
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (seeWARNINGS;Gastrointestinal Bleeding, Ulceration, and Perforation).
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium extended-release tablets and seek immediate medical therapy (seeWARNINGS;Hepatotoxicity).
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure, including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (seeWARNINGS;Heart Failure and Edema).
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (seeWARNINGS;Anaphylactic Reactions).
Serious Skin Reactions, Including DRESS
Advise patients to stop diclofenac sodium extended-release tablets immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible (seeWARNINGS;Serious Skin Reactions).
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium extended-release tablets, may be associated with a reversible delay in ovulation (seePRECAUTIONS;Carcinogenesis, Mutagenesis, Impairment of Fertility).
Fetal Toxicity
Inform pregnant women to avoid use of diclofenac sodium extended-release tablets and other NSAIDs, starting at 30-weeks’ gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with diclofenac sodium extended-release tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours. (seeWARNINGS;Fetal Toxicity,PRECAUTIONS;Pregnancy).
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of diclofenac sodium extended-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (seeWARNINGS;Gastrointestinal Bleeding, Ulceration, and PerforationandDrug Interactions). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium extended-release tablets until they talk to their healthcare provider (seePRECAUTIONS;Drug Interactions).
Masking of Inflammation and Fever
The pharmacological activity of diclofenac sodium extended-release tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically (seeWARNINGS;Gastrointestinal Bleeding, Ulceration and Perforation, andHepatotoxicity).
Drug Interactions
See Table 2 for clinically significant drug interactions with diclofenac.
Table 2. Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants, such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac sodium extended-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS ; Hematological Toxicity ). Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS ; Gastrointestinal Bleeding, Ulceration, and Perforation ). Intervention: Concomitant use of diclofenac sodium extended-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS ; Hematological Toxicity ). Diclofenac sodium extended-release tablets are not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of diclofenac sodium extended-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium extended-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS ; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium extended-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy, including antihypertensive effects (see WARNINGS ; Renal Toxicity and Hyperkalemia ). Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac sodium extended-release tablets and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium extended-release tablets and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac sodium extended-release tablets and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac sodium extended-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of diclofenac sodium extended-release tablets and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS ; Gastrointestinal Bleeding, Ulceration, and Perforation ). Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac sodium extended-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium extended-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. CYP2C9 Inhibitors or Inducers Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Coadministration of diclofenac with CYP2C9 inhibitors (e.g., voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY ; Pharmacokinetics ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times the maximum recommended human dose (MRHD) of diclofenac sodium extended-release tablets, 200 mg/day, based on body surface area (BSA) comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.
Mutagenesis
Diclofenac sodium did not show mutagenic activity in in vitropoint mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitroand in vivotests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters.
Impairment of Fertility
Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based on BSA comparison) did not affect fertility.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium extended-release tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium extended-release tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pregnancy
Risk Summary
Use of NSAIDs, including diclofenac sodium extended-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium extended-release tablets use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium extended-release tablets use at about 30 weeks of gestation and later in pregnancy (seeWARNINGS;Fetal Toxicity).
Premature Closure of Fetal Ductus Arteriosus
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
There are no adequate and well-controlled studies of diclofenac sodium extended-release tablets in pregnant women.
Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium extended-release tablets, despite the presence of maternal and fetal toxicity at these doses (see Data).
Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Premature Closure of Fetal Ductus Arteriosus:
Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium extended-release tablets, can cause premature closure of the fetal ductus arteriosus (seeWARNINGS;Fetal Toxicity).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium extended-release tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium extended-release tablets and follow up according to clinical practice (seeWARNINGS;Fetal Toxicity).
Labor or Delivery
There are no studies on the effects of diclofenac sodium extended-release tablets during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Data
Human Data
Premature Closure of Fetal Ductus Arteriosus:
Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment:
Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.
Animal Data
Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of diclofenac sodium extended-release tablets, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.
Nursing Mothers
Risk Summary
Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium extended-release tablets and any potential adverse effects on the breastfed infant from the diclofenac sodium extended-release tablets or from the underlying maternal condition.
Data
One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (seeWARNINGS;Cardiovascular Thrombotic Events,Gastrointestinal Bleeding, Ulceration, and Perforation,Hepatotoxicity,Renal Toxicity and Hyperkalemia,PRECAUTIONS;Laboratory Monitoring).
Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (seeCLINICAL PHARMACOLOGY,ADVERSE REACTIONS).
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Cardiovascular Thrombotic Events (see WARNINGS )
GI Bleeding, Ulceration and Perforation (see WARNINGS )
Hepatotoxicity (see WARNINGS )
Hypertension (see WARNINGS )
Heart Failure and Edema (see WARNINGS )
Renal Toxicity and Hyperkalemia (see WARNINGS )
Anaphylactic Reactions (see WARNINGS )
Serious Skin Reactions (see WARNINGS )
Hematologic Toxicity (see WARNINGS )
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In patients taking diclofenac sodium extended-release tablets or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are:
Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), and vomiting.
Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus.
Additional adverse experiences reported occasionally include:
Body as a Whole:fever, infection, sepsis
Cardiovascular System:congestive heart failure, hypertension, tachycardia, syncope
Digestive System:dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice
Hemic and Lymphatic System:ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia
Metabolic and Nutritional:weight changes
Nervous System:anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory System:asthma, dyspnea
Skin and Appendages:alopecia, photosensitivity, sweating increased
Special Senses:blurred vision
Urogenital System:cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions, which occur rarely are:
Body as a Whole:anaphylactic reactions, appetite changes, death
Cardiovascular System:arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis
Digestive System:colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis
Hemic and Lymphatic System:agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia
Metabolic and Nutritional:hyperglycemia
Nervous System:convulsions, coma, hallucinations, meningitis
Respiratory System:respiratory depression, pneumonia
Skin and Appendages:angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special Senses:conjunctivitis, hearing impairment
To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (seeWARNINGS;Cardiovascular Thrombotic Events,Gastrointestinal Bleeding, Ulceration, and Perforation,Hypertension,Renal Toxicity and Hyperkalemia).
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of diclofenac sodium extended-release tablets and other treatment options before deciding to use diclofenac sodium extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (seeWARNINGS).
After observing the response to initial therapy with diclofenac sodium extended release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.
For the relief of osteoarthritis, the recommended dosage is 100-mg daily.
For the relief of rheumatoid arthritis, the recommended dosage is 100-mg daily. In the rare patient where diclofenac sodium extended release tablets 100 mg/day is unsatisfactory, the dose may be increased to 100 mg twice a day, if the benefits outweigh the clinical risks of increased side effects.
Different formulations of diclofenac [VOLTAREN ®(diclofenac sodium enteric-coated tablets); diclofenac sodium extended-release tablets; CATAFLAM ®(diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same.
HOW SUPPLIED
Diclofenac sodium extended-release tablets, USP
100 mg –Pink, round, convex film coated tablets debossed with ING on one side and 278 on the other side.
Bottles of 100: NDC:50742-278-01
Preserve in well-closed containers. Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.
Manufactured for:
Ingenus Pharmaceuticals, LLC
Orlando, FL 32839-6408
Revised: 02/2022
Dispense with Medication Guide available at: www.ingenus.com/medguide/diclofenac-sodium-er-tablets.pdf
ingenus
Dispense with Medication Guide available at: www.ingenus.com/medguide/diclofenac-sodium-er-tablets.pdf
MEDICATION GUIDEDiclofenac Sodium (dye-KLOE-fen-ak SOE-dee-um)Extended-Release Tablets, USP
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: any time during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" increasing doses of NSAIDs longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions, such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breastfeed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?" new or worse high blood pressure heart failure liver problems, including liver failure kidney problems, including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, dizziness. Get emergency help right away if you have any of the following symptoms: shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms and legs, hands, and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away.These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDsMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. 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Numbers 18 KJV NET Parallel
KJV Parallel NET [BSB CSB ESV
HCS KJV ISV NAS NET NIV NLT
HEB]
King James Bible NET Bible
1 And the LORD said unto Aaron, Thou and thy sons and thy father's house with thee shall bear the iniquity of the sanctuary: and thou and thy sons with thee shall bear the iniquity of your priesthood. 1 The LORD said to Aaron, "You and your sons and your tribe with you must bear the iniquity of the sanctuary, and you and your sons with you must bear the iniquity of your priesthood.
2 And thy brethren also of the tribe of Levi, the tribe of thy father, bring thou with thee, that they may be joined unto thee, and minister unto thee: but thou and thy sons with thee
shall minister
before the tabernacle of witness.
2 "Bring with you your brothers, the tribe of Levi, the tribe of your father, so that they may join with you and minister to you while you and your sons with you are before the tent of the testimony.
3 And they shall keep thy charge, and the charge of all the tabernacle: only they shall not come nigh the vessels of the sanctuary and the altar, that neither they, nor ye also, die. 3 They must be responsible to care for you and to care for the entire tabernacle. However, they must not come near the furnishings of the sanctuary and the altar, or both they and you will die.
4 And they shall be joined unto thee, and keep the charge of the tabernacle of the congregation, for all the service of the tabernacle: and a stranger shall not come nigh unto you. 4 They must join with you, and they will be responsible for the care of the tent of meeting, for all the service of the tent, but no unauthorized person may approach you.
5 And ye shall keep the charge of the sanctuary, and the charge of the altar: that there be no wrath any more upon the children of Israel. 5 You will be responsible for the care of the sanctuary and the care of the altar, so that there will be no more wrath on the Israelites.
6 And I, behold, I have taken your brethren the Levites from among the children of Israel: to you they are
given as a gift for the LORD, to do the service of the tabernacle of the congregation.
6 I myself have chosen your brothers the Levites from among the Israelites. They are given to you as a gift from the LORD, to perform the duties of the tent of meeting.
7 Therefore thou and thy sons with thee shall keep your priest's office for every thing of the altar, and within the vail; and ye shall serve: I have given your priest's office
unto you as a service of gift: and the stranger that cometh nigh shall be put to death.
7 But you and your sons with you are responsible for your priestly duties, for everything at the altar and within the curtain. And you must serve. I give you the priesthood as a gift for service; but the unauthorized person who approaches must be put to death."
8 And the LORD spake unto Aaron, Behold, I also have given thee the charge of mine heave offerings of all the hallowed things of the children of Israel; unto thee have I given them by reason of the anointing, and to thy sons, by an ordinance for ever. 8 The LORD spoke to Aaron, "See, I have given you the responsibility for my raised offerings; I have given all the holy things of the Israelites to you as your priestly portion and to your sons as a perpetual ordinance.
9 This shall be thine of the most holy things,
reserved from the fire: every oblation of theirs, every meat offering of theirs, and every sin offering of theirs, and every trespass offering of theirs, which they shall render unto me,
shall be
most holy for thee and for thy sons.
9 Of all the most holy offerings reserved from the fire this will be yours: Every offering of theirs, whether from every grain offering or from every purification offering or from every reparation offering which they bring to me, will be most holy for you and for your sons.
10 In the most holy place shalt thou eat it; every male shall eat it: it shall be holy unto thee.
10 You are to eat it as a most holy offering; every male may eat it. It will be holy to you.
11 And this is
thine; the heave offering of their gift, with all the wave offerings of the children of Israel: I have given them unto thee, and to thy sons and to thy daughters with thee, by a statute for ever: every one that is clean in thy house shall eat of it.
11 "And this is yours: the raised offering of their gift, along with all the wave offerings of the Israelites. I have given them to you and to your sons and daughters with you as a perpetual ordinance. Everyone who is ceremonially clean in your household may eat of it.
12 All the best of the oil, and all the best of the wine, and of the wheat, the firstfruits of them which they shall offer unto the LORD, them have I given thee. 12 "All the best of the olive oil and all the best of the wine and of the wheat, the first fruits of these things that they give to the LORD, I have given to you.
13 And
whatsoever is first ripe in the land, which they shall bring unto the LORD, shall be thine; every one that is clean in thine house shall eat of it.
13 And whatever first ripe fruit in their land they bring to the LORD will be yours; everyone who is ceremonially clean in your household may eat of it.
14 Every thing devoted in Israel shall be thine. 14 "Everything devoted in Israel will be yours.
15 Every thing that openeth the matrix in all flesh, which they bring unto the LORD,
whether it be
of men or beasts, shall be thine: nevertheless the firstborn of man shalt thou surely redeem, and the firstling of unclean beasts shalt thou redeem.
15 The firstborn of every womb which they present to the LORD, whether human or animal, will be yours. Nevertheless, the firstborn sons you must redeem, and the firstborn males of unclean animals you must redeem.
16 And those that are to be redeemed from a month old shalt thou redeem, according to thine estimation, for the money of five shekels, after the shekel of the sanctuary, which is twenty gerahs.
16 And those that must be redeemed you are to redeem when they are a month old, according to your estimation, for five shekels of silver according to the sanctuary shekel (which is twenty gerahs).
17 But the firstling of a cow, or the firstling of a sheep, or the firstling of a goat, thou shalt not redeem; they are holy: thou shalt sprinkle their blood upon the altar, and shalt burn their fat for
an offering made by fire, for a sweet savour unto the LORD.
17 But you must not redeem the firstborn of a cow or a sheep or a goat; they are holy. You must splash their blood on the altar and burn their fat for an offering made by fire for a pleasing aroma to the LORD.
18 And the flesh of them shall be thine, as the wave breast and as the right shoulder are thine. 18 And their meat will be yours, just as the breast and the right hip of the raised offering is yours.
19 All the heave offerings of the holy things, which the children of Israel offer unto the LORD, have I given thee, and thy sons and thy daughters with thee, by a statute for ever: it is a covenant of salt for ever before the LORD unto thee and to thy seed with thee.
19 All the raised offerings of the holy things that the Israelites offer to the LORD, I have given to you, and to your sons and daughters with you, as a perpetual ordinance. It is a covenant of salt forever before the LORD for you and for your descendants with you."
20 And the LORD spake unto Aaron, Thou shalt have no inheritance in their land, neither shalt thou have any part among them: I am thy part and thine inheritance among the children of Israel.
20 The LORD spoke to Aaron, "You will have no inheritance in their land, nor will you have any portion of property among them--I am your portion and your inheritance among the Israelites.
21 And, behold, I have given the children of Levi all the tenth in Israel for an inheritance, for their service which they serve, even the service of the tabernacle of the congregation.
21 See, I have given the Levites all the tithes in Israel for an inheritance, for their service which they perform--the service of the tent of meeting.
22 Neither must the children of Israel henceforth come nigh the tabernacle of the congregation, lest they bear sin, and die. 22 No longer may the Israelites approach the tent of meeting, or else they will bear their sin and die.
23 But the Levites shall do the service of the tabernacle of the congregation, and they shall bear their iniquity:
it shall be
a statute for ever throughout your generations, that among the children of Israel they have no inheritance.
23 But the Levites must perform the service of the tent of meeting, and they must bear their iniquity. It will be a perpetual ordinance throughout your generations that among the Israelites the Levites have no inheritance.
24 But the tithes of the children of Israel, which they offer as an heave offering unto the LORD, I have given to the Levites to inherit: therefore I have said unto them, Among the children of Israel they shall have no inheritance.
24 But I have given to the Levites for an inheritance the tithes of the Israelites that are offered to the LORD as a raised offering. That is why I said to them that among the Israelites they are to have no inheritance."
25 And the LORD spake unto Moses, saying, 25 The LORD spoke to Moses:
26 Thus speak unto the Levites, and say unto them, When ye take of the children of Israel the tithes which I have given you from them for your inheritance, then ye shall offer up an heave offering of it for the LORD,
even a tenth part
of the tithe.
26 "You are to speak to the Levites, and you must tell them, 'When you receive from the Israelites the tithe that I have given you from them as your inheritance, then you are to offer up from it as a raised offering to the LORD a tenth of the tithe.
27 And this your heave offering shall be reckoned unto you, as though
it were
the corn of the threshingfloor, and as the fulness of the winepress.
27 And your raised offering will be credited to you as though it were grain from the threshing floor or as new wine from the winepress.
28 Thus ye also shall offer an heave offering unto the LORD of all your tithes, which ye receive of the children of Israel; and ye shall give thereof the LORD'S heave offering to Aaron the priest. 28 Thus you are to offer up a raised offering to the LORD of all your tithes which you receive from the Israelites; and you must give the LORD's raised offering from it to Aaron the priest.
29 Out of all your gifts ye shall offer every heave offering of the LORD, of all the best thereof,
even the hallowed part thereof out of it.
29 From all your gifts you must offer up every raised offering due the LORD, from all the best of it, and the holiest part of it.'
30 Therefore thou shalt say unto them, When ye have heaved the best thereof from it, then it shall be counted unto the Levites as the increase of the threshingfloor, and as the increase of the winepress. 30 "Therefore you will say to them, 'When you offer up the best of it, then it will be credited to the Levites as the product of the threshing floor and as the product of the winepress.
31 And ye shall eat it in every place, ye and your households: for it is your reward for your service in the tabernacle of the congregation.
31 And you may eat it in any place, you and your household, because it is your wages for your service in the tent of meeting.
32 And ye shall bear no sin by reason of it, when ye have heaved from it the best of it: neither shall ye pollute the holy things of the children of Israel, lest ye die. 32 And you will bear no sin concerning it when you offer up the best of it. And you must not profane the holy things of the Israelites, or else you will die.'" | https://biblehub.com/p/kjv/net/numbers/18.shtml |
The Importance of Cosmology in Culture: Contexts and Consequences | IntechOpen
Scientific cosmology is the study of the universe through astronomy and physics. However, cosmology also has a significant cultural impact. People construct anthropological cosmologies (notions about the way the world works), drawing in scientific theories in order to construct models for activities in disciplines, such as politics and psychology. In addition, the arts (literature, film and painting, for example) comment on cosmological ideas and use them to develop plot lines and content. This chapter illustrates examples of such work, arguing that scientific cosmology should be understood as a significant cultural influence.
Open access peer-reviewed chapter
The Importance of Cosmology in Culture: Contexts and Consequences
Written By
Nicholas Campion
Submitted: November 3rd, 2016 Reviewed: February 17th, 2017 Published: June 7th, 2017
DOI: 10.5772/67976
IntechOpen Trends in Modern Cosmology Edited by Abraao Capistrano
From the Edited Volume
Trends in Modern Cosmology
Edited by Abraao Jesse Capistrano de Souza
Abstract
cosmology
culture
politics
psychology
literature
film
space travel
Chapter sections
1. Introduction
Modern scientific cosmology is valuable in itself for what it reveals about the nature of the cosmos we inhabit [1]. It is a demonstration of the power of modern science to transform our understanding of who we are and where we came from. However, most cosmologists focus on scientific questions and are not fully aware of the impact of cosmological theories on culture, including politics and the arts. This chapter introduces this wider context on the basis that both scientists and the public should be aware of the broader importance of their work and its influence on the way we think. Cosmologists often rely on the fascination the subject brings: as Rowe observed in his textbook way back in 1968, ‘In the fields of astronomy and cosmology we live in a period of excitement’ [2]. Cosmology therefore both impacts culture and is described and represented by it. This chapter explores some ways in which this happens. As Muriel Rukeyser wrote, ‘The universe is made of stories, not of atoms’ [3]; see also Impey [4].
If we select four fundamental causes of changes in our perceptions of the world in the last century, then they would be first relativity, second quantum mechanics, third the expanding universe and fourth, the space programme. The first three date from a fairly narrow time band, if we date special relativity from 1905, general relativity from 1915, that the universe is expanding and is much bigger than previous thought from Edwin Hubble’s publications from 1924 to around 1930 and quantum mechanics from Niels Bohr and Werner Heisenberg’s formulation of the Copenhagen interpretation in 1925–1927 [5]. This epic revision of scientific knowledge of underlying structures of the universe was therefore concentrated into just a quarter of a century. The dramatic period of the human space programme was concentrated into just over 8 years from the first human space flight in 1961 to the Moon landing in 1969.
All have fundamentally altered the way that we think about life here on Earth. Often these changes are taken for granted. For example, mobile phone technology, dependent as it is on satellite networks, is transforming not only the social lives of teenagers in the west, but also the economic muscle of poor farmers across the third world. Meanwhile, super‐fast quantum computing makes use of phenomena such as entanglement and is driving the development of artificial intelligence, and hence of robotics. The implications for society over the next few decades are potentially enormous. The most important conclusion to be drawn from this combination of revolutionary changes is the role of the observer: as the basis of differing perspectives of time and space in relativity, an influence on the world (at least, at the sub‐atomic level) in quantum mechanics, and the witness for the first time, of the spherical earth, hanging in space, in photographs taken by Apollo astronauts in 1968. Such ideas and experiences have decisively underpinned modern ideas that one person’s complete individual experience or perception is as equally valid as anyone else’s. Einstein is held particularly responsible for these ideas [6,7] as a result of popular equations between relativity on the one hand, and cultural relativism (the idea that no one culture is superior or inferior to another) on the other. Moral relativism (the idea that no one culture is morally superior or inferior to another) is controversial and widely rejected, but cultural relativism does have beneficial scholarly consequences. This is especially the case in the new field of cultural anthropology in which academic rigour requires that in order to better understand other cultures, researchers must abandon any idea that one culture is superior or inferior to another.
2. Defining cosmology
The term cosmology can be traced to the 1730s, although its appearance in a scientific sense dates from only after the Second World War [8]. The logos, which is the root of ‘logy’, means ‘an account’, so that, as a preliminary working definition, cosmology is simply ‘an account of the cosmos’. The primary Latin equivalent of the Greek Kosmosis Universus, from Unus verto, or ‘changing into one’, thereby suggesting unity. We can divide the definitions of cosmology into two: the scientific and the anthropological. The scientific are perhaps the more familiar, but even here there is variation. Scientific definitions range from the narrow, such as ‘the study of the universe’ [9], to the broad (‘the science, theory or study of the universe as an orderly system, and of the laws that govern it; in particular, a branch of astronomy that deals with the structure and evolution of the universe’) [10]. The idea that cosmology is synonymous with astronomy is widespread [2,11]. Yet the relationship between astronomy and cosmology is not settled, and Hawley and Holcomb [9] argue that cosmology is a separate discipline, which combines features of both astronomy and physics. There are other places where disciplines overlap. For example, astronomy has to include geophysics precisely because the Earth itself is in space [12].
Anthropological cosmologies are based on the proposition that ideas about the cosmos are integral part of human cultural and social systems. For example, the archaeologist Timothy Darvill talks of a cosmology as being, ‘The world view and belief system of a community based upon their understanding of order in the universe’ [13]. George Gumerman and Miranda Warburton argued that ‘… to truly comprehend a culture we must have some sense of its cosmology – the group’s conception of themselves in relation to the heavens’ [14]. And without diminishing the scientific status of modern cosmology, ideas do not come from theory and experiment alone, but can be inspired by wider cultural influences, as Holton [15] illustrates in relation to Einstein’s reading and education before he formulated the theory of special relativity. Heisenberg [16] actually argued that science and art are parallel attempts to describe the world, and may both be part of a wider cultural picture. Bell [17] then talks of ‘complex subsystems of cosmic exchange’ which underpin mundane systems of behaviour, such as socio‐economic exchange, but are designed to reinforce individual and social existence within the cosmos.
The philosopher Terry Eagleton concluded, ‘“Culture” is said to be one of the two or three most complex words in the English language’ [18]. A good working definition, though, is offered by the anthropologist Clifford Geertz, who argued that culture is ‘an historically transmitted pattern of meanings embodied in symbols, a system of inherited conceptions expressed in symbolic forms by means of which men communicate, perpetuate and develop their knowledge of and attitudes toward life’ [19]. The influence of cosmology on culture then becomes a matter of exploring its impact on political and religious ideas, and its use in the arts, perhaps mainly in literature, painting and film. Michael Rowan‐Robinson wrote that ‘the intellectual horizon of the human race at any time has always been inextricably bound up with the scale of the universe… there can be little doubt that a people’s perceived scale of the universe must play a fundamental role in its culture and consciousness’ [20]. He could equally have said that culture and consciousness are bound up with conceptions of the universe as a whole. It was Einstein himself who made the case for the cosmologist intervening in culture. In 1936 he wrote, ‘the physicist cannot simply surrender to the philosopher the critical contemplation of the theoretical foundations’ of the universe, and ‘the critical thinking of the physicist cannot possibly be restricted to examination of his own field. He cannot proceed without considering critically a much more difficult problem, the problem of analysing the nature of everyday thinking’ [21]. Mostly the cosmologist does not intervene directly in modern culture. Instead other people interpret and represent cosmological ideas.
4. Politics
Cosmology has had a substantial impact on political theory and continues to do so. We can therefore talk about ‘political cosmology’ [22]. The earliest recorded societies used the stars or planets to represent their rulers or guide their actions, functions which tended to overlap with religion. The Egyptians and Inca saw their rulers embodied in the Sun, the Chinese in the Pole Star, and in Babylon the chief god, Marduk, was represented by Jupiter. On a practical level, most pre‐modern cultures structured their religious sanctuaries, and sometimes their urban communities, according to their conceptions of the cosmos. Hence we may speak of ‘cosmopolises’ or ‘cosmograms’. A ‘cosmic state’ is one in which the entire state is organized to embody the structure of the cosmos.
The significant step into modelling politics on the cosmos as an organised system was taken by the Greek philosopher Plato (ca. 428/7?–348/7). Plato’s cosmos emanated out of a single consciousness which existed in a realm of unchanging eternity. The material world was then an imperfect representation of the world of Ideas (Plato spoke of the physical world being embedded in the world‐soul) and was governed by time, the mathematically regulated, harmonious rhythms measurable by the motions of the planets. Plato’s mathematical universe provides a rationale for scientific speculation to the present day [23,24].
Plato advocated an education emphasising such subjects as music, mathematics and geometry, and a political system based on rule by philosophers, all designed to harmonise society with the cosmos, for the common good. This concept of the perfect society underpins the entire history of utopianism down to the present day. There were two main consequences of Plato’s system, with consequences down to the present day. First, the perfect ruler was envisioned as the Philosopher King, whose right to rule was justified by his wisdom and understanding of cosmic principles. Second, the system tended to be authoritarian because, being founded on cosmic principle, it could brook no opposition. Plato’s ideas were revived in Renaissance Europe and were to become extremely influential. The notion of human history as the progressive unfolding of the world soul towards a final, perfect condition was central to the ideas of Georg Friedrich Hegel (1770–1831). Hegel’s influence on Karl Marx (1818–1883) led the twentieth century philosopher of science, Popper [25], to see Plato’s thought as the foundation of modern totalitarianism: where Plato influenced Marx, via Hegel, was in the notion that history has an inescapable trajectory, founded in the structure of the cosmos itself. For revolutionary Marxists, such as Lenin, Stalin and Mao Tse‐tung, it was then inconceivable that anyone could oppose their rule, for to do so was to oppose the cosmos.
Separate to the platonic strand in European political cosmology, the astronomical discoveries from Copernicus onwards all helped shape western politics. Copernicus’ argument that the Sun, not the Earth, is the centre of the universe (or the solar system as we would now say) was attached to the ancient idea that the Sun is associated with kings. It was then used to support claims that, just as the entire universe orbits the Sun, so the whole of society orbits the king [26]. Propaganda in support of absolute monarchy then reached its height in the iconography of the French king Louis XIV. Such authoritarian ideas were directly countered by what I have called Political Newtonianism [22]. This held that, just as Newton had argued that one law governed the whole universe, so the same principle must apply to terrestrial affairs and one law must govern the whole of human society. In principle, then, all people were equal, and there was no justification for monarchy. Such ideas were influential among both the American revolutionaries of 1776 [27] and the French in 1789.
Newtonianism was taken one step further by Auguste Comte (1798–1857), the founder of sociology. Adding Galileo and Kepler to Newton as sources of authority, Comte [28] argued that if the entire universe was a mathematically regulated mechanism, so human society must also be governed by the same principle. If planets moved in mathematically determined patterns, Comte reasoned, so must people. By collecting and analysing data on human behaviour, Comte concluded, the same laws that controlled the wider universe should be discovered in human affairs. And in turn the state, governed by experts who were the modern equivalent of Plato’s philosophers, could be managed for the good of all. This remains the foundation of twenty‐first century sociology.
There have been a few attempts, for example, to identify Einsteinian relativity either as a form of political discourse, or to draw political implications from it. As far as the former is concerned, I refer to the French feminist and social theorist Luce Irigaray who has identified the theory of relativity as a political rather than scientific formula [29]. Sokal and Bricmont [28], meanwhile, noted how the notion of relativity in time and space was used by postmodern theorists in order to advocate cultural relativity on the grounds that, if the universe has no single centre, neither does culture.
The anthropologist Falzon [30] has defended multi‐sited ethnography against the charge of lack of depth by arguing that it takes into account shifting perceptions of space and time. The anthropologist Marcus [31] refers to ‘space‐time compression’, in which the essential difference between space and time contracts in light of the recognition that both are socially produced as a result of what Falzon calls ‘a product of interrelations’; Marcus derived his understanding from special relativity, and so directly from his understanding of Einstein. Elsewhere, Einstein’s call for humanity in general to take on the implications of the new cosmology has been used to advocate a collaborative global order in which international problems are solved thought global institutions rather than war [32].
5. Psychology
The consequences of Newtonianism (the belief that the entire universe is mathematically regulated) permeate western thought wherever there has been a search for a universal law based on supposedly hard data. Psychology is a prime example. When the word ‘psychology’ was coined around 1800, it was thought that, since Newtonian science explained everything that exists and occurs in the material world, there could and should be just one science explaining what exists and occurs in the psychological world. As Gilbert Ryle wrote, ‘“Psychology” was supposed to be the title of the empirical study of “mental phenomena”’, a counterpart to Newtonian celestial mechanics [33]. Concepts such as normality and deviation have dominated some of the major schools of western psychology, their roots in Newtonian cosmology’s devotion to predictable order unrecognised and forgotten. The measurement and mathematical analysis of the human mind then became the basis of much psychiatry and academic psychology. Even the notion developed by Sigmund Freud (1856–1939), that psychic—or psychological—material can be ‘repressed’, as if by some kind of downward pressure, is derived from Newtonian mechanics through the influential German physicist Hermann von Helmholtz (1821–1894) [34]. The goal of Freudian psychoanalysis is for the patient to become aware of such repressed material through the so‐called talking cure, the conversations which take place during sessions with the psychoanalyst, thus releasing in downward pressure.
Freud’s student C.G. Jung opened a radically different strand of thought in modern psychology which is highly influential in many schools of psychotherapy and counselling practiced in society as a whole, although usually outside the academic system. Jung revived the Platonic theory that everything in the world is a manifestation of an original pure idea or archetype. Jung’s system, known as analytical psychology, adheres to a kind of archetypal philosophy in which all psychological types correspond to an archetype, such as the eternal youth (the puer aeternus), anima (female principle) or senex (wise old man), which exist in the collective unconscious, Jung’s update of the Platonic world‐soul. The aim of Jung’s therapeutic model is for the individual to become truly themselves by recognising the role of the archetypes in their lives and, in effect, understanding their true connections to the cosmos. The idea that one can become one who truly is also relates back to Aristotelian cosmology in which it was thought that the four elements (fire, earth, air and water) all try to find their natural place in the world. This, Aristotle thought, was why flames go up to the sky, where fire belongs, and water falls to the ground, because that is where it finds its natural home. In Aristotelian politics, kings are at the top of society and peasants at the bottom, because that is the natural state of affairs; in Aristotelian psychology every individual then has a natural way of being. Jung, though, was equally concerned with the latest science, and formed a collaboration and friendship with the quantum physicist Wolfgang Pauli (1900–1958) [35]. Together they formulated the concept of synchronicity by which meaningful events are connected because they take place at the same time, without any causal connection [36]. Newtonian psychology—the belief that all mental states can be measured—survives in university departments and psychiatry. But in the wider world, where increasing numbers of people seek counselling and psychotherapy, Einstein is taken as the inspiration for the argument that therapists and analysts must be ‘less concerned with the basic nature of time and more with the human experience of it’ [37].
6. Literature and film
One of the major genres of writing in western culture goes under the name ‘celestial journey literature’, derived from ancient texts on the soul’s journey. The soul’s journey was secularised in Dante’s (1265–1321) ‘Divine Comedy’ [38]. Inspired by Plato’s myth of Er, Dante is guided by the poet Virgil and his love, Beatrice, through the spheres of Hell, Purgatory and Paradise (Hell and Purgatory are structured in spheres analogous to the spheres on which the planets and stars orbit). The last great example of the celestial journey of the soul or a dream world was Johannes Kepler’s ‘Somnium’, an account of lunar astronomy written in 1608 but published in 1634, and sometimes referred to as the first work of science fiction. The genre took a decisive step forward in Francis Godwin’s ‘Man in the Moon’ [39], published in 1638. Like Dante, Godwin used his story to describe the structure of the cosmos, now, after Johannes Kepler and Galileo, rejecting the planetary spheres and challenging the Aristotelian idea that all things have their natural place. Godwin departed from the old idea of a journey of the soul or a dream world. Instead, his hero, Gonzales, flies to the Moon carried by giant geese. From Godwin onwards the celestial journey becomes physical, arriving at the Moon rocket in Jules Verne’s 1865 novel, ‘From the Earth to the Moon’. Verne’s book was one of the inspirations for what may be the first space film, Georges Méliès’ ‘Le Voyage dans la Lune’—in English ‘A Trip to the Moon’—after which astronomy and cosmology have a regular presence in film culture [40]. In Méliès’ film, the astronomers encounter the inhabitants of the Moon, known as Selenites, in what is clearly a parable for European colonialism: the film was released midway through the so‐called ‘Scramble for Africa’, the final face of the European take‐over of Africa from the 1880s to 1914. From Méliès on, the major celestial journey novels have often been filmed. Perhaps the most famous is Stanley Kubrick’s film of Arthur C. Clarke’s ‘2001: A Space Odyssey’. Clarke’s metaphysical story is vividly portrayed first through the transition from ape to human, and then, in the final scene, the transformation of the dying astronaut into the star child. Accompanied by the stirring music of Wagner’s ‘Also sprach Zarathustra’, Kubrick created a vivid evocation of both ancient beliefs in the soul’s ascent to the stars and modern ideas that human destiny may take us to realms beyond our current imagination.
While celestial journey films can be enjoyed as simple adventures, they often contain deeper meanings. The 1951 movie ‘The Day the Earth Stood Still’ exploited the current public interest in Flying Saucers. Released at a time when the Cold War was reaching its height with the conflict in Korea, the story featured a wise alien who arrived from space in order to reveal to humanity the error of its ways. The rejection of the alien’s words of wisdom presented a gloomy view of humanity as incapable of solving its problems. Cosmology, through film, then becomes a means of commenting on societal change. ‘Star Trek’, the biggest celestial journey TV franchise of them all, was launched in 1966. ‘Star Trek’ was altogether more sophisticated than ‘Lost in Space’ and was entirely more optimistic. It is set in a utopian future in which there is one world government, collaborating with other worlds through United Federation of Planets, and money has been abolished. In the crew’s adventures, the European voyages of the fifteenth and sixteenth centuries are replayed in a universe of an infinite number of galaxies, except that now alien cultures are to be respected and preserved rather than conquered and destroyed. The values espoused by the Federation were American: freedom from tyranny, freedom of expression and respect for minorities. Compared to ‘Star Trek’, the blockbuster film franchise, ‘Star Wars’, launched in 1976 and still going strong forty years later, projects into space a simpler version of the endless struggle for freedom against an evil empire, very much an update of anti‐Nazi war films. In all such cases the cosmos is seen as a blank slate, a tabula rasa, on which human concerns are imposed.
There is a constant strand of literary comment on cosmology in the nineteenth century. Edgar Allan Poe (1809–1849), often known as the author of the first detective novel, wrote a remarkable work which he called ‘Eureka’ [41], deliberately suggesting an imaginative breakthrough in the understanding of the cosmos. Poe realised that in a Newtonian universe the stars are likely to collapse in on each other, and that therefore the universe must be evolving [42]. Thomas Hardy (1840–1928) was as fascinated by cosmology as Poe, but unlike him lived to see the publication of Darwin’s ‘Origin of Species’ in 1959 (when he was just 19). For Hardy evolution was a reality. He combined his encyclopaedic knowledge of myth, astronomy and cosmology into a ‘moral astrophysics’ [43] which provided the background for the individual conflicts and tragedies in novels such as ‘Far from the Madding Crowd’ (1874) and ‘Tess of the d’Urbervilles’ (1891/1892). Virginia Woolf (1882–1941) used Edwin Hubble’s discovery of the expanding universe in the 1920s as a metaphor for personal and political insecurity in the 1930s. In Woolf’s view, as we all live together on the same delicate, vulnerable planet in a vastness of space, it is incumbent upon us to live together rather than fight [44]. The Marxist playwright Bertolt Brecht (1898–1956) looked back to an earlier cosmology but equally wanted to illustrate a modern point in his 1938 play, ‘Galileo’. His portrayal of Galileo as the heroic intellectual defending Copernicus, struggling against an obscurantist Inquisition (inaccurate because many in the senior Catholic hierarchy were Copernicans), was an allegory of the revolutionary struggles of the 1930s.
One of the other familiar tropes derived from modern cosmology is time travel, a topic rarely dealt with in ‘Star Trek’, in spite of the regular use of faster‐than‐light travel. There is now a considerable literature which draws on Gerald Feinberg’s 1967 paper ‘Possibility of faster‐than‐light particles’, which proposed the existence of the tachyon [45]. This hypothetical particle, the tachyon, might as Martin Rees [46], says alter the order of events, if a signal from a tachyon arrived before it was sent. The genre’s earliest notable example was Wells’ novel ‘The Time Machine’ (1895) [47]. Wells coined the phrase time machine to describe a time‐travelling vehicle which moved because the fourth dimension was of time rather than space. Wells was a utopian socialist and his main preoccupation was to explore varieties of human society, considering whether progress inevitably resulted in human improvement: it’s clear that he didn’t think that this was the case, and that ignorance and superstition could easily flourish in the future. Neither does ‘Dr Who’, the most successful TV time travel franchise, explain how it is possible to travel to the distant past or future. The time machine, the TARDIS (short for Time and Relative Dimensions in Space), is bigger inside than outside and references Einstein by referencing relativity in its name. The Doctor himself is increasingly represented as a lonely figure, destined to exist in perpetual sadness caused by the death or departure of his companions.
The concept of alienation is developed by Alan Lightman in his ‘Einstein’s Dreams’ [48], a journal set in 1905—the ‘annus mirabilis’ when Einstein developed the theory of Special Relativity. Lightman’s character experiences the alienation of a world in which any particular point in space‐time is delicate, temporary and liable to vanish, an ‘exile in time’ [48]. In a later entry, Lightman’s diarist writes ‘There is a place where time stands still. Raindrops hang motionless in air. Pendulums of clocks float mid‐swing’ [49]. At the centre of space‐time nothing moves. The concept that all time exists simultaneously actually has a long lineage. It is central to Plato’s cosmology, occurs in the Bible (Ecclesiastes 3.15), and was elaborated by St. Augustine (V.9) in the fifth century [50]. He described a universal paradox whereby even if a future event in our individual lives already exists, it depends on an act of our free‐will in order to take place. T.S. Elliot, impressed by Einstein, combined the lessons of relativity with Plato, Ecclesiastes and Augustine. Following Einstein’s English visit in 1921, the year he won the Nobel Prize, Elliot wrote, ‘Einstein the Great has visited England (and) has taken his place in the newspapers with the comet, the sunspots, the poisonous xxx‐jellyfish and octopus at Margate, and other natural phenomena’ [51].
In two poems composed in the 1930s, and published in 1941–1942, Elliot considered the conundrum of time for the human condition. In ‘Burnt Norton’ he wrote that ‘All time is unredeemable’, for if the past exists in the future and the future exists in the past, all possibilities are eternally present, and in ‘East Coker’ he wrote the famous line ‘In my beginning is my end’ [52]. Elliot’s speculations on time were shared by Priestly in such metaphysical plays as ‘Time and the Conways’ (1937) and, perhaps his most famous work, ‘An Inspector Calls’ (1947), in which a detective from the future extracts confessions of guilt for a poor girl’s suicide from a comfortable middle class family. Priestley’s immediate inspiration was Dunne’s [53] work on time, which drew on Einstein (a cautiously supportive note was included by Arthur Eddington in the appendix to the third edition) in order to explain why the future could be predicted by precognition.
The popular end of such speculation is best represented by the collected works of Philip K. Dick (1928–1982). Like Elliot, Dick was inspired by ancient philosophy and modern science, especially the conclusions of quantum mechanics as expressed in Heisenberg’s uncertainty principle and Erwin Schrȍdinger’s famous thought‐experiment with the cat (1935), ideas responsible for modern multi‐verse theory. If one cannot tell both where a particle is and where it is travelling to, whether it is even a particle at all (or a wave), and how far the act of observing it has altered its state, how can one ever trust what appears to be real. For example, in the ‘The Cosmic Puppets’ (1957), an ordinary suburban couple return to their hometown after a gap of several years to find that everyone and everything has changed, and nobody recognises them. The novel then shifts into a traditional religious mode, located in the Zoroastrian (Persian) struggle between the good god Ormazd and his evil rival Ahriman. Eventually Ormazd triumphs, the illusory world created by Ahriman is removed, and reality returns. In Dick’s award‐winning counter‐factual history, ‘The Man in the High Castle’ (1962), the ability of the observer to act on—and change—the material world is described via the lead characters’ use of the Chinese oracle, the I Ching, to alter the future.
Dick’s intensity is absent from the most whimsical of recent cosmological fiction, that of Italo Calvino (1923–1985). Calvino took cosmological ideas and exaggerated them until they were absurd. His short story, ‘The Form of Space’ (2002), points out that if one fell in curved space, one would logically fall for ever, while ‘the Distance of the Moon’ imagines a time in the distant past when the Moon was closer to the Earth, close enough for people to jump up to it and gather such delicacies as Moon‐milk.
7. The visual arts
Representations of the sky, stars or cosmos in visual form date back to the Stone Age and are familiar throughout the ancient world. They may be symbolic, as in Egyptian astronomical‐ceilings, or take on human form, as in Roman images of planetary deities. Later they might be decorative, as in Renaissance star maps, or attempt accuracy, as in modern star maps, or be entirely abstract, as in twentieth century surrealism. The Sun and Moon make regular appearances in western painting, as one would expect. The cosmological statements, though, are often simple. Often the Sun and Moon are poetic additions, symbolising time or heaven in medieval and Renaissance art, casting light or embodying the power of nature, and even serve as political satire in the nineteenth century [54]. Cosmological changes encouraged the new spirit: the philosopher Berlin [55] argued that the astronomical revolution’s abandonment of the old crystalline planetary spheres in favour of a universe without boundaries encouraged the emergence of the chaos and adventurism of Romantic art. Painting began the shift towards the abstract with the extraordinary work of Joseph Turner, who drew on both esoteric wisdom and the latest science in his portrayal of light [56,57]. Perhaps the most famous example of nineteenth century astronomical art is van Gogh’s 1889 masterpiece ‘The Starry Night’, a painting partly inspired by the pre‐dawn rising of Venus, but easily interpreted as representing the swirling chaos of van Gogh’s inner world.
The relationship between modern art movements and science is complicated by many artists’ multiple affiliations. For example, many notable early twentieth century painters were followers of Theosophy, a spiritual teaching highly indebted to Plato, Renaissance alchemy and Freudian psychoanalysis, all of which could deal with unseen realities and the interdependence of all things in the cosmos. It is therefore not easy to distinguish scientific influences on twentieth art from mystical or magic ones and it is up to art historians to interpret [58]. However, it is clear that the new physics encouraged the move towards radical, abstract forms of expression. Heisenberg’s uncertainty principle appears to have supported the playful, apparently chaotic, practices of Dada, in which nothing is quite as it seems. When Marcel Duchamp (1887–1968) displayed a urinal in 1917 he was making a radical statement that, if art is not what one imagines it is, neither is anything else.
André Breton (1896–1966), the poet and author of the Surrealist Manifesto, singled out Einstein (along with Freud) as significant in 1922. J.W. Dunne’s adaptation of Einstein to precognition and psychology was popular with the surrealists, as it as with Priestley. That the observer stands at the centre of time and space, as popular conceptions of relativity and quantum mechanics assume, underpins the playful juxtaposition of images and ideas, sense and nonsense, which runs through the entire history of modern abstract and conceptual art. When Joan Miro paints a picture such as ‘Dog barking at the Moon’ (1926), he is alluding to ideas that the Moon makes one mad— lunatic—as well as departing significantly from naturalism, but also raising a smile.
A separate strand of painting drew on mathematical conceptions of the universe, as did Duchamp’s earlier painting ‘Nude Descending a Staircase’ (1912), or Man Ray’s (1890–1976) geometrical models, such as ‘Polyèdres’ (1934–1936). The distinctive angular lines of Picasso’s painting were also decisively influenced by the idea of multi‐dimensional mathematics as explained by Miller [59]. By contrast, the whirling lines in Max Ernst’s ‘…sur le plan de la Physique’ (1943) evoke the spinning of atoms. And for Klee [60], writing in 1920, movement in painting was essential because everything in the universe is characterised by motion. Perhaps the most famous portrayals of the new physics are Salvador Dali’s (1904–1989) paintings of bent clocks as representations of distorted space‐time, as in ‘The Persistence of the Disintegration of Memory’ (1952).
8. Space flight
It is well understood that the photographs of the whole Earth taken by the Apollo astronauts encouraged concepts of the global village, a world devoid of racial divisions, religious schism and political boundaries [61,62]. The first major use of the Apollo photographs was on the cover of the first Whole Earth Catalogue in 1968, placed there by the editor, political activist Stewart Brand. Subsequently, the photographs became an inspiration for the emerging environmental movement.
Since 1968/1969 we have been able to look down on our sky from space. The euphoric consequences of this experience, still enjoyed by a few hundred people, was named the ‘Overview Effect’ by Frank White in 1987 [63]. Interviewed on BBC Radio 4’s iPM programme on 25 May 2013, the astronaut Geoff Hoffman described his own experience of the effect [64]. He recalled the strange sensation of looking down at the Earth, watching the terrestrial sky from above instead of from below, witnessing the flash of lightning storms and streaks of light as meteors plunged into the atmosphere. He saw the world as one, drawing salutary ecological lessons from the visible deforestation of tropical areas. Inspired by the ethereal nature of the Earth’s halo, Hoffman hesitated to use the word ‘spiritual’, put to him by his interviewer in a leading question, but was happy to describe the condition he experienced on his mission as being a ‘state of grace’, words which he said had been suggested to him by a Jesuit priest. Shamans, Pharaohs and Platonic souls may have seen the Earth in their imaginations, but astronauts experience it physically.
The ‘Overview Effect’ has been institutionalised in the Overview Institute, whose purpose is to utilise the Effect for the common good. The Institute’s apocalyptic and utopian agenda draws a direct connection between the experience of space travel and the need to save the Earth: ‘We live at a critical moment in human history. The challenges of climate change, food, water and energy shortages as well as the increasing disparity between the developed and developing nations are testing our will to unite, while differences in religions, cultures, and politics continue to keep us apart. The creation of a ‘global village’ through satellite TV and the Internet is still struggling to connect the world into one community. At this critical moment, our greatest need is for a global vision of planetary unity and purpose for humanity as a whole’ [65]. In this sense, the institute completes the earlier visions of Virginia Woolf and Stewart Brand.
9. Conclusion
Modern scientific cosmology needs to be valued not just for what it tells us about the universe, but for how what it tells us informs the ways that people think and behave in wider culture. A number of themes emerge, including the vastness of space as a metaphor for loneliness and insecurity, and the new physics as a source of freedom and adventure. Scientific cosmology’s wider significance needs to be more widely acknowledged, for modern society still benefits from ‘complex subsystems of cosmic exchange’ between scientists —cosmologists—and the general public.
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Evaluation of resistance to powdery mildew and identification of resistance genes in wheat cultivars [PeerJ]
Wheat powdery mildew, caused by the biotrophic fungus Blumeria graminis f. sp. tritici (Bgt), is a serious disease of wheat worldwide that can cause significant yield losses. Growing resistant cultivars is the most cost-effective and eco-soundly strategy to manage the disease. Therefore, a high breeding priority is to identify genes that can be readily used either singly or in combination for effective resistance to powdery mildew and also in combination with genes for resistance to other diseases. Yunnan Province, with complex and diverse ecological environments and climates, is one of the main wheat growing regions in China. This region provides initial inoculum for starting epidemics of wheat powdery mildew in the region and other regions and thus, plays a key role in the regional and large-scale epidemics of the disease throughout China. The objectives of this study were to evaluate seedling resistance of 69 main wheat cultivars to powdery mildew and to determine the presence of resistance genes Pm3, Pm8, Pm13, Pm16, and Pm21in these cultivars using gene specific DNA markers. Evaluation of 69 wheat cultivars with six Bgt isolates showed that only four cultivars were resistant to all tested isolates, indicating that the overall level of powdery mildew resistance of Yunnan wheat cultivars is inadequate. The molecular marker results showed that 27 cultivars likely have at least one of these genes. Six cultivars were found likely to have Pm3,18 likely to have Pm8,5 likely to have Pm16,and 3 likely to have Pm21. No cultivar was found to carry Pm13. The information on the presence of the Pmresistance genes in Yunnan wheat cultivars can be used in future wheat disease breeding programs. In particular, cultivars carrying Pm21, which is effective against all Bgtraces in China, should be pyramided with other effective genes to developing new cultivars with durable resistance to powdery mildew.
Evaluation of resistance to powdery mildew and identification of resistance genes in wheat cultivars
Research article
Agricultural Science
Genetics
Molecular Biology
Mycology
Plant Science
Xianxin Wu 1 , Qiang Bian 2 , Yue Gao 1 , Xinyu Ni 1 , Yanqiu Sun 1 , Yuanhu Xuan 1 , Yuanyin Cao 1 , Tianya Li 1
Published January 11, 2021
Author and article information
1 College of Plant Protection, Shenyang Agricultural University , Shenyang , China
2 National Pesticide Engineering Research Center, Nankai University , Nanjing , China
DOI
10.7717/peerj.10425
Published
2021-01-11
Accepted
2020-11-03
Received
2020-08-27
Academic Editor
Carlos Zuniga-Gonzalez
Subject Areas
Agricultural Science , Genetics , Molecular Biology , Mycology , Plant Science
Keywords
Powdery mildew , Resistance genes , Molecular markers , Wheat
Copyright
© 2021 Wu et al.
Licence
This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
Cite this article
Wu X, Bian Q, Gao Y, Ni X, Sun Y, Xuan Y, Cao Y, Li T. 2021 . Evaluation of resistance to powdery mildew and identification of resistance genes in wheat cultivars . PeerJ 9 : e10425 https://doi.org/10.7717/peerj.10425
Abstract
Wheat powdery mildew, caused by the biotrophic fungus Blumeria graminisf. sp. tritici( Bgt), is a serious disease of wheat worldwide that can cause significant yield losses. Growing resistant cultivars is the most cost-effective and eco-soundly strategy to manage the disease. Therefore, a high breeding priority is to identify genes that can be readily used either singly or in combination for effective resistance to powdery mildew and also in combination with genes for resistance to other diseases. Yunnan Province, with complex and diverse ecological environments and climates, is one of the main wheat growing regions in China. This region provides initial inoculum for starting epidemics of wheat powdery mildew in the region and other regions and thus, plays a key role in the regional and large-scale epidemics of the disease throughout China. The objectives of this study were to evaluate seedling resistance of 69 main wheat cultivars to powdery mildew and to determine the presence of resistance genes Pm3, Pm8, Pm13, Pm16, and Pm21in these cultivars using gene specific DNA markers. Evaluation of 69 wheat cultivars with six Bgtisolates showed that only four cultivars were resistant to all tested isolates, indicating that the overall level of powdery mildew resistance of Yunnan wheat cultivars is inadequate. The molecular marker results showed that 27 cultivars likely have at least one of these genes. Six cultivars were found likely to have Pm3,18 likely to have Pm8,5 likely to have Pm16,and 3 likely to have Pm21. No cultivar was found to carry Pm13. The information on the presence of the Pmresistance genes in Yunnan wheat cultivars can be used in future wheat disease breeding programs. In particular, cultivars carrying Pm21, which is effective against all Bgtraces in China, should be pyramided with other effective genes to developing new cultivars with durable resistance to powdery mildew.
Cite this as
Wu X, Bian Q, Gao Y, Ni X, Sun Y, Xuan Y, Cao Y, Li T.
2021
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Evaluation of resistance to powdery mildew and identification of resistance genes in wheat cultivars
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PeerJ 9
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e10425
https://doi.org/10.7717/peerj.10425
Main article text
Introduction
Wheat ( Triticum aestivumL.) is one of the most important food crops, which plays a very key role in the world food supply and food security, but its production is constantly challenged by various diseases ( Ma et al., 2014 ; Zhang et al., 2017). Powdery mildew, caused by the biotrophic fungus Blumeria graminisf. sp. tritici( Bgt), is one of the most serious diseases limiting wheat production in many regions of the world ( Zhang et al., 2016). Breeding and growing resistant cultivars is generally considered to be the most economical, effective, and environmentally friendly method to control this disease (Petersen et al., 2015;El-Shamy, Emara & Mohamed, 2016). The first powdery mildew ( Pm) resistance gene in wheat was found in wheat variety ‘Thew’ by Australian researcher Waterhouse in 1930 ( Zeller, 1973). Since then, new powdery mildew resistance genes have been identified from common wheat and wheat relatives. In the meantime, the inheritance characteristics and chromosome locations of powdery mildew resistance genes were studied extensively (Bhullar et al., 2010;Brunner et al., 2012;Hanusova et al., 1996). To date, over 91 Pmresistance genes , mapped to 61 loci, have been characterized, and new genes are continually described in common wheat and relatives ( Hao et al., 2015 ; Li et al., 2017 ; Li et al., 2019 ; Tan et al., 2019 ; Zhang et al., 2017). Many of these Pmgenes have been used widely in wheat breeding programs ( Li et al., 2019). Unfortunately, the Pmgenes only confer resistance to specific Bgtraces, and the race-specific nature is not ideal, since virulent mutants of Bgtcan escape recognition of the resistance gene and making resistance genes ineffective ( Zhang et al., 2017). For instance, the resistance gene Pm8, in a cluster with Yr9, Lr26, and Sr31for resistance to stripe rust, leaf rust, and stem rust, respectively, on 1BL/1RS was transferred into wheat cultivars from ‘Petkus’ rye in 1970s, and has a profound impact on wheat disease resistance breeding in the world ( Hurni et al., 2014). Since then, a large number of wheat cultivars carrying 1BL/1RS have been released and widely grown in the world due to the resistance to multiple diseases. However, the overuse of the 1BL/1RS translocation in breeding and production has resulted in the rapid emergence of new pathotypes with the corresponding virulence genes, which have overcome the resistance genes, leading to serious epidemics of these diseases ( Mago et al., 2005 ; Pretorius et al., 2000).
Recently, powdery mildew has become more significant with increased use of nitrogen fertilizer, changes in irrigation, and the increase of global average temperature ( Tang et al., 2017). Therefore, cultivars become susceptible more quickly under the high disease pressure and more rapid changes of virulence in the pathogen population. Knowledge of the identity of race-specific resistance genes in wheat cultivars is a requirement to identify which resistance genes becoming ineffective. The use of molecular marker assisted selection breeding is a quick and easy approach to identify resistance genes. Molecular markers have been used to identify resistance genes against various diseases in wheat. Among various types of markers, simple sequence repeat (SSR) and single-nucleotide polymorphism (SNP) markers have recently been widely used in studying genes for resistance to powdery mildew ( Keller et al., 1999 ; Liu et al., 2002 ; Wu et al., 2019).
Yunnan Province, located in the southwest of China, has complex and diverse ecological environments and climates. In this region, wheat powdery mildew is very serious and epidemic occurs every year. Because of the disease-favorable environments, Yunnan provides initial inoculum for wheat powdery mildew, stem rust, leaf rust, and stripe rust, playing a key role in the regional spread and large-scale epidemic of the diseases in China ( Li et al., 2012 ; Li et al., 2016). Therefore, assessment of the resistance level of the main production cultivars to these diseases as well as identification of resistance genes in the cultivars can provide a theoretical basis for diseases management by rationally deploying cultivars with various resistance genes in different areas. Resistance to stripe rust in Yunnan wheat cultivars has been studied byLi (2013). In our previous study, resistance to stem rust in main wheat cultivars of the region was also studied ( Li et al., 2016 ; Xu et al., 2017). In recent years, the epidemic level of powdery mildew has been increasing in Yunnan (Tang et al., 2017). Therefore, this study was carried out to determine the level of seedling resistance to powdery mildew and to identify Pmgenes in wheat cultivars using molecular markers. This information will be useful for developing wheat cultivars with durable resistance to powdery mildew.
Table 1:
Pedigrees of 69 wheat cultivars used in this study.
Cultivar/line Pedigree Cultivar/line Pedigree 017-10 Bolsena-1CH/[SieteCerros/XBVT223// AWX011.G.48.2/XBVT221] Mianyang 19 Selected from Fan 6/70-5858 with systemic selection 02D2-282 Yunmai 39/Yunmai 42 Mentana Reiti /Wilhelmina// Akagomughi 06D6-6 Yumai 39/992-3 Mian1971-98 96-18-6/92R178 91E001 Selected from Mexico wheat Yunmai 43 Unkonwn Chumai 12 Selected from the observation materials of 02d-195 with systemic selection Mianyang 20 Selected from 70-5858/ Fan 6 with systemic selection De 4-8 Unknown Nanyuan 1 Mentana /Yuannong 1 De 05-81 9213-194/9213-4074 R101 AGA/HORK“S” De 08-3 Unkownn R57 Selected from Mexico wheat Wenmai 12 Selected from the hybrid advanced lines of ‘0581-1’ with systemic selection Wenmai 11 Selected from the hybrid advanced lines of ‘0581-39’ with systemic selection Demai 3 Longchun 2/Mocha Demai 4 782-88/Zhongyin 1022 Demai 5 Mianyang 11/Yun 80-1 Yimai 1 Unknown Yimai lines 2003-13 Chuanmai 24/96-16 Yimai 10 Selected from Yimai 1 with systemic selection Demai 7 Yunzhi 437/892- 17 E33 Selected from Mexico wheat Feng 05-394 Selected from Fengmai 31’s with single systemic selection Yimai lines 2003-27 96-23/96-14 Feng 1124 E33/58769-6 Yixi 2003-64 96-23/96-14 Fengmai 13 Unknown Yumai 1 Xingaibai/Germanic dunmai Fengmai 24 Moba 65/Precocious Ajin/Mosha F 6 /750025-12/ Mexico advanced lines 965 Fengmai 36 Selected from Fengmai 31’s with single systemic selection Yunmai 29 Zhushi Wheat/Fuli Wheat Yumai 3 82-1/8334 Fengmai 34 9034M3-2-2/YV91-1167 Yunmai 101 963-8224/98042-7 Fengmai 35 Fengmai 24//806-14-2-15/85-7421 F1 Yunmai 11-12 NG8319//SHA4/LTRA Fengmai 37 9034M8-17/Fengmai 24 Yunmai 39 Zhushi Wheat/Fuli Wheat/Fticher’s Fengmai 38 Momai Lines 91E001/Advanced lines 8941 Yunmai 42 Kangxiu 782/Yunmai 29//YKLO-PAM S Fengmai 39 Selected from Fengmai 31’s with single systemic selection Yunxuan 3 SW8488*2/4/SIN/TRAP#1/3/KAUZ*2/TRAP//KAUZ Jingmai 11 Kavkaz 78-385/Mo 980// Multiparent mixed pollen Yunmai 47 852-18/852-181//86-4437-75/3/822-852/785//842-929/4/G angu 436/5/923-3763 Jing 0202 Jingmia 10/96 Feng 1 Yunmai 48 48 99213/92B-4074 Jing 06-4 849M 2 -11-23/7730-1-149 Yunmai 51 91B-831/92B-84 Fengyin 03-2 Unknown Yunmai 52 92R149/963-11185 Jingmai 12 7901/792364//9118 Yunmai 53 96B-254/96B-6 Jingmai 14 Sumai 3/Qing 30// 8619-10 Yunmai 54 Yunmai 39/S-792 Kun 022-222-1 Selected from the advanced lines 022-222 with systemic selection Yunmai 56 Advanced lines 932-625/A dvanced lines 822-16-7-3 Kunmai 4 Selected from the kunmai 2 with systemic selection Yunmai 57 Screening wheat materials from CIMMYT Kunmai 5 992-17/Huelauen Yunza 5 01Y1-1069/K78S Liangmai 4 N1491/N1071 Yunza 6 K78S/01Y1-608 Linmai 15 A122/(87-5/E232) Yunza 7 K78S/02Y1-101 Linmai 6 86 Jian 22/84-346
DOI: 10.7717/peerj.10425/table-1
Table 2:
Infection types of 37 wheat genotypes with known Pm genes to tested isolates of Blumeria graminis f. sp. tritici .
Cultivars (line) Pm gene Infection types to B. graminis f. sp. tritici isolates a . 09558-1 W1 W12 L14 T7 H1-5-1 Aminster/8cc Pm1 4 0 3 4 4 3 Ulka/8cc Pm2 4 3 4 0 3 4 Asosan/8cc Pm3a 4 0 3 4 4 3 Chul/8cc Pm3b 4 0 3 3 4 0 Sonora/8cc Pm3c 4 3 4 4 4 3 Kolibri Pm3d 4 0 1 1 4 4 W150 Pm3e 4 0 4 3 4 4 Mich.Amber/8cc Pm3f 4 4 4 2 4 4 Whapli/8cc Pm4a 4 1 3 1 4 4 Armada Pm4b 4 3 4 3 4 4 Hope/8cc Pm5 4 1 4 1 4 3 Coker983 Pm5+6 4 2 0 4 0 3 Tingalen Pm6 4 3 1 2 3 2 Coker747 Pm6 4 3 3 3 4 3 CI14189 Pm7 4 0; 1 3 4 4 Kavkaz Pm8 4 3 3 2 0 0; Kenguia Pm4+8 4 3 4 3 4 3 Normandie Pm1+2+9 4 3 1 3 4 4 R4A Pm13 0; 1 0 0 0; 1 Brigand Pm16 3 0 3 1 3 4 MIN Pm18 0 1 2 0 0 1 KS93WGRC28 Pm20 4 3 3 3 4 3 Yangmai 5/sub.6v Pm21 0 0 0 0 0 1 Virest Pm22 0 0 4 1 0 2 line81-7241 Pm23 4 0; 3 1 4 3 Chiyacao Pm24 4 3 3 0 4 3 5P27 Pm30 4 3 4 1 4 4 Mission Pm4b+mli 4 3 4 0 4 4 Maris Dire Pm2+mld 3 1 4 0 0 3 Xiaobaidongmai PmXBD 4 1 4 0 1 1 Baimian 3 Pm4+8 3 1 3 0 4 4 CI12632 Pm4+8 4 1 4 0 4 3 Maris Huntsman Pm2 + 6 + 3 4 3 4 1 3 Era – 4 3 4 0 0 2 Amigo Pm17 4 1 1 3 4 4 XX186 Pm19 4 3 4 3 4 4 Funo - 4 4 4 3 4 4
DOI: 10.7717/peerj.10425/table-2
Notes:
a Infection types: 0 = no visible symptoms; 0; = hypersensitive necrotic flecks; 1 = minute colonies with few conidia; 2 = colonies with moderately developed hyphae, but few conidia; 3 = colonies with well-developed hyphae and abundant conidia, but colonies not joined together; and 4 = colonies with welldeveloped hyphae and abundant conidia, and colonies mostly joined together.
Material and Methods
Wheat cultivars and Pm resistance lines
A total of 69 wheat cultivars and breeding lines used in the present study included main cultivars grown in Yunnan province and genetic stocks used in breeding programs, and seeds were provided by Pro. Mingju Li, Institute of Agricultural Environment and Resources, Yunnan Academy of Agricultural Sciences. The pedigrees of the cultivars are listed inTable 1. A set of 37 wheat lines carrying known powdery mildew resistance genes (Table 2) were also used in the present study as Pmgene references, and seeds were provided by Prof. Yilin Zhou, State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences.
Isolates of B. graminis f. sp. tritici
Six isolates of B. graminisf. sp. triticiwith different virulence patterns were used to evaluate resistance in the wheat cultivars and breeding lines. These isolates were selected from the collection of the Plant Immunity Institute, Shenyang Agricultural University, China. Their virulence/avirulence patterns to the 37 wheat differentials carrying known Pmgenes are shown inTable 2.
Evaluation of seedling resistance
The 69 wheat cultivars and breeding lines were evaluated in the seedling stage for resistance to powdery mildew using the six Bgtisolates in the greenhouse at the College of Plant Protection, Shenyang Agricultural University, using the method described in a previous study ( Xiang et al., 1994). About 10 seeds of each cultivar were sown in a pot of 12 cm in diameter. Highly susceptible cultivar Chancellor was used as a control for evaluating uniformity of inoculation. Plants in different trays were inoculated with the six Bgtisolates separately, and each tray was covered with a glass shroud to avoid cross infection of different strains after inoculation, when the primary leaves were fully expanded (about 10 days after planting). When the susceptible cultivar Chancellor was heavily infected, about 10 days after inoculation, infection types (ITs) were recorded. A 0-to-4 ITs scale was used for recording the host response to infection ( Si et al., 1987), where 0= no visible symptoms; 0; = hypersensitive necrotic flecks; 1 = minute colonies with few conidia produced; 2 = colonies with moderately developed hyphae, but few conidia; 3 = colonies with well-developed hyphae and abundant conidia, but colonies not joined together; and 4 = colonies with well-developed hyphae and abundant conidia, and colonies mostly joined together. ITs 0–2 were considered as ‘R’ (resistant), and ITs 3–4 as ‘S’ (susceptible).
DNA extraction and PCR amplification
Genomic DNA was extracted from 100 mg young leaves of seven-day old seedlings from each cultivar, using a DNA extraction kit (Sangon Biotech, Shanghai, CHINA). Pm-gene specific primers were synthesized by Shanghai Biotech Biotech Co., Ltd, China (Table 3). Polymerase chain reactions (PCR) were carried out using a S1000™ Thermal Cycler in 25 µL volume, including 2 µL of 50 ng µL −1DNA, 1 µL of 10 μmol L −1of each primer, 2.5 µL of 10 × buffer (Mg 2+), 0.2 µL of 5 U µL −1 Taqpolymerase, and 0.5 µL of 10 mmol ⋅ L −1deoxyribonucleoside triphosphates. The PCR procedure was as follows: 94 °C for 5 min, 30 cycles of 94 °C for 45 s, 60 °C for 45 s, and 72 °C for 1 min, followed by the final extension at 72 °C for 8 min. PCR products were separated on 1.5–2% agarose.
Table 3:
Molecular markers linked to resistance genes Pm 3, Pm 8, Pm 13, Pm 6, and Pm 21 with their forward and backward primers.
Tagged Pm gene Primer Fragment size (bp) Primer sequence (5′–3′) Pm3 Pm3a 624 GGA GTC TCT TCG CAT AGA CAG CTT CTA AGA TCA AGG AT Pm8 IAG95 1050 AGCAACCAAACACACCCATC ATACTACGAACACACACCCC Pm13 UTV14F/R 517 CGCCAGCCAATTATCTCCATGA AGCCATGCGCGGTGTCATGTGAA Pm16 Xgwm159 201 GGGCCAACACTGGAACAC GCAGAAGCTTGTTGGTAGGC Pm21 Scar1265 1265 CACTCTCCTCCACTAACAGAGG GTTTGTTCACGTTGAATGAATC
DOI: 10.7717/peerj.10425/table-3
Results
Wheat seedling resistance to B. graminis f. sp. tritici
The powdery mildew infection types of 69 main wheat cultivars and breeding lines to all tested isolates were presented inTable 4. Five wheat cultivars, De 4-8, Kunmai 4, Yixi 2003-64, Yimai lines 2003-13, and Yimai lines 2003-27 were resistant (ITs 0-2) to all tested isolates at seedling stage, accounting for only 5.8% of the tested cultivars and breeding lines. The remaining 64 wheat cultivars were susceptible to one or more tested isolates (Fig. 1,Table 4).
Table 4:
Percentages of susceptible and resistant wheat cultivars to six isolates of Blumeria graminis f. sp. tritici .
Isolates Susceptible Resistance Number of cultivars Percentage (%) Number of cultivars Percentage (%) 09558-1 61 88.4 8 11.6 W1 46 66.7 23 33.3 W12 54 78.3 15 21.7 L14 54 78.3 15 21.7 T7 56 81.2 13 18.8 H1-5-1 61 88.4 8 11.6 All tested isolates 65 94.2 4 5.8
DOI: 10.7717/peerj.10425/table-4
Figure 1: Number of wheat cultivars and breeding lines showing different infections in seedlings when tested with six isolates of Blumeria graminis f. sp. tritici .
DOI: 10.7717/peerj.10425/fig-1
Molecular identification of Pm3
Pm3is a single, dominant locus on the short arm of wheat chromosome 1A and contains more alleles than any other identified Pmloci ( Tommasini et al., 2006). Seven specific markers for the Pm3alleles ( Pm3a- Pm3g) based on nucleotide polymorphisms of coding and adjacent noncoding regions were used to identify Pm3alleles in the wheat cultivars. The specific fragment of 624-bp for Pm3awas amplified in the positive control Asonsan/8cc that is known to carry Pm3aand six cultivars (Fengmai 35, Jing 0202, Liangmai 4, Wenmai 11, Yumai 3, and Yunmai 51), indicating that these cultivars are most likely to carry Pm3a(Fig. 2A,Table 5).
Figure 2: Electrophoretograms of primers for different Pm genes.
The corresponding primers for Pm3a (A), Pm8 (B), and Pm21 (C) were used to screen Yunnan wheat cultivars and breeding lines.
DOI: 10.7717/peerj.10425/fig-2
Molecular identification of Pm8
The best known and widely deployed Pm8is located on a 1BL.1RS translocation in hexaploid wheat. It was originally derived from the introgression of the 1RS rye chromosome from rye cultivar ‘Petkus’. A sequence-tagged site (STS) marker, IAG95, was developed to identify Pm8( Mohler et al., 2001). Wheat cultivars with the chromatin from ‘Petkus’ carry the resistance allele amplified as 1,050 bp fragment by the IAG95 primer pair. In this study, the positive control ‘Kavkaz’ ( Pm8) and 18 wheat cultivars had the 1,050 bp fragment, indicating that these cultivars are most likely to carry Pm8(Fig. 2B).
Molecular identification of Pm13
Cenci et al. (1999)amplified a 517-bp specific fragment in cultivars containing the Pm13genes by using STS UTV14F/R primers. A 517-bp fragment was amplified in the wheat line R4A ( Pm13) as a positive control, and no fragment was amplified in the negative control Chancellor as expected. However, no specific fragment was amplified in all tested wheat cultivars and breeding lines, indicating that none of these wheat varieties (lines) are most likely to carry Pm13.
Table 5:
Seedling infection types to Blumeria graminis f. sp. tritici and resistance genes detected with molecular markers.
Cultivars/ lines Infection types a Resistance gene 09558-1 W1 W12 L14 T7 H1-5-1 Pm3 Pm8 Pm13 Pm16 Pm21 017-10 4 3 4 3 3 4 – – – – – 02D2-282 4 4 4 4 4 4 – – – – – 06D6-6 4 4 4 4 4 3 – – – – – 91E001 4 3 3 4 3 4 – – – – – Chumai 12 3 4 3 4 4 4 – – – – – De 4-8 0 0 0; 0 0; 0 – – – – + De 05-81 3 4 4 3 4 3 – + – – – De 08-3 2 0 0 1 0; 0 – – – – – Demai 3 4 3 4 3 3 3 – – – – – Demai 4 3 3 4 4 4 4 – + – – – Demai 5 4 4 4 3 3 4 – – – – – Demai 7 4 4 4 4 4 4 – + – – – E33 4 3 4 4 3 3 – + – – – Feng 05-394 4 3 4 4 3 4 – – – – – Feng 1124 3 2 3 0 3 3 – – – + – Fengmai 13 4 3 4 3 4 4 – – – – – Fengmai 24 4 4 4 4 4 4 – – – – – Fengmai 34 3 3 4 4 4 4 – – – – – Fengmai 35 4 2 0 3 3 3 + – – – – Fengmai 36 4 3 4 4 3 3 – – – – – Fengmai 37 4 0 2 3 0 3 – – – – – Fengmai 38 4 0; 0 4 3 4 – – – – – Fengmai 39 4 3 4 2 4 3 – – – – – Fengyin 03-2 4 2 4 2 3 4 – – – + – Jing 0202 3 2 3 4 0 4 + + – – – Jing 06-4 3 3 4 3 4 4 – + – – – Jingmai 11 4 0 0; 3 4 3 – + – – – Jingmai 12 4 3 4 4 3 4 – + – – – Jingmai 14 4 4 3 4 4 4 – + – – – Kun 022 − 222 − 1 4 4 3 3 4 4 – – – – – Kunmai 4 0 0; 0 1 0 1 – – – – + Kunmai 5 4 3 0 0; 4 4 – + – – – Liangmai 4 4 2 4 1 3 3 + + – – – Linmai 15 3 4 4 4 3 4 – + – – – Linmai 6 4 4 3 4 4 4 – – – – – Mentana 3 3 4 3 3 3 – – – – – Mian 1971-98 4 0; 3 4 4 3 – – – – – Mianyang 19 3 3 4 3 4 4 – – – – – Mianyang 20 4 4 3 4 4 4 – – – – – Nanyuan 1 4 3 3 4 3 4 – – – – – R101 3 4 3 3 3 3 – – – – – R57 4 0 4 3 2 4 – + – – – Wenmai 11 4 0; 4 3 1 4 + + – – – Wenmai 12 4 3 1 2 4 3 – + – – – Yimai 1 4 4 4 4 4 4 – – – – – Yimai 10 3 4 4 4 4 4 – – – – – Yimai lines 2003-13 1 0 1 0; 1 1 – – – – – Yimai lines 2003-27 0 1 1 0; 1 0; – – – – – Yixi 2003-64 0; 0 1 0; 1 0 – – – – + Yumai 1 4 4 4 4 4 4 – + – – – Yumai 3 3 2 4 3 3 4 + + – – – Yunmai 101 3 4 3 3 4 4 – + – – – Yunmai 11-12 4 3 4 4 3 4 – – – – – Yunmai 29 4 3 4 3 4 4 – – – – – Yunmai 39 3 3 2 3 4 4 – – – + – Yunmai 42 3 3 4 3 3 4 – – – + – Yunmai 43 4 4 3 3 4 1 – – – – – Yunmai 47 3 4 4 4 3 3 – – – – – Yunmai 48 2 4 3 0 4 4 – – – – – Yunmai 51 4 0; 4 3 3 3 + – – – – Yunmai 52 4 4 3 4 3 4 – – – – – Yunmai 53 3 2 3 0 0; 1 – – – – – Yunmai 54 4 3 4 4 3 4 – – – – – Yunmai 56 3 0 0 4 1 3 – – – – – Yunmai 57 4 4 0 3 0; 4 – – – – – Yunxuan 3 4 3 3 4 4 4 – – – – – Yunza 5 4 4 3 3 3 3 – – – – – Yunza 6 4 4 4 3 4 3 – – – – – Yunza 7 4 3 4 4 3 4 – – – – –
DOI: 10.7717/peerj.10425/table-5
Molecular identification of Pm21
Liu et al. (1999)detected a 1265-bp fragment in Yangmai 5/Sub−6 V ( Pm21) by amplification using the STS 1265 marker of Pm21. In our study, this specific fragment was amplified in the Pm21positive control, but not in the susceptible control Chancellor. This gene was also detected in cultivars Kunmai 4, Yixi 2003-64, and De 4-8, but not in the rest of the cultivars and breeding lines, indicating that these three Yunnan cultivars are most likely to contain Pm21(Fig. 2C).
Molecular identification of Pm16
SSR marker Xgwm159for Pm16developed byChen et al. (2005)was used to test wheat cultivars and breeding lines. PAGE (polyacrylamide gel electrophoresis) showed that the fragment amplified by the varieties containing Pm16was about 201-bp, while the fragment amplified by the varieties without Pm16was about 190-bp. Cultivars Yunmai 39, Yunmai 42, Yunmai 47, Feng 1124 and Fengyin 03-2 had the same fragment as the positive control of the Pm16single-gene line indicating that these five cultivars are most likely to contain Pm16(Fig. 3).
Figure 3: Amplification result for parts of wheat varieties amplified with premier Xgwm159 of Pm16 .
DOI: 10.7717/peerj.10425/fig-3
Discussion
Since the 1970s, wheat powdery mildew has been prevalent all over the world, causing different degrees of economic losses every year. Developing powdery mildew resistant cultivars has always been an important breeding goal of wheat. Powdery mildew has been well controlled, and the losses caused by the disease have been reduced in different stages in history. However, in recent years, wheat powdery mildew has been increasing as a result of losses of varietal resistance caused by the high heterogeneity and frequent virulence changes in the pathogen population. Many wheat cultivars planted at present show a trend of high susceptibility to powdery mildew. Therefore, it is urgent to improve resistance to powdery mildew. In the present study, the resistance level of wheat cultivars in Yunnan province to six Bgtisolates was evaluated. The results showed that most of tested wheat cultivars were highly susceptible to Bgt, indicating that effective genes are lack in Yunnan cultivars. In addition, currently effective genes ( Pm13, Pm16, and Pm21) to Bgtin Chinese wheat cultivars are in very low frequencies as only four cultivars contain Pm16, and 3 cultivars contain Pm21, while no cultivars contain Pm13. Therefore, in order to improve the resistance level of wheat cultivars to powdery mildew, it is necessary to pyramid some other effective genes into new cultivars.
The Pm3locus was one of the first described loci for resistance to powdery mildew ( Briggle & Sears, 1966). Some of the resistance alleles have been widely used in wheat breeding programs in the many countries including China, and some of the resistance alleles have remained effective ( Bougot et al., 2002 ; Wu et al., 2019).Liu et al. (2019)reported about 95.1% wheat cultivars from Heilongjiang Province carrying Pm3. In the present study, we identified the gene in only six cultivars grown in Yunnan (Fengmai 35, Jing 0202, Liangmai 4, Wenmai 11, Yumai 3, and Yunmai 51).
The gene Pm8on 1BL/1RS was transferred into many bread wheat cultivars from ‘Petkus’ rye ( Graybosch, 2001). The 1BL/1RS translocation has been playing an important role in wheat disease resistance breeding in the world, because this locus is closely linked to disease resistance genes, including Sr31, Lr26, and Yr9for resistance to stem rust, leaf rust, and stripe rust, respectively. It is reported that more 50% of the wheat cultivars grown in total wheat planting areas in China carry this translocation ( Li et al., 2011). Our results showed that eighteen wheat cultivars contain Pm8, accounting for 26.1% of the tested cultivars from Yunnan. Conversely, pedigree tracking indicated that resistant stocks carrying Pm 8, such as ‘Kavkaz’ and ‘Lovrin’ lines, were widely used in wheat breeding in Yunnan Province, suggesting the origin of resistance genes in these wheat cultivars ( Li et al., 2016). Our results were consistent with previous reports. For example,Liu et al. (2019)found that the frequency of 1BL/1R translocation in Huang-Huai wheat region was as high as 59%. In addition, no virulent races of P. graminisf. sp. triticito resistance gene Sr31has been found in China. Therefore, this gene will still have an impact on wheat breeding for disease resistance, although the resistance to Bgthas been lost in China. Thus, Pm8should be used in combination with other genes for effective resistance to Bgtin wheat breeding programs to maintain the long-term resistance of cultivars.
Gene Pm13originated from Aegilops longissimaand was located on the 6VS of the translocation chromosome T6AL/6VS of wheat/ Aegilops longissimatranslocation. It is one of the effective resistance genes to powdery mildew in the world including China.Cenci et al. (1999)was first developed the STS linkage marker of Pm13, which is widely used in marker assisted selection breeding. In our previous study, Pm13was found to be effective in northeastern China ( Wu et al., 2019). However, Pm13was not found in any of the Yunnan wheat cultivars tested in the present study. Similarly,Li et al. (2009)andLiu et al. (2010)did not detected Pm13in any of the cultivars, including 50 and 101 cultivars from different regions of China. Their results, together with our study, indicate that Pm13is absent in Chinese wheat cultivars, and this effective gene should be used in breeding programs.
Gene Pm16was the first wheat powdery mildew resistance genes transferred from Triticum dicoccoidesKorn into Triticum aestivumL. and was first reported in chromosome 4A at the earliest ( Reader & Miller, 1991). However, subsequent studies did not show a consistent chromosomal location.Wang (2004)reported the gene on 5DS, whileChen et al. (2005)reported it on 5BS. Therefore, multiple markers have been reported for Pm16. However these markers may not be specific. In the present study, the SSR marker reported byChen et al. (2005)was used, and four cultivars, Yunmai 39, Yunmai 42, Yunmai 47, and Fengyin 03-2, were positive for the marker. The pedigree of Yunmai 39 is Secale cerealeL./Fuli wheat/Fticher’s, and Yunmai 42 is rust-resistant 782/ Secale cereale/Fuli wheat//YKLO-PAM“S”. As S. cerealeis susceptible to powdery mildew, Pm16might originate from common wheat Fuli. The genealogy of Yunmai 47 is 852-18/852-181//86-4437-75/3/822-852/785// 842-929/4/Gangu436/5/923-3763. As most of genotypes in this pedigree are breeding line numbers, it is impossible to identify the donor for the powdery mildew resistance gene. Fengyin 03-2 originated from Anmai 5 (L9288022-2-1/Xingnong 5) in Guizhou.Zhao et al. (2007)found that Anmai 5 was highly resistant to powdery mildew, so Pm16in Fengyin 03-2 may come from Anmai 5. The pedigree of Feng1124 is E33/58769-6. E33 is an excellent powdery mildew resistant stock imported from Mexico and may contain Pm16.
Gene Pm21is derived from Haynaldia villosa, located on the short arm of chromosome 6V (6VS). As this gene has a wide resistance spectrum of Bgtisolates in the world, it has been widely studied ( Cao et al., 2011 ; Wu et al., 2019). Pm21provides a high level and stable resistance in different genetic backgrounds. Meanwhile, wheat cultivars that carry this gene usually have excellent other agronomic traits. Therefore, this gene has been widely deployed in Sichuan Basin and southern Gansu since the middle 1990s. Since then, Pm21has been widely used in different wheat production areas in China ( Zhan et al., 2010).Jiang et al. (2014)identified 7.4% of the tested 118 Chinese cultivars contained this gene using marker Scar1265 closely linked to Pm21. Our results showed that cultivars Kunmai 4, Yixi 2003-64, and De 4-8 contain this gene. Kunmai 4 has ALB“S”/BOW“S” in its pedigree, and ALB“S”/BOW“S” is a Chile wheat line highly resistant to powdery mildew. In addition,Li et al. (2012)found Kunmai 4 was highly resistant to all tested Bgtisolates. We found that this cultivar likely have Pm21. As the genealogical information is not available for Yixi 2003-64 and De 4-8, we could not identify the Pm21donor in these cultivars. Unfortunately only these three cultivars (4.3%) potentially have Pm21among the 69 tested wheat cultivars and breeding lines from Yunnan. Pm21should be pyramided with other effective genes to developing wheat cultivars with durable resistance to powdery mildew.
Conclusions
Breeding resistant cultivars is the most cost-effective and eco-soundly strategy to protect wheat from disease. In the present study, the seedling resistance of 69 main wheat cultivars in Yunnan Province were evaluated using 6 isolates of Bgt. Overall, the seedling resistance level of wheat cultivars to powdery mildew resistance were very poor in Yunnan Province. Based on this, the presence of genes Pm3, Pm8, Pm13, Pm16, and Pm21in these cultivars were detected using gene specific DNA markers. Six cultivars were found likely to have Pm3, 18 were likely to have Pm8, five were likely to have Pm16, and three were likely to have Pm21. No cultivar was found to carry Pm13. The information on the presence of the Pmresistance genes in Yunnan wheat cultivars can be used in future wheat durable disease breeding programs.
Supplemental Information
The raw data for Figs. 2 and 3
DOI: 10.7717/peerj.10425/supp-1
The raw data for Fig. 1
DOI: 10.7717/peerj.10425/supp-2
Additional Information and Declarations
Competing Interests
The authors declare there are no competing interests.
Author Contributions
Xianxin Wuconceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, and approved the final draft.
Qiang BianandYuanhu Xuanperformed the experiments, prepared figures and/or tables, and approved the final draft.
Yue GaoandXinyu Nianalyzed the data, prepared figures and/or tables, and approved the final draft.
Yanqiu Sunanalyzed the data, authored or reviewed drafts of the paper, and approved the final draft.
Yuanyin Caoconceived and designed the experiments, authored or reviewed drafts of the paper, and approved the final draft.
Tianya Liconceived and designed the experiments, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft.
Data Availability
The following information was supplied regarding data availability:
The raw measurements are available in theSupplementary Files.
Funding
This study was supported by the National Natural Science Foundation of China (No. 31701738). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
| https://peerj.com/articles/10425/ |
Uyghur y-dna [Archive] - Eupedia Forum
Wikipedia and Eupedia web sites tell that Uyghur people have a high frequency of R1a and R1b haplogroups. Is there any recent Y-DNA study about Uyghur Y-DNA ?
View Full Version :Uyghur y-dna
Wikipedia and Eupedia web sites tell that Uyghur people have a high frequency of R1a and R1b haplogroups. Is there any recent Y-DNA study about Uyghur Y-DNA ?
no ? http://scienceblogs.com/gnxp/uyger2.jpg M9 lineage = K, L (M20), M (P256), NO (M214) (N and O), P (M45) (Q and R), S (M230) and T (M70) M130 = C1, C2, C3, C4, C5 YAP = all E, D M89 = G (M201), H (M52), I (M170), J (12f2.1), K M45 = P M173 = R1 M17 = R1a Xue Yali et al. (2006) have tested two samples of Uyghurs, one from Urumqi and the other from Ili, and found the following distribution of Y-DNA haplogroups. Uygur/Urumqi: 1/31 = 3.2% Y*(xA, C, DE, J, K) (This could be B, F*, G, H, or I, but, judging from other sources of Uyghur Y-DNA data, it is most likely G-M201.) 1/31 = 3.2% C*(xC1, C3) (This might be related to haplogroup C5-M356, which has been found in South Asia and Arabia.) 2/31 = 6.5% E 8/31 = 25.8% J 1/31 = 3.2% N1*-LLY22g(xN1a, N1b, N1c) 2/31 = 6.5% N1b 1/31 = 3.2% O1a 1/31 = 3.2% O3a3c*-M134(xO3a3c1-M117) 1/31 = 3.2% O3a3c1-M117 6/31 = 19.4% P*(xR1a) (This could be P*, Q, R*, R1b, or R2. I would guess that it is mostly R1b, mixed with smaller numbers of Q and R2.) 7/31 = 22.6% R1a Uygur/Yili: 8/39 = 20.5% Y*(xA, C, DE, J, K) (This would be one of the highest frequencies of haplogroup G in the entire world if it were really all G-M201.) 1/39 = 2.6% C*(xC1, C3) 3/39 = 7.7% C3c 1/39 = 2.6% DE(xE) 5/39 = 12.8% K*(xNO, P) 1/39 = 2.6% N1*-LLY22g(xN1a, N1b, N1c) 2/39 = 5.1% N1c1 2/39 = 5.1% O3* 2/39 = 5.1% O3a3c*-M134(xO3a3c1-M117) 2/39 = 5.1% O3a3c1-M117 6/39 = 15.4% P*(xR1a) 6/39 = 15.4% R1a
Here is the full PDF article for north-east Asian Y-DNA by Yali Xue (http://www.genetics.org/cgi/reprint/172/4/2431) cited above.
The high frequency of R1a and R1b in Uyghurs is probably the trace of Tokharians. These Tokharians are related to Afanasevo culture (see http://en.wikipedia.org/wiki/Afanasevo_culture) who migrated from Pontic Steppes about 3.500 BC. This is another clue which shows that these haplogroups are related to IE and Steppes during copper age.
The high frequency of R1a and R1b in Uyghurs is probably the trace of Tokharians. These Tokharians are related to Afanasevo culture (see http://en.wikipedia.org/wiki/Afanasevo_culture) who migrated from Pontic Steppes about 3.500 BC. This is another clue which shows that these haplogroups are related to IE and Steppes during copper age. I have just read that Maciamo 's PDF so R1a is well mentioned but there is no R1b ? or tell me where ?
I have just read that Maciamo 's PDF so R1a is well mentioned but there is no R1b ? or tell me where ? That's the P*(xR1a) which confirm oldest study: http://www.scs.uiuc.edu/~mcdonald/WorldHaplogroupsMaps.pdf
That's the P*(xR1a) which confirm oldest study: http://www.scs.uiuc.edu/~mcdonald/WorldHaplogroupsMaps.pdf (http://www.scs.uiuc.edu/%7Emcdonald/WorldHaplogroupsMaps.pdf) P*(xR1a) means R1b ok !
SecherBernard : "The high frequency of R1a and R1b in Uyghurs is probably the trace of Tokharians. These Tokharians are related to Afanasevo culture" Not sure at all about R1b. So far, only R1a1a is visible in the aDNA of the region of Afanasevo culture. In south Siberia, during bronze age, all the y-DNA was R1a1 and the mtDNA lineages were 90% west Eurasian (67% during Iron age) in "Ancient DNA provides new insights into the history of south Siberian Kurgan people" (sorry you have to google it up, I still can't post links). part of the abstract : "Our autosomal, Y-chromosomal and mitochondrial DNA analyses reveal that whereas few specimens seem to be related matrilineally or patrilineally, nearly all subjects belong to haplogroup R1a1-M17 which is thought to mark the eastward migration of the early Indo-Europeans. Our results also confirm that at the Bronze and Iron Ages, south Siberia was a region of overwhelmingly predominant European settlement, suggesting an eastward migration of Kurgan people across the Russo-Kazakh steppe. Finally, our data indicate that at the Bronze and Iron Age timeframe, south Siberians were blue (or green)-eyed, fair-skinned and light-haired people and that they might have played a role in the early development of the Tarim Basin civilization (i.e. in Xinjiang)." And also in Xinjiang (study of the 2,000 BC remains of the Xiaohe peoples : (“Evidence that a West-East admixed population lived in the Tarim Basin as early as the early Bronze Age” ) Interesting bits : "Mitochondrial DNA analysis showed that the Xiaohe people carried both the East Eurasian haplogroup (C) and the West Eurasian haplogroups (H and K), whereas Y chromosomal DNA analysis revealed only the West Eurasian haplogroup R1a1a in the male individuals." " Besides the East Eurasian lineage, two West Eurasian mtDNA haplogroups H and K were found among the Xiaohe people. H lineage is the most common mtDNA haplogroup in West Eurasia [20], but haplogroup H with a 16260T was shared by only nine modern people in Genbank, including one Italian, one German, one Hungarian, one Portuguese, one Icelander and four English people."
ok thank you : only R1a not R1b
Afanasievo is not Tocharian, neither is it certain that the Tarim mummies were Tocharians. I know that R1b runs at about a 20-25% frequency among the Uyghurs, but I can't find the study where I saw that (about three or four years ago). Some of that R1b was R1b1b1 (M73), as I recall. Here is a map with a Uyghur pie chart (labeled "UG") showing the proportions of the various y haplogroups: http://www.scs.uiuc.edu/~mcdonald/WorldHaplogroupsMaps.pdf
rms2 : "Afanasievo is not Tocharian, neither is it certain that the Tarim mummies were Tocharians." Indeed but the probability is still high in both cases (Afanasevo culture speaking the ancestor of Tocharian and the Tarim mummies speaking recent ancestor of Tocharian languages).That's hypothetical though, of course. As for R1b and J2 we will have to wait for more ancient DNA to have certitudes about their origin and time of arrival. The fact remains that so far, we only have R1a1a + west eurasian mtDNA (+ Asian mtDNA too at some point of course, especially more and more visible during early Iron age; Before that, west eurasian mtDNA hgs in Kazakhstan and south Siberia were overwhelmingly west eurasian / this shift in population types is also confirmed by the skeletal remains of the regions - first, caucasoids then more and more mongoloids with Iron age, becoming predominant up to today). Maybe new studies will depict a more complex picture though, concerning the ancient haplogroups of Xinjiang but at the moment I'll go with what we actually have...
Folks, just imagine R1a abd R1b are ancient TURKIC (who were NON MONGOLOID) HG moving from WEST (homeland) to EAST, mixing with asiatic HG Q, C and becoming utterly mongoloid but preserving their language. Also, studies show scythians could have been turkic speakers, not IE - runic writings can be easily read in Turkic languages of modern times! The R1b & R1a found in Europe are ancient native HG and Turkic languages are originally European and are at the very base (almost untraceble) of many European languages! The most ancient ancestors of Europeans could have been proto-turks... When they came back to Europe much much later all Europe saw was mongolisised turks mixed with actual mongols and obviusly decided they have nothing to do with them! Eventually Turcophobia took toll in Europe due to the faced brutalities disallowing scholars to think straight about their ancestry and misleading them to IE origins of R1a and R1b HG! Just imagine! Your thoughts?
Folks, just imagine R1a abd R1b are ancient TURKIC (who were NON MONGOLOID) HG moving from WEST (homeland) to EAST, mixing with asiatic HG Q, C and becoming utterly mongoloid but preserving their language. Also, studies show scythians could have been turkic speakers, not IE - runic writings can be easily read in Turkic languages of modern times! The R1b & R1a found in Europe are ancient native HG and Turkic languages are originally European and are at the very base (almost untraceble) of many European languages! The most ancient ancestors of Europeans could have been proto-turks... When they came back to Europe much much later all Europe saw was mongolisised turks mixed with actual mongols and obviusly decided they have nothing to do with them! Eventually Turcophobia took toll in Europe due to the faced brutalities disallowing scholars to think straight about their ancestry and misleading them to IE origins of R1a and R1b HG! Just imagine! Your thoughts? simply the linguistic approach is different, that means that Turks do not speak their language,!!!!!!!!!! that means that Turks who are J in Turkey just imagine that they Greeks !!!!!!!!!!!! Hahahahahaha Turks that speak IE (include Greek language) and Greeks who speak Turkish Ahahahahahahahahahaha :laughing: :laughing: :laughing: well I am not sure and I want to ask some here, did the Y-Dna of Turk Sultans ever tested? I am suspicius of Alan G an not 'White desert' origin Uyghur Even linguistically they are more connected with ancient Anatolian and middle East than with 'White Desert'
Haplogorups R1a & R1b are archaic Euro-Asiatic haplgoroups. Both, native Europeans and native Central Asians, like Turkic people were R1.. (and N, Q) folks. Haplgroup R1.. was spread all over the northern part of the Eurasian continent. It has not so much to do with the proto-IE folks. You obviously don't know much about phylogeny and subclades dating. The R1b found among Uyghurs is not the archaic R1b* but the much more recent R1b1b1 and R1b1b2. Same for R1a. All over North Asia and Central Asia the type of R1a found is R1a1a1, the same as in Europe.
The high frequency of R1a and R1b in Uyghurs is probably the trace of Tokharians. These Tokharians are related to Afanasevo culture (see http://en.wikipedia.org/wiki/Afanasevo_culture) who migrated from Pontic Steppes about 3.500 BC. This is another clue which shows that these haplogroups are related to IE and Steppes during copper age. Wikipedia also says that Afanasevo culture was dominated by R1a with a small trace of Mongoloid C. No R1b was found there so if it was the homeland of Tokharians they should be R1a only, and the R1b found in Uyghurs is not explained. Could it be that R1b in Central Asia were Turkish speakers? (especially the M73 subclade which is dominant in Turkmens too)
You obviously don't know much about phylogeny and subclades dating. The R1b found among Uyghurs is not the archaic R1b* but the much more recent R1b1b1 and R1b1b2. Same for R1a. All over North Asia and Central Asia the type of R1a found is R1a1a1, the same as in Europe. MAybe Uyghurs were the same folks like r1b Europeans, but those r1b Europeans mixed with i1 and i2 folks and Uyghurs with the Asiatic people. There is very much of haplogroups n and q in northern Europe, like all over the northern part of the Eurasian continent. So it must be native to Europe, like r1 is also native to Central Asia. The archaic r1 evolved somewhere in Asia.
You obviously don't know much about phylogeny and subclades dating. The R1b found among Uyghurs is not the archaic R1b* but the much more recent R1b1b1 and R1b1b2. Same for R1a. All over North Asia and Central Asia the type of R1a found is R1a1a1, the same as in Europe. Russian DNA Genealogy says Uigur, Kazakh and Bashkir R1b1 is 16000 years old! ???
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New on the Menu: Warming beef dishes and a Lunar New Year salad | Restaurant Hospitality
Plus Roberto Santibañez’s rotisserie chicken and a spirit-free cocktail for Dry February
New on the Menu: Warming beef dishes and a Lunar New Year salad
January 2021 was arguably the most stressful American January on record, and Kimpton Hotels understand if your attempts not to drink for the month fell short. That’s why restaurants like Geraldine’s at the Hotel Van Zandt in Austin, Texas, are observing Dry February with spirit-free cocktails such as this one, developed by chief of bar operations Caitlyn Jackson, made with lime juice, cilantro-jalapeño syrup, mole bitters, sour cream and sparkling Richard’s Rainwater
Price:$14
For the first time, Din Tai Fung is offering an item made with wagyu beef. Available only at its restaurant at the Aria hotel in Las Vegas.
Chef Chen Wei starts by slowly infusing shallot into warm soybean oil until the shallot is crispy, then using that oil to gently fry chopped garlic. Then he adds rock sugar until it’s combined with the garlic, and then adds ground black pepper. Next he adds balsamic vinegar, followed by oyster sauce, sweet soy sauce and beef broth, seasoning it with chicken bouillon powder and salt. He cooks that for 15 minutes, removes it from the heat and then emulsifies it with butter and red beef tallow, then finally mixing in the crisped shallot that was used to flavor the oil. He lets that refrigerate overnight.
The next day at service he stir-fries eight ounces of diced Mishima American Wagyu beef tenderloin with bell peppers, onion, shimeji mushrooms and the black pepper sauce.
Price: $38
Doron Wong, executive chef of Lotus & Cleaver, a fast-casual Chinese restaurant that recently opened in the Queens neighborhood of Long Island City, N.Y., is offering this item for takeout only to celebrate Lunar New Year. It must be booked in advance via the reservations app Resy and is made with salmon sashimi, house-marinated salmon roe, shrimp, house-made pickles, candied pecans, fried shredded taro, shredded carrot, cucumber, fresh and pickled daikon, scallions, pickled ginger, fried noodles, crispy shallots, peanuts, sesame seeds, radish sprouts, shiso sprouts and cilantro, all tossed with salted plum dressing. It serves 2 to 4 people.
Price:$28
This is one of the preparations of the Winter Hot Pot Series at Ramen-San in Chicago. The meals are made for two people and available for carryout, with all of the vegetables, sauces, proteins and broth, plus instructions, to enjoy a hot-pot meal at home. Customers can even add a hot pot and long spoons to your order if they like.
Partner Amarit Dulyapaibul said the hot pots are intended bring global flavors to guests at this time when they are unable to travel.
This Korean-inspired preparation was made with thinly sliced beef sirloin, a vegetable medley, three dipping sauces (seasoned sesame oil and mild and spicy bulgogi sauces redolent of garlic ang ginger), and a Korean variant on the Japanese broth dashi. It also came with Korean side dishes, or banchan, including cabbage kimchi, cucumber kimchi, spicy bean sprouts, kale-scallion salad and marinated tofu.
Price: $65
This dish at Mi Vida in Washington, D.C., is inspired by culinary director Roberto Santibañez’s childhood in Mexico City, Mexico, where he says chicken rotisseries dotted each neighborhood (Chilango is slang for someone from Mexico City).
For the dish, melted butter is infused with Mexican oregano, onions and garlic. That’s rubbed on the whole chicken which is allowed to marinate in that before being roasted. It’s served with esquites — roasted corn with mayonnaise, cotija cheese, chile powder, lime juice and salt — seasonal vegetables with pickled jalapeños, and roasted tomato salsa with, roasted garlic and jalapeños, raw onion and cilantro.
Price: $29
Spices n’ Herbs
January 2021 was arguably the most stressful American January on record, and Kimpton Hotels understand if your attempts not to drink for the month fell short. That’s why restaurants like Geraldine’s at the Hotel Van Zandt in Austin, Texas, are observing Dry February with spirit-free cocktails such as this one, developed by chief of bar operations Caitlyn Jackson, made with lime juice, cilantro-jalapeño syrup, mole bitters, sour cream and sparkling Richard’s Rainwater
Price: $14
| https://www.restaurant-hospitality.com/food-drink/new-menu-warming-beef-dishes-and-lunar-new-year-salad/gallery?curr=18 |
Pioglitazone and Glimepiride in Diabetes Mellitus - Clinical Trials Registry - ICH GCP
The purpose of this study was to determine the efficacy of pioglitazone, once daily (QD), compared to glimepiride on atherosclerotic disease measured by intrava...
Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus (PERISCOPE)
A Double-Blind, Randomized, Comparator-Controlled Study In Subjects With Type 2 Diabetes Mellitus Comparing the Effects of Pioglitazone HCl Versus Glimepiride on the Rate of Progression of Coronary Atherosclerotic Disease as Measured by Intravascular Ultrasound
The purpose of this study was to determine the efficacy of pioglitazone, once daily (QD), compared to glimepiride on atherosclerotic disease measured by intravascular ultrasound.
Study Overview
Status
Completed
Conditions
Diabetes Mellitus
Intervention / Treatment
Drug: Pioglitazone
Drug: Glimepiride
Detailed Description
Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity.
Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral tissue cells to circulating insulin (ie, insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (ie, insulin deficiency due to beta-cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes.
In the United States, an estimated 21 million people have diabetes, with type 2 diabetes occurring in approximately 90% to 95% of cases.
The goal of treating type 2 diabetes is to control blood glucose and thereby prevent long-term complications.
Adequate glycemic control is paramount in attempting to avert chronic complications, including blindness; renal dysfunction resulting in dialysis or renal transplantation; neuropathy; non-traumatic amputations; and macrovascular complications, including myocardial ischemia and myocardial infarction, stroke, and peripheral arterial disease.
Intensive glucose management in the early stages of diabetes may help forestall such complications.
Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance.
Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal by binding to nuclear receptors known as peroxisome proliferator-activated receptors.
Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis), with no direct impact on insulin secretion.
Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin without predisposing patients to hypoglycemia.
Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver.
The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue.
This study was designed to compare the effects of pioglitazone compared to glimepiride on progression of atherosclerotic disease, as measured by intravascular ultrasound.
Study Type
Interventional
Enrollment (Actual)
547
Phase
Phase 3
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
Argentina
Ciudad de Buenos Aires, Argentina
Cordoba, Argentina
Quilmes, Argentina
Canada
Alberta
Edmonton, Alberta, Canada
British Columbia
Vancouver, British Columbia, Canada
Victoria, British Columbia, Canada
Manitoba
Winnepeg, Manitoba, Canada
New Brunswick
Saint John, New Brunswick, Canada
Ontario
London, Ontario, Canada
Ottawa, Ontario, Canada
Quebec
Montreal, Quebec, Canada
Sainte Foy, Quebec, Canada
Saskatchewan
Saskatoon, Saskatchewan, Canada
Chile
Santiago, Chile
United States
Alabama
Birmingham, Alabama, United States
Arizona
Phoenix, Arizona, United States
California
Huntington Beach, California, United States
Los Angeles, California, United States
Sacramento, California, United States
San Diego, California, United States
Torrance, California, United States
Connecticut
Bridgeport, Connecticut, United States
Farmington, Connecticut, United States
District of Columbia
Washington, District of Columbia, United States
Florida
Bay Pines, Florida, United States
Jacksonville, Florida, United States
Georgia
Decatur, Georgia, United States
Idaho
Boise, Idaho, United States
Illinois
Chicago, Illinois, United States
Kentucky
Edgewood, Kentucky, United States
Lexington, Kentucky, United States
Louisville, Kentucky, United States
Louisiana
New Orleans, Louisiana, United States
Maine
Bangor, Maine, United States
Maryland
Baltimore, Maryland, United States
Michigan
Detroit, Michigan, United States
Flint, Michigan, United States
Kalamazoo, Michigan, United States
Petoskey, Michigan, United States
Pontiac, Michigan, United States
Royal Oak, Michigan, United States
Ypsilanti, Michigan, United States
Minnesota
Duluth, Minnesota, United States
Minneapolis, Minnesota, United States
St. Cloud, Minnesota, United States
Missouri
Columbia, Missouri, United States
New Jersey
Camden, New Jersey, United States
New York
Albany, New York, United States
Bronx, New York, United States
Mineola, New York, United States
New York, New York, United States
Rochester, New York, United States
Troy, New York, United States
West Islip, New York, United States
Williamsville, New York, United States
North Carolina
Winston-Salem, North Carolina, United States
Ohio
Cincinnati, Ohio, United States
Cleveland, Ohio, United States
Columbus, Ohio, United States
Westlake, Ohio, United States
Oklahoma
Oklahoma City, Oklahoma, United States
Tulsa, Oklahoma, United States
Pennsylvania
Abington, Pennsylvania, United States
Bryn Mawr, Pennsylvania, United States
Hershey, Pennsylvania, United States
Pittsburgh, Pennsylvania, United States
Rhode Island
Providence, Rhode Island, United States
South Carolina
Greenville, South Carolina, United States
Tennessee
Memphis, Tennessee, United States
Oak Ridge, Tennessee, United States
Texas
Amarillo, Texas, United States
Houston, Texas, United States
Lubbock, Texas, United States
San Antonio, Texas, United States
Virginia
Charlottesville, Virginia, United States
Norfolk, Virginia, United States
Richmond, Virginia, United States
Washington
Everett, Washington, United States
Wisconsin
Green Bay, Wisconsin, United States
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
35 years to 85 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
Females of childbearing potential who were sexually active agreed to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
Had a diagnosis of type 2 diabetes mellitus
Have received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise.
naïve to or was not currently taking antidiabetic therapy, or were currently treated with monotherapy or combination therapy.
Had a glycosylated hemoglobin level greater than or equal to 6.0% and less than 9% at screening if taking antidiabetic medication or greater than or equal to 6.5% and less than 10% at screening if naive to or not taking antidiabetic medication.
Angiographic criteria:
Entire Coronary Circulation: must have angiographic evidence of coronary heart disease as defined by at least 1 lesion in a native coronary artery that has greater than or equal to 20% reduction in lumen diameter by angiographic visual estimation.
Left Main Coronary Artery: must not have greater than 50% reduction in lumen diameter by visual angiographic estimation.
Target Coronary Artery:
The target vessel, which includes the main artery and all of its side branches, had not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery.
The target vessel, which includes the main artery and all of its side branches, was not currently a candidate for intervention or a likely candidate for intervention over the next 72 weeks.
The target vessel was not a bypass graft.
The target vessel was not infarct related.
Had previous coronary artery bypass surgery at least six weeks prior to the qualifying intravascular ultrasound are eligible provided they are stable and meet all other entry criteria.
Had an intravascular ultrasound tape deemed to be of acceptable intravascular ultrasound image quality and demonstrated adherence to the intravascular ultrasound interrogation protocol, as determined by the intravascular ultrasound Core Laboratory™ assessment.
Exclusion Criteria:
Had type I diabetes mellitus.
Had participated in another investigational study, or participated in an investigational study 30 days prior to the start of this study, or who were scheduled to participate in an investigational study during the time frame of this study.
Male subjects who had a serum creatinine level greater than or equal to 2.0 mg/dL (greater than or equal to 177 µmol/L) (greater than or equal to 1.5 mg/dL; [greater than or equal to 133 µmol /L] if taking metformin) and female subjects who have serum creatinine greater than or equal to 1.8 mg/dL [greater than or equal to 159 µmol /L] (greater than or equal to 1.4 mg/dL [greater than or equal to 124 µmol /L] if taking metformin).
Had unexplained microscopic hematuria greater than +1, confirmed by repeat testing.
Had a history of drug abuse or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years.
Had clinical cardiac failure as defined by New York Heart Association class III or IV, or known left ventricular dysfunction measured as left ventricular ejection fraction less than 40%, or by current use of diuretics or angiotensin converting enzyme inhibitors for treatment of heart failure.
Had an alanine transaminase level of greater than 2.5 times the upper limit of normal active liver disease, or jaundice.
Had a body mass index greater than 48 kg/m2 as calculated by weight (kg)/height (m2) or weight (pounds)/height (inches) 2 x 703.
Was required to take or intended to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including:
Chronically used oral glucocorticoids (eg, prednisone, cortisone, hydrocortisone, dexamethasone)
Niacin greater than100 mg a day, including niacin-containing products such as Advicor®
Chronically used steroid-joint injections
Thiazolidinediones
Sulfonylureas
Metformin/sulfonylurea combination
Other oral antidiabetic medications (eg, nateglinide [Starlix®], acarbose [Precose®]) with the exception of metformin
Had known or suspected malignancy or recurrence of malignancy within the past 5 years, with the exception of basal cell carcinoma and Stage 1 squamous cell carcinoma of the skin.
Had any disease where, in the opinion of the investigator (or designee), survival is expected to be less than 72 weeks.
Clinical status was unstable (ie, requiring vasopressors or intravenous inotropes, intra-aortic balloon pump, hypotension [systolic blood pressure less than 90 mm Hg]).
Prior to the screening visit, was scheduled for a staged cardiac intervention (percutaneous coronary intervention), peripheral vascular intervention, or coronary artery bypass graft surgery following the screening angiography.
In the opinion of the investigator (or designee) had clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study.
Had persistent, uncontrolled hypertension (ie, sitting systolic blood pressure greater than 160 mm Hg or sitting diastolic blood pressure greater than 100 mm Hg) at randomization.
Males who had hemoglobin less than 10.5 g/dL (less than 105 g/L) and female subjects who had hemoglobin less than 10.0 g/dL (less than 100 g/L).
Had a triglyceride level greater than 500 mg/dL (greater than 5.6 mmol/L).
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: Quadruple
2
Arms and Interventions
<table><tr><th> Participant Group / Arm</th><th> Intervention / Treatment</th></tr><tbody><tr><td> Experimental: Pioglitazone QD</td><td> Drug: Pioglitazone Up to 45 mg pioglitazone (optimized for glucose control), tablets, orally, once daily for up to 72 weeks. Other Names: ACTOS® AD4833</td></tr><tr><td> Active Comparator: Glimepiride QD</td><td> Drug: Glimepiride Up to 4 mg of glimepiride (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.</td></tr></tbody></table>
What is the study measuring?
Primary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Nominal Change From Baseline in Percent Atheroma Volume Time Frame: Baseline and Final Visit (up to 72 weeks)</td><td> The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery.
Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.</td><td> Baseline and Final Visit (up to 72 weeks)</td></tr></tbody></table>
Secondary Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Nominal Change From Baseline in Normalized Total Atheroma Volume Time Frame: Baseline and Final Visit (up to 72 weeks)</td><td> The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population.
Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.</td><td> Baseline and Final Visit (up to 72 weeks)</td></tr><tr><td> Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events Time Frame: Up to 72 weeks</td><td> Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence.
Endpoint A conditions listed in Limitations and Caveats section.</td><td> Up to 72 weeks</td></tr><tr><td> Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events Time Frame: Up to 72 weeks</td><td> Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence.
Endpoint B conditions listed in Limitations and Caveats section.</td><td> Up to 72 weeks</td></tr><tr><td> Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events Time Frame: Up to 72 weeks</td><td> Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence.
Endpoint C conditions listed in Limitations and Caveats section.</td><td> Up to 72 weeks</td></tr></tbody></table>
Other Outcome Measures
<table><tr><th> Outcome Measure</th><th> Measure Description</th><th> Time Frame</th></tr><tbody><tr><td> Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee Time Frame: Up to 72 weeks</td><td> The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee.
Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure.</td><td> Up to 72 weeks</td></tr></tbody></table>
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Takeda
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
Betteridge DJ. CHICAGO, PERISCOPE and PROactive: CV risk modification in diabetes with pioglitazone. Fundam Clin Pharmacol. 2009 Dec;23(6):675-9. doi: 10.1111/j.1472-8206.2009.00741.x. Epub 2009 Sep 10.
Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochelliere R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008 Apr 2;299(13):1561-73. doi: 10.1001/jama.299.13.1561. Epub 2008 Mar 31.
Nicholls SJ, Tuzcu EM, Wolski K, Bayturan O, Lavoie A, Uno K, Kupfer S, Perez A, Nesto R, Nissen SE. Lowering the triglyceride/high-density lipoprotein cholesterol ratio is associated with the beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients: insights from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. J Am Coll Cardiol. 2011 Jan 11;57(2):153-9. doi: 10.1016/j.jacc.2010.06.055.
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
July 1, 2003
Primary Completion (Actual)
October 1, 2007
Study Completion (Actual)
October 1, 2007
Study Registration Dates
First Submitted
September 21, 2005
First Submitted That Met QC Criteria
September 21, 2005
First Posted (Estimate)
September 23, 2005
Study Record Updates
Last Update Posted (Estimate)
February 28, 2012
Last Update Submitted That Met QC Criteria
February 27, 2012
Other Study ID Numbers
01-01-TL-OPI-516
U1111-1114-0400 (Registry Identifier: WHO)
NCT05933174
NCT05932953
NCT05933161
NCT05932251
NCT05919147
NCT05875675
NCT05838287
NCT05813249
NCT05775380
NCT05753657
| https://ichgcp.net/clinical-trials-registry/NCT00225277 |
Realscreen » Archive » Broadcaster Profile: Channel 4’s Steve Hewlett talks factual strategy
In British broadcasting's recent round of executive musical chairs, one of the undoubted beneficiaries has been Steve Hewlett - the new controller of documentaries and features at Channel 4. Having made his mark within the bbc, most recently as editor of...
Broadcaster Profile: Channel 4’s Steve Hewlett talks factual strategy
In British broadcasting's recent round of executive musical chairs, one of the undoubted beneficiaries has been Steve Hewlett - the new controller of documentaries and features at Channel 4. Having made his mark within the bbc, most recently as editor of...
In British broadcasting’s recent round of executive musical chairs, one of the undoubted beneficiaries has been Steve Hewlett – the new controller of documentaries and features at Channel 4. Having made his mark within the bbc, most recently as editor of flagship current-affairs strand Panorama, Hewlett was one of the first targets for C4 chief executive Michael Jackson, following his own departure from the bbc last summer.
Jackson’s regard for Hewlett is evident in the broad remit handed to his former colleague. Hewlett’s factual-programming fiefdom includes anchors such as documentaries, history, science and leisure. In addition, he oversees religion, music & arts, features, talks, multicultural programming and the Independent Film & Video Unit’s radical output. Only news and current affairs are beyond his grasp. ‘The breadth of the role was one of the things that attracted me to the job,’ says Hewlett. ‘It is an opportunity to see if my programming instincts will stand the test across a wide range of programs.’
The decision to join C4 at a time when the bbc is so clearly undergoing a factual-programming renaissance is rooted in a variety of factors – not least of which are Hewlett’s fond memories of working at C4 during its launch phase. ‘It was exciting for me to be involved with the sort of public broadcaster that Channel 4 was set up to be. It represented a genuine flowering of talent.’
He stayed from 1982-87, working on current-affairs series Alternative Friday and Diverse Reports, before joining the bbc. During the next decade at the corporation, he devised concepts such as Children’s Hospital and Airport, as well as editing both Inside Story and Panorama. His greatest coup was the exclusive Panorama interview with the late Diana Spencer which topped the u.k. ratings.
During his years at the bbc, however, Hewlett witnessed a realignment within the u.k. factual-programming sector which he believes was led by C4. ‘They made the first big turn of the wheel,’ he says. ‘They upset the status quo both politically and in craft terms, and introduced the sort of quality control which had previously only existed in bbc. The channel was definitely leading the way with strands like Cutting Edge.’
Subsequently, in Hewlett’s opinion, the bbc has fought back. Now, he believes British factual programming is poised for ‘the next turn of the wheel which will set the pace for the coming five to ten years. Instinctively, I think it will emerge here. But I might be wrong, because the bbc is no slouch.’
For Hewlett, the appeal of C4 is its freedom to operate creatively. ‘There is something that inevitably constrains the bbc. The public and politicians feel that they own the bbc, which means that things which don’t bat an eyelid on Channel 4 seem controversial on bbc1. I don’t think that’s wrong. But creatively, I wonder if the bbc is really capable of making big changes.’
This institutional observation is reinforced by the weight of the bbc’s ongoing efficiency drive. ‘Cost-cutting never stopped me doing anything while I was there, but it was coming pretty close,’ says Hewlett. ‘That is depressing for editorial managers who are there because they want to make programs.’
Although he talks in terms of epoch-changing television, Hewlett claims that he has not come to C4 with the intention of rewriting the schedule. ‘There is genuinely no sense of me saying, ‘This is all crap. Do it my way.’ The organization has a fantastic base, but it is clearly time to take stock of how we put the channel and the audience together for the next five years.’
Hewlett has now met each of the commissioning editors who report to him, and is keen to stress that the overriding responsibility still lies in their hands. ‘My role only works if it is strategic. If I said I would do the commissioning, it would be about three weeks before the office was full of paper and no decisions were being made at all.’
He rejects the idea that this is antagonistic to C4’s commercial ambition – or that innovation is only suitable for the fringes of the schedule. ‘I think it is invidious to say we get all our radical stuff from ifv and the audiences from Cutting Edge. The two aims aren’t contradictory. We want the best audiences possible given the editorial mission of the strand or department.’
Under Hewlett, existing strands appear to be safe. Cutting Edge, Secret Lives, Witness and Equinox ‘are huge strengths right at the heart of Channel 4. Maybe they need to be reinvigorated in places, but in a crowded market, brands are critical.’ Another brand he defends is Undercover. ‘It is a great strand and, providing it is possible, we should do more. But the standards are exacting. Amassing evidence to justify the intrusion is very demanding and getting them on the air is a big job. There is a reasonably high failure rate.’
There are areas where Hewlett sees room for improvement. With the ‘honourable exceptions’ of shows like TV Dinners and The Real Holiday Show, he believes that C4 has struggled to compete with the bbc in leisure programming. Arts is a genre where ‘you will see efforts to make greater impact,’ says Hewlett. Religion and multicultural programming are areas where he believes that broadcasting in general is ‘slightly behind the experience of most people.’
If there has been a general concern about documentary-making in the u.k., it is that there has been a gradual victory of directorial style over journalistic content – a criticism which Hewlett acknowledges. ‘I see lots of young, fantastically proficient people with ideas. But I think there has been a move towards the commissioning of documentaries where entertainment supersedes the objectives of insight or information.’
He is keen to reinforce C4’s commitment to the authoritative documentary. ‘I don’t believe documentaries should be watched as a penance. But we have to consider the situation for productions which seek to deal with serious and important things which can’t be presented in an entertaining way.’
A key distinction between C4 and the bbc is the former’s complete reliance on the independent sector – a factor which appeals to Hewlett. ‘The independent sector offers ideas that are unconstrained by corporate issues. The number of companies capable of delivering at a very high level of quality has rocketed in the last few years.’
That said, the existence for many is hand to mouth. Not only are there acute political questions about whether indies should be able to wrest greater control of their rights from C4, but there is a question about how far C4 should seek to nurture development.
‘There is a danger in the strictly contract-for-program, program-transmitted, money-paid realtionship,’ he says. ‘It is incumbent on us to enable independents to do their best work, which might mean engaging in a more constructive dialogue with them at an earlier stage. Channel 4 has got to ensure that it looks carefully at the kind of encouragement we can give people.’
For the foreseeable future, he sees strong support for factual’s central role in the C4 schedule. ‘There is no free ride. But Michael Jackson has worked in factual programs and knows what they can do for him.’
He believes one source of extra funding is the coproduction environment which has become more favourable. ‘People are more grown up about it now. And I think the bbc’s partnership with Discovery opens up the field for us.’
Hewlett’s ability to fulfill the C4 remit will require more than just scheduling success. ‘The spirit of mischief and challenge to orthodoxy that ifv represents needs to infect the whole of the channel,’ he says.
‘If anything is under threat in documentary-making, which I am determined to make sure survives at Channel 4, it is the spirit of enquiry. It is important to embrace projects of real editorial ambition which connect with the way people are leading their lives.’.
| https://realscreen.com/1998/03/01/21084-19980301/ |
Cells | Free Full-Text | The RNA-Binding Landscape of HAX1 Protein Indicates Its Involvement in Translation and Ribosome Assembly
HAX1 is a human protein with no known homologues or structural domains. Mutations in the HAX1 gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here, we report the transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in translation, ribosome biogenesis, and rRNA processing. Using CRISPR knockouts, we find that HAX1 RNA targets partially overlap with transcripts downregulated in HAX1 KO, implying a role in mRNA stabilization. Gene ontology analysis demonstrated that genes differentially expressed in HAX1 KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with HAX1 expression in four analyzed neoplasms. The functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in HAX1 WT/KO. We speculate that changes in HAX1 expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation.
The RNA-Binding Landscape of HAX1 Protein Indicates Its Involvement in Translation and Ribosome Assembly
Anna Balcerak 1,† ,
Ewelina Macech-Klicka 1,† ,
Maciej Wakula 1,† ,
Krzysztof Goryca 4 ,
Malgorzata Rydzanicz 5 ,
Mateusz Chmielarczyk 1 ,
Malgorzata Szostakowska-Rodzos 1 ,
Marta Wisniewska 6 ,
Filip Lyczek 1 ,
Aleksandra Helwak 7 ,
David Tollervey 7 ,
Grzegorz Kudla 8 and
Ewa A. Grzybowska 1,*
1
Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
2
Laboratory of RNA Processing and Decay, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
3
Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw, 02-106 Warsaw, Poland
4
Genomics Core Facility, Centre of New Technologies University of Warsaw, 02-097 Warsaw, Poland
5
Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland
6
Laboratory of Biological Chemistry of Metal Ions, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
8
MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2022 , 11 (19), 2943; https://doi.org/10.3390/cells11192943
Received: 16 August 2022 / Revised: 13 September 2022 / Accepted: 15 September 2022 / Published: 20 September 2022
Abstract
HAX1 is a human protein with no known homologues or structural domains. Mutations in the
HAX1
gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here, we report the transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in translation, ribosome biogenesis, and rRNA processing. Using CRISPR knockouts, we find that HAX1 RNA targets partially overlap with transcripts downregulated in
HAX1
HAX1
KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with
HAX1
expression in four analyzed neoplasms. The functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in
HAX1
WT/KO. We speculate that changes in
HAX1
expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation.
Keywords:
RNA–protein binding
;
HAX1
;
RIP-seq
;
CRAC
;
translation
;
ribosome assembly
1. Introduction
HAX1 (HCLS1-associated protein X-1) is known as an antiapoptotic protein with a role in the regulation of cell migration, cell adhesion, and calcium homeostasis [ 1 ]. HAX1 deficiency, due to mutations in the HAX1 gene, results in the autosomal recessive severe congenital neutropenia (SCN) called Kostmann disease [ 2 ]. This myelopoietic disorder is caused by the arrest of granulocyte maturation and the resulting paucity of mature neutrophils, leading to life-threatening infections. This effect has been attributed to excessive apoptosis caused by HAX1 deficiency, but the exact molecular mechanism was not demonstrated. On the other hand, HAX1 overexpression was documented in several neoplasms [ 3 , 4 , 5 , 6 ]. Here, we propose that these effects may be linked to ribosome dysfunction.
To date, HAX1’s RNA-binding propensity has been reported in two particular cases: for the vimentin transcript [ 7 ] and the DNA polymerase beta transcript [ 8 ]. Both instances pertained to strong hairpin structures at the 3′UTR of these transcripts, although the comparison of the hairpin motifs in vimentin and Pol β mRNAs did not reveal any significant similarities, apart from the presence of U-rich single-stranded regions [ 8 ]. In our recent report [ 9 ], in which we described the HAX1 protein interactome, we also suggested the possibility of RNA-binding by HAX1 deduced from neighboring proteins (first observed by Brannan et al. [ 10 ]).
The role of HAX1 RNA binding in cellular processes has not been clarified so far, except for some suggestions of its involvement in the regulation of specific mRNAs [ 11 , 12 ].
The HAX1 protein has no homologues or known domains, except for a PEST sequence, a specific signal which was linked to a shorter half-life of the protein and its proteasomal degradation [ 13 ]. The presence of BCL2-like domains was disproved [ 14 ]. Consequently, HAX1 does not possess any known RNA-binding domain, and a large proportion of the protein is predicted to be disordered [ 15 , 16 ], so RNA binding probably occurs in a nonconventional manner.
The current study provides for the first time a comprehensive analysis of the HAX1–RNA interactome, with two independent approaches for the isolation of its RNA targets. Subsequent analysis of the impact of HAX1 on the cell transcriptome and analysis of expression in several cancer databases produced coherent results that indicate the unanticipated role of HAX1 in ribosome biogenesis and translation. Comparison of the experimental data obtained for HAX1 RNA binding and transcriptome profiling indicates that HAX1 may regulate the stability of the bound transcripts. These results were corroborated by the observation that
HAX1
KO affects the ribosomal profile, especially with respect to the ratio of the small ribosomal subunit to the monosome. The involvement of HAX1 in ribosome biogenesis and translation emerging from this work may help to elucidate its many-sided effects on cellular processes and HAX1-associated diseases.
2. Results
2.1. Different High-Throughput Analyses of HAX1 Binding Targets Consistently Reveal Its Involvement in Translation and Ribosome Biogenesis
HAX1 is predicted to contain few secondary structure elements, while most of its sequence is predicted to be disordered and there is no conventional RNA-binding domain ( Figure 1 A, [ 15 , 16 ]). Nevertheless, the RNA-binding propensity of HAX1 was previously reported [ 7 , 8 ]. Furthermore, three different RNA-binding prediction algorithms suggest that HAX1 may bind to RNA: RNApred (amino acid composition-based method, the score for putative RBD: 0.58 SVM (support vector machine), cutoff: 0.5, RNApred. Available online: https://webs.iiitd.edu.in/raghava/rnapred/ , accessed on 10 April 2019) [ 17 ], RBPPred (sequence-based method, the score for putative RBD: 0.928 SVM, cutoff: 0.5, RBPPred. Available online: http://rnabinding.com/RBPPred.html , accessed on 12 Februray 2020) [ 18 ], and CatRapid (secondary structure, hydrogen bonding, and van der Waals forces-based prediction, the score for putative RBD: 0.61, threshold 0.5, CatRapid. Available online: http://s.tartaglialab.com/page/catrapid_group , accessed on 21 March 2019) [ 19 ] ( Figure 1 B). Algorithms that compare three-dimensional structures cannot be used, since HAX1 has no homologs, is mostly disordered, and has not been crystalized.
Figure 1. Experimental design of HAX1–RNA interactome studies. ( A ) HAX1 amino acid sequence with characteristic features and regions (acid box, PEST domain, structural elements predicted using PSIPRED (PSI-blast-based secondary structure PREDiction)). ( B ) CatRapid prediction of HAX1 RNA binding propensity classifies it as a putative RBP, but binding does not occur via classical elements. ( C ) Schematic of RIP experiments: no crosslink, single purification step with HAX1-specific antibody. ( D ) Schematic of CRAC experiments, sequential steps: UV crosslink of RNA targets, double purification with Sepharose and NiNTA resin, isotope labeling and extraction of the RNA–protein complexes from polyacrylamide gel, RNA extraction, reverse transcription, PCR, and next generation sequencing of the RNA targets.
To verify and globally characterize the RNA-binding propensity of HAX1, we used two independent, high-throughput screens (RIP-seq and CRAC) for the HAX1 RNA targets ( Figure 1 C,D). RIP-seq is simpler, with one purification step and without the crosslinking step, and thus it yields more background noise (>5000 hits). On the contrary, CRAC involved RNA crosslinking and two purification steps; thus, the results were more specific and enabled the analysis of the bound RNA regions. Both approaches unanimously revealed enrichment in the RNAs linked to translation, ribosome biogenesis, and RNA processing.
2.1.1. RIP-Seq Results
RNA target identification was performed in the human leukemia cell line HL-60, because promyelocytes represent the most affected cell type in patients with a recessive mutation in both HAX1 alleles (severe neutropenia). This condition is lethal when untreated, so the analysis of the role of HAX1 in these cells seems to be the most physiologically relevant. The experiment was carried out in five replicates for each, with a HAX1-IP and IgG control (correct clustering confirmed by principal component analysis, Figure S2A ). HAX1-associated transcriptome was identified by employing next generation sequencing after the RNA immunoprecipitation (RIP-seq) of the HAX1 complexes. Transcripts were classified as positive targets using an adjusted p -value cutoff of 0.05. Enrichment analysis (the Database for Annotation, Visualization and Integrated Discovery; DAVID) of the obtained dataset indicates involvement in RNA processing, translation, and ribosome biogenesis, including a strong category of targets involved in rRNA processing ( Figure 2 A, Supplementary Data File S1 ). Using the DAVID Functional Classification Tool, which performs background compensation for Homo sapiens expression profile, ensures that the obtained pool of highly expressed transcripts encoding proteins involved in translation and ribosome biogenesis represents a truly significant output. Plotting enrichment against the false discovery rate (FDR) for GO terms obtained by gene ontology enrichment analysis (Panther) in the Biological Process category revealed that the terms related to ribosome (including ribosome biogenesis and rRNA processing) and translation are of high significance (high enrichment, low FDR, Figure 2 B). Most of the RNA targets obtained in the RIP analysis represent mRNA ( Figure 2 C). Figure 2 D represents the RIP-seq coverage (X-axis; FPKM, fragments per kilobase per million, to compensate for the length of the transcript) plotted against log2 enrichment in RIP-seq (RIP-seq_HAX1/RIP-seq_IgG). The red points above (or below) the horizontal axis represent transcripts that are significantly enriched (or depleted) in the HAX1 pulldown compared to their total abundance in cells.
Figure 2.
Identification of HAX1-associated RNA targets by RIP-seq analysis in HL-60 cells. (
A
) Functional annotation enrichment of HAX1 target genes. Enriched gene ontology terms (DAVID: Biological Process) presented in bar plot, the length of each bar corresponds to statistical significance of the enrichment (−log10
p
-value). The top twenty terms are presented. (
B
) Enriched Biological Process terms (Panther GO) plotted with fold enrichment (log2) against False Discovery Rate (−log10). The most reliable results are in the upper right corner. Categories associated with ribosome biogenesis, rRNA processing, and translation are marked red. Categories associated with RNA metabolism (other than rRNA) are marked light orange. Detailed description of GO terms in
Supplementary File S1
. (
C
) Distribution of RNA classes among HAX1 RIP targets. (
D
) MA plot showing RIP targets counts (X-axis) calculated as fragments per kilobase per million (FPKM); Y-axis: log2FC(RIP_HAX1/RIP_IgG), red—significant, grey—not significant. The internal frame indicates positive log2 FC (physiologically relevant as possible binding targets).
2.1.2. CRAC Results
CRAC (crosslinking and cDNA) analysis was performed in the HEK293FlpInTRex human embryonic kidney cell line modified to overexpress HAX1 after doxycycline induction. This cell line was used because it has been standardized for CRAC experiments. Two different cell lines were generated expressing a protein with a tag added at the 5′ or 3′ end of the HAX1 coding sequence and compared to the negative control cell line (experiments were performed in two replicates for each cell line). Pooled results for N- and C-tagged protein were considered for analysis (log2FC[CRAC_HAX1/CRAC_NC] > 0). Enrichment analysis (DAVID) revealed involvement in translation and ribosome assembly, including translation and cytoplasmic translation, rRNA processing, and ribosome biogenesis (
Figure 3
A,
Supplementary Data File S2
). Enrichment values plotted against false discovery rate (FDR) for GO terms obtained by gene ontology enrichment analysis (Panther) revealed that similar terms as in RIP (involving translation, rRNA processing, and ribosome biogenesis) are of the highest significance (
Figure 3
B).
Figure 3.
Identification of HAX1-associated RNA targets by CRAC analysis (HEK293 cells). (
A
) Functional annotation enrichment of HAX1 target genes (results from the pooled N- and C-tagged protein approach). Enriched gene ontology terms (DAVID: Biological Process) presented in bar plot, the length of each bar corresponds to statistical significance of the enrichment (−log10
p
-value). The top 20 terms are presented for each category. (
B
) Enriched Biological Process terms (Panther GO) plotted with fold enrichment (log2) against false discovery rate (−log10). The most reliable results are in the upper right corner. Terms associated with ribosome biogenesis, rRNA processing, and translation are marked red. Terms associated with RNA metabolism (other than rRNA) are marked in light orange. Detailed description of GO terms in
Supplemental Data File S2
. (
C
) Distribution of RNA species in HAX1 targets. (
D
) Coverage of HAX1 CRAC reads along small (18S) and large (28S) ribosomal subunits. Reads for negative control shown below. (
E
) Consensus motif identified by STREME in the HAX1-targets dataset (combined experimental data from C- and N-tagged HAX1). The E-value is the
p
-value multiplied by the number of motifs reported by STREME. (
F
) Genomic position of HAX1 binding in CRAC-identified targets (269 targets overlapping in C- and N-tagged datasets) established using UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19) Assembly.
The transcript biotype analysis indicates a high proportion of rRNA and tRNA (respectively 54% and 17%), with mRNA representing 10% of CRAC targets ( Figure 3 C). Discrepancy with RIP results may result from methodical differences (UV crosslink, overexpression of the protein, see Discussion). Detailed analysis of the coverage of HAX1 reads along small (18S) and large (28S) ribosomal subunits shows high reads for the region of 1368–1407 in the large subunit, indicating a possible interaction site ( Figure 3 D and Figure S3 ).
The CRAC method enables the assessment of the enrichment in recurring sequence patterns (motifs) in an analyzed experimental dataset. The motif finding was performed using STREME (The MEME Suite; motif-based sequence analysis tools), resulting in a characterization of a guanine-rich motif for the C- and N-terminally tagged combined datasets ( Figure 3 E and Figure S4 ).
The analysis of the genomic position of the detected mRNA targets (269 best quality targets from the pooled C and N dataset) revealed the predominant binding of HAX1 to the coding sequence (CDS) region and the substantial number of targets located in both CDS and 5′ or 3′ UTRs. Only 11% of targets were mapped only in noncoding regions. Interestingly, introns plus CDS represent about 6% of targets, and half of these intronic targets encode snoRNA ( Figure 3 F, Supplementary Data File S2 ).
2.1.3. Comparison of the RIP-Seq and CRAC Results
In both approaches, the enriched GO terms encompassed translation, ribosome biogenesis, rRNA processing, and RNA processing in general. Enrichment in the same categories was detected for the group of 629 targets that overlapped on both screens, and these categories were also the most probable (
Figure 4
A–C), with a high proportion of transcripts encoding ribosomal proteins (including 33 proteins of large and small ribosomal subunits), ribosome assembly factors, and translation factors (
Supplementary File S3
). These results point to the probable role of HAX1 in ribosome assembly and translation.
Figure 4.
Characterization of the overlapping CRAC–RIP subset of HAX1 mRNA targets. (
A
) Overlapping targets in RIP and CRAC_C (629 mRNAs) represent, respectively, 13.7% and 38.5% of the overall results. Hypergeometric test for these overlap gives
p
-values of 9.8e–42 (total gene set: 15220). (
B
) Functional annotation enrichment of the RIP/CRAC overlap of HAX1 target genes (DAVID, top 20 terms) maintains a high enrichment in terms associated with translation, RNA and rRNA processing, and ribosome biogenesis (Biological Process) (
C
) Enriched Biological Process terms found for the overlap subset (Panther GO) plotted with fold enrichment (log2) against false discovery rate (−log10) reveal that terms associated with translation and ribosome biogenesis are the most probable. (
D
) Target validation by microscale thermophoresis (MST) performed for the RPL19 in vitro transcript (sense). From 33 transcripts encoding ribosomal proteins present in the overlapping RIP/CRAC target list, a fragment of the RPL19 coding sequence was selected for validation. The interaction with purified and the fluorescently labeled HAX1 protein was confirmed in 4 independent measurements by thermophoresis under different conditions (MST power medium to high). For each measurement, the dissociation constant (Kd) and half maximal effective concentration (EC50) were assigned. No interaction was observed with antisense transcript (negative control).
2.1.4. Validation of a Selected Target by Microscale Thermophoresis
Microscale thermophoresis (MST) was performed for the in vitro transcript containing a fragment of the coding sequence of the RPL19 ribosomal protein. This target was selected due to its relatively high rank on the list of overlapping RIP and CRAC targets. The specific sequence was based on the CRAC identification of the binding region within exon3. The titration of the target RNA to a constant concentration of the fluorescently labeled HAX1 protein allowed for the determination of the ligand dissociation constants (Kd) and the systematic comparison of their binding affinity. The half maximal effective concentration (EC50) was calculated by the Hill fit model. The results reveal binding for the sense transcript, but not for the antisense negative control ( Figure 4 D and Figure S5 ).
2.2. HAX1 KO Affects the Expression Profile of HL-60 Cells
To assess the impact of HAX1 on the HL-60 transcriptome, two independent cell lines with HAX1 CRISPR/Cas9 knockout were generated (HAX1 KO#1, KO#2,
Figure S1
) and used in the RNA-seq experiment to compare expression profiles with HAX1 WT cells. Statistical significance was assigned only for genes differentially expressed in both
HAX1
KO cell lines vs. WT and in the same direction (
p
-value cutoff 0.05). Gene ontology analysis revealed that HAX1 knockout affects the expression profile of the HL-60 cells in several terms of the Biological Process (
Figure 5
A–C). Weighted analysis of the RNA-seq results (String 11, functional enrichment analysis for proteins ranked according to fold change [RNA-seq_
HAX1
KO/RNA-seq_WT]) allows to distinguish two main groups: GO terms linked to ribosome biogenesis, rRNA processing and translation (including mitochondrial translation), and terms linked to energy generation in mitochondria: respiratory electron transport chain and oxidative phosphorylation (details of GO analysis in
Supplementary Data File S4
).
HAX1
knockout significantly affects the expression of 2344 genes (1158 upregulated and 1186 downregulated in KO). As indicated in
Figure 5
C, genes related to ribosome biogenesis, translation, and energy generation in mitochondria tend to be downregulated in
HAX1
KO cells.
Figure 5.
HAX1
KO affects the expression profile in HL-60 cells. (
A
) Enrichment plots generated by GSEA analysis for the chosen categories (translation, rRNA processing, respiratory electron transport) (
B
) Enrichment in GO Biological Process terms for genes differentially expressed in
HAX1
KO vs.
HAX1
WT (String 11 weighted analysis with log2[RNA-Seq_
HAX1
_KO/RNA-Seq WT] as values) indicates participation in translation (including mitochondrial translation), rRNA processing/ribosome biogenesis, and energy generation in mitochondria. Detailed description of GO terms in
Supplementary Data File S4
. (
C
) Scatter plot showing differentially expressed genes in
HAX1
KO. Of the total 1186 transcripts significantly downregulated in KO, 172 are associated with translation and 202 with energy generation, while from the 1158 transcripts significantly upregulated in KO, 13 and 58, respectively, are associated with these categories. The
p
-value cutoff: 0.05. A total of 14 outliers were omitted. The statistical significance of the downregulation of the transcripts involved in ribosome biogenesis and translation and cellular respiration was assessed by the Chi-Square test and was shown to be high (
p
-value = 5.5 × 10
−20
and 1.2 × 10
−5
, respectively). For the other two groups (all mapped results and all DEGs), there was no statistical significance associated with downregulation.
2.3. Correlation Analysis of HAX1 Expression in Cancer Databases Reveals Differences in the Same GO Terms as Transcription Profiling in HL-60 Cells
The correlation of
HAX1
expression with other genes can be analyzed in expression databases created using high-throughput methods applied to patient samples from many different neoplasms. Neoplasms selected for the correlation analysis were chosen to correspond to the HL-60 cell line (leukemia) and another hematologic neoplasm (lymphoma) or common types of epithelial origin cancer (breast, cervical cancer).
Coexpression analysis was performed using cBioPortal for Cancer Genomics with TCGA data (The Cancer Genome Atlas, PanCancer Atlas) for the four neoplasms (Cervical Cancer—297 patients, Breast Cancer—1084 patients, Acute Myeloid Leukemia—200 patients, and Diffuse Large B-cell Lymphoma—48 patients). Gene lists with Spearman rank correlation coefficients were used in the String 11 gene ontology analysis (with Spearman coefficients as values/ranks) and the obtained Biological Process terms were plotted in
Figure 6
A–D, showing that the terms with the highest enrichment and the lowest false discovery rate are similar to the expression profiling obtained in HL-60 cells (RNA-seq). The most enriched and probable terms revealed by the weighted analysis of the genes whose expression significantly correlates with
HAX1
expression included those involved in translation (cotranslational protein targeting to membrane, mitochondrial translation, translational elongation, translational initiation, cytoplasmic translation), ribosome assembly, and rRNA processing, but also energy generation in mitochondria (respiratory electron transport chain, oxidative phosphorylation, cellular respiration), and RNA processing in general. These enrichments were observed in all neoplasms analyzed. For details, see the
Supplementary Data File S5
.
Figure 6. The subset of genes whose expression correlates with HAX1 in the four different neoplasms exhibits enrichment in the same biological processes as shown for HAX1 KO. Correlation analysis was performed using cBioPortal Cancer Genomics. Clinical data obtained from the TCGA database. Enrichment analysis was performed using String 11 with correlation coefficients as values. ( A ) Acute myeloid leukemia (AML, 200 patients); ( B ) Diffuse large B-cell lymphoma (DLBCL, 48 patients); ( C ) Cervical cancer (297 patients); ( D ) Invasive breast cancer (1084 patients) C. Detailed description of genes, Spearman coefficients and GO terms in the Supplementary Data File S5 .
Similar enrichments were also observed in other types of cancer (renal cell carcinoma, glioblastoma; data not shown).
2.4. Comparison of RIP-Seq and RNA-Seq Suggests That HAX1 Binding May Stabilize a Subset of Transcripts Involved in Ribosome Biogenesis
RIP-seq analysis and RNA-seq for
HAX1
KO/WT were performed in the same HL-60 cell line; thus, the comparison should reveal whether RNA binding has an effect on RNA stability.
The RNA-seq fold change (RNA-seq_
HAX1
_KO/RNA-seq_WT) distributions of the transcripts representing the HAX1 targets (RIP target subset) and the rest of the transcripts (non-RIP target subset) were compared (
Figure 7
A), showing that the changes in the distribution towards the downregulation of the RIP-associated transcripts in
HAX1
KO increase with the increasing probability of the HAX1-specific RNA interaction (lower FDR), suggesting that the RIP targets are less stable. The effect, although statistically significant, is not ubiquitous and does not affect all RIP targets equally, suggesting some other layers of regulation. Distribution analysis performed only for transcripts involved in ribosome biogenesis (red line) shows a much more substantial shift toward lower FC values (log2[RNA-seq_
HAX1
_KO/RNA-seq_WT]). Furthermore, the fraction of transcripts involved in ribosome biogenesis increases when the RIP results are analyzed with the same FDR cut-offs in the weighted analysis (String 11, Biological Process) with FC from RNA-seq as values (
Figure 7
B).
Figure 7.
HAX1 binding to RNA targets may be responsible for changes in the expression profile (
A
). Comparison of the distribution of FC changes caused by HAX1 knockout (data obtained in RNA-seq) in the subset of transcripts present between targets identified by RIP (RIP target) and not identified by RIP (non-RIP target). Three different RIP target subsets were compared with cut-offs determined according to the decreasing FDR, showing a shift towards lower FC values (RIP_HAX1/RIP_IgG) in the subsets with lower FDR. Red line: a subset of transcripts involved in ribosome biogenesis, identified by String 11 weighted analysis for RIP-target transcripts (RIP_HAX1/RIP_IgG FC as values). Significance calculated by the Kolmogorov–Smirnov test (
B
). The fraction of transcripts involved in ribosome biogenesis increases with decreasing FDR for the subset of RIP targets. Pathway enrichment calculated in String 11 weighted analysis with FC values from RNA-seq (RNA-seq_
HAX1
_KO/RNA-seq_WT). (
C
) Enrichment in GO terms assessed by String 11 weighted analysis with FC values from RNA-seq for a subset of downregulated transcripts. Analogous analysis for the upregulated subset produced no results. (
D
) The degradation of DHX37 and RRP7 mRNAs is more dynamic in
HAX1
KO cells. Cells were treated with Actinomycin D (10 μg/mL). Relative expression was quantified by qPCR at designated time points. The experiment was carried out in several biological repeats and evaluated by the t-test (DHX37, n = 4,
p
-value: 0.026, 6 h, RRP7A n = 3,
p
-value: 0.035, 3 h). Error bars: SEM.
Interestingly, HAX1 binding seems to be limited to transcripts linked to translation/ribosome biogenesis and includes far fewer transcripts linked to the oxidative phosphorylation/respiratory electron chain, which were also significantly downregulated in
HAX1
KO, indicating a different mode of regulation for this other group of transcripts. Furthermore, mRNA RIP targets (RIP target subset) along with their respective FCs in RNA-seq were analyzed in weighted analysis (String 11, values, Biological Process), separately for the downregulated and upregulated transcripts, revealing an enrichment in ribosome biogenesis and rRNA processing (GO:0042254 and GO:0006364) for the group of downregulated transcripts, while the same analysis of the upregulated group did not reveal any enrichment (
Figure 7
C).
The possibility of the direct stabilization of transcripts by HAX1 binding was tested for two mRNAs: DHX37(encoding DEAH-box helicase 37, involved in ribosome biogenesis and translation initiation) and RRP7A (encoding ribosomal RNA processing 7 homolog A, predicted to be involved in rRNA processing and small ribosomal subunit assembly). The mRNA targets were selected from transcripts downregulated in
HAX1
KO and simultaneously from the results of the RIP/CRAC analysis as potential HAX1 targets with a binding region within the coding sequence of the transcript. Transcription was inhibited by Actinomycin D treatment and subsequent mRNA degradation was analyzed by qPCR in
HAX1
WT and
HAX1
KO cell lines, indicating faster degradation in the HAX1-deficient cell line (
Figure 7
D).
To test the possibility that the effect of HAX1 on the transcriptome may not be direct but may instead consist of influencing the transcription factors (TFs) and propagating the effect to the group of genes regulated by these factors, TFs potentially regulating the subset of genes for which the expression has changed in the
HAX1
KO were identified using the Enrichr package (Transcription, ENCODE and ChEA) and juxtaposed with the ranked list of RIP targets. TFs of the highest rank (FC, FDR) and the highest combined score provided by Enrichr are listed in
Figure S6A
. YY1 and USF1 are the only TFs with FC > 2, but MYC, which has the highest combined score, although not highly ranked itself, should be considered because MYC-binding proteins are also among the RIP targets, with MYCBP of FC>3. Genes regulated by all these TFs are mostly downregulated in
HAX1
KO (
Figure S6B
). However, the expression of all of these TFs is not changed at the mRNA level, as determined by RNA-seq, undermining the possibility of the indirect regulation via TFs.
2.5. HAX1 KO Affects the 40S:80S Ratio
To assess the physiological effect of HAX1 deficiency in the context of ribosome biogenesis, ribosome sedimentation in the sucrose density gradient was performed for HAX1 WT and HAX1 KO HL-60 cells. The ribosomal P/M (polysome-to-monosome) stoichiometry ratio did not reveal significant changes between the WT and KO cell lines, but the 40S to 80S ratio revealed that the peak corresponding to the small subunit increases in HAX1 KO compared to WT ( Figure 8 A,B). The overall subunits:monosome ratio (40S + 60S:80S) is also significantly increased in HAX1 KO compared to WT ( Figure 8 B).
Figure 8.
HAX1
KO affects the subunit:monosome ratio. (
A
) Representative absorbance profiles at 254 nm of sucrose gradient (10–50%) sedimentation of HL-60 cell extracts. The three leftmost peaks include ribosomal subunits (40S and 60S) and nontranslating monosomes (80S). The remaining peaks represent polysomes. Western blots for HAX1 and RPL26 ribosomal protein (large subunit) performed for the corresponding fractions are presented under the profiles. (
B
) Quantitative analysis of sedimentation profiles indicates that free subunits are more abundant in
HAX1
KO in relation to the monosome (upper graph: 40S:80S ratio, lower graph: subunits/monosome ratio). The area under each peak was quantified using ImageJ (n = 6 in each sample), statistical significance determined with an unpaired
t
-test. Analysis by one-way ANOVA and Tukey multiple comparison test also show statistically significant difference for the 40S:80S ratio (
p
-value: 0.003 and 0.0486 for
HAX1
KO #1 and #2, respectively) and for the subunits:monosome ratio (
p
-value: 0.0296 for
HAX1
KO #1, for
HAX1
KO #2,
p
-value: 0.15).
3. Discussion
In this manuscript we report a comprehensive analysis of the HAX1–RNA interactome by two independent, high-throughput methods, which both suggest HAX1 involvement in the regulation of transcripts controlling translation, rRNA processing, and ribosome biogenesis. The two methods differ in complexity and specificity (
Figure 1
A), and the experiments were carried out in two different cell lines (HL-60 promyelocytic cell line, selected due to the strong effect of HAX1 inactivation in these cells, and HEK293 embryonic kidney cells with adrenal endocrine characteristics, selected for technical reasons). Nevertheless, both approaches yielded enrichment in similar GO terms in the Biological Process category (translation, rRNA processing, and ribosome biogenesis). The pool of overlapping targets obtained simultaneously by both methods also shows involvement in translation, rRNA processing, and ribosome biogenesis.
The distribution of RNA biotypes detected in both methods was different, with RIP targets predominantly consisting of mRNA and CRAC targets with a high proportion of rRNA and tRNA. These differences may stem from the fact that in CRAC: (1) the protein of interest was overexpressed, which should increase the abundance of nonmitochondrial protein able to interact with rRNA compared to endogenous RIP; (2) RNA targets were UV-crosslinked to it, which may shift the distribution towards less stable, transient interactions eliminated in RIP; (3) the background (negative control sample) is cleaner than in RIP-seq, and thus it may be easier to detect significant fold changes for very abundant transcripts (rRNAs, tRNAs, and snRNAs).
The next important question was if the expression of HAX1 RNA targets has changed after
HAX1
knockout. This comparison was made for HL-60 cells, since this cell line was used in both RIP and RNA-seq expression profiling for
HAX1
KO vs. WT. The results indicate a partial overlap between HAX1 RNA targets and mRNAs downregulated in
HAX1
KO and the overlap is related to transcripts involved in ribosome biogenesis and translation, and, only to a very small extent, to the transcripts involved in energy generation in mitochondria, which are also significantly downregulated in
HAX1
KO. This result suggests that only the subset involved in ribosome biogenesis and translation is regulated through direct HAX1 binding and the subsequent stabilization of the mRNA. Therefore, the other detected changes (especially the downregulation of a very important subset of transcripts involved in energy generation) must be therefore regulated by a different mechanism.
Further support for the hypothesis of the HAX1 transcript-stabilizing role is provided by the quantitative assessment of DHX37 and RRP7A mRNA degradation. The DHX37 RNA helicase is involved in ribosome biogenesis, including the formation of the central pseudoknot structure of the small ribosomal subunit [
20
]. RRP7A is also predicted to be involved in rRNA processing and assembly of the small ribosomal subunit. Both transcripts represent top RIP/CRAC targets, which are downregulated in
HAX1
KO cells. Quantification of the degradation of the DHX37 and RRP7A transcripts revealed more dynamic degradation in
HAX1
KO cells, suggesting stabilization by HAX1.
Analysis of the genomic position of the RNA targets obtained using the CRAC method revealed the prevalence of coding sequence (CDS) regions, which is not typical for the regulatory RNA sequence and is not consistent with the genomic position of previously characterized HAX1 binding regions (3′UTR). However, new high-throughput analyses demonstrated that binding to CDS is not as uncommon as previously thought and may play a role in the regulation of mRNA stability [
21
]. Interestingly, this stabilization should refer to the situation when mRNA is not actively translated, and thus it is not covered and protected by ribosomes and susceptible to endonuclease attack, as in the case of protein CRD-BP, which binds to c-myc mRNA, thus protecting it [
22
]. Furthermore, CDS binding was also observed for the FMRP protein and was related to the recruitment of the APP mRNA to processing bodies (P-bodies), which was proposed to restrict translation [
23
]. In line with this observation, we previously reported that HAX1 was observed to colocalize with the P-body marker, Dcp1 [
12
], pointing to its possible role in transcript stabilization during storage.
Interaction with one of the targets within CDS reported by both methods (RPL19) was confirmed by microscale thermophoresis, with the dissociation constants indicating relatively weak binding (K
d
in a range of 0.1–0.2 μM, comparing, for example, to the strong FMRP interaction with N19 RNA with a K
d
of 1 nM [
24
]). These values suggest a transient, regulatory interaction. Interestingly, the K
d
values previously reported for HAX1 binding to 3′UTR are lower [
8
], indicating a different strength of interaction and, possibly, a different mode of binding for the CDS and 3′UTR regions. A similar phenomenon was also observed for the GLD-1 and FMRP proteins, involved in translation regulation [
21
].
Analysis of the possibility of indirect regulation mediated by transcription factors indicated that such regulation is improbable, since the expression of TFs itself is not changed in
HAX1
KO. However, this hypothesis cannot be totally dismissed, since TF-encoding transcripts may be differentially translated, or their protein product may be degraded in
HAX1
KO cells, resulting in differences in TFs at the protein level and subsequent changes in specific groups of transcripts regulated by those TFs.
Interestingly, the analysis of the correlation of expression with HAX1, performed for the TCGA database in four neoplasms (AML, DLBCL, breast cancer, cervical cancer), identified enrichment in the same biological processes as detected for
HAX1
KO vs. WT in the HL-60 cell line, indicating that these results are not cell line or neoplasm-specific, and thus further corroborating these findings.
The observed changes in expression related to ribosome assembly and translation are not huge, but reproducible, and refer to a relatively large group of transcripts and do not appear to be cell-type or neoplasm-specific. Relatively weak binding and small but reliable changes in expression suggest regulation via small, additive effects. It is an open question whether these effects can manifest more robustly in nonquiescent cells subjected to some kind of stress. This conjecture is supported by the reported changes in the location of HAX1 after stress, including nucleocytoplasmic shuttling [
11
], which could be linked to ribosome biogenesis and RNA binding in the nucleus/nucleolus. Furthermore, the abundance of rRNA observed as a potential target in the CRAC analysis suggests the possibility of a more direct involvement in ribosome biogenesis. The suggested binding site (
Figure S3
) maps within rRNA expansion segments, for which the function in ribosome biogenesis was proposed [
25
]. Thus, the involvement of HAX1 in ribosome assembly could encompass not only the regulation of the stability of mRNAs that encode ribosomal proteins and assembly factors, but also a direct interaction with ribosomal RNA. Interestingly, the possibility of the simultaneous regulation of translation by direct ribosome binding and controlling mRNA stability was described for the FMRP protein [
26
], already mentioned here for similar mode of binding and possible recruitment of transcripts to P-bodies.
To test the physiological consequences of
HAX1
KO on ribosome status, we performed ribosome sedimentation profiling, demonstrating a difference in the 40S:monosome ratio for HAX1-deficient cells. The shift towards free subunits in
HAX1
KO may indicate less efficient monosome assembly, resulting from lower expression of ribosomal assembly factors and ribosomal components.
In conclusion, we provide evidence for the involvement of HAX1 in ribosome assembly and translation, which represents a new finding. Previously, it was reported that HAX1 has an interaction with PELO, a protein involved in ribosomal rescue during ribosome stalling, but no mechanism for HAX1 involvement was proposed and no physiological effect was observed [
27
]. Recently, You et al. [
28
] demonstrated, among other things, that HAX1 levels correlate with ribosome formation and that HAX1 promotes the translation of the transcript encoding integrin subunit beta 6 in endothelial cells, partially matching the findings presented here.
Thus, the results presented suggest the possibility that HAX1 binds to the CDS of the nontranslated transcripts, protecting them from degradation, and that the main mRNA targets subjected to this regulation include transcripts involved in ribosome biogenesis.
Changes in ribosomal status and translation efficiency affect proliferation, which in turn can contribute (in opposite directions) to neutropenia and/or cancer. Indeed, the status of HAX1 has already been shown to affect proliferation [ 29 ], and we also observed this effect in our cell lines (data not shown). Further research should elucidate the exact role of HAX1 in maintaining translation efficiency, but the results presented here provide a starting point to explore these new and unanticipated possibilities.
4. Materials and Methods
4.1. Generation of Cell Lines
4.1.1. HEK293FlpInTRex with Induced Overexpression of HAX1
Plasmid design and molecular subcloning:
HAX1
CDS was obtained by PCR and cloned into prepared vector (pcDNA5FRT TO) with a special gene coding tag (Protein A fragment, TEV protease cleavage site, and His-tag) in two orientations (tag at the 3′ or 5′ end of the
HAX1
coding sequence).
Cell line generation: HEK293-FlpIn cells (ThermoFisher Scientific) were transfected with an empty vector (negative control, NC) or plasmid with the
HAX1
cDNA with a tag at the 3′ end or 5′ end of the gene, and cotransfected with pOG44 vector, containing Flp recombinase, for Flp–FRT recombination. Transfection was carried out according to the manufacturers’ instructions (LipofectamineTM2000, ThermoFisher Scientific, Waltham, MA, USA). Cells were detached and seeded on 100 mm plates in a concentration enabling obtaining single colonies (selection: Blasticidin 15 μg/mL and Higromycin B 100 μg/mL) for 2 weeks. Single colonies were passaged to 24-well plates and tested by Western blot and qPCR with and without doxycycline induction (18–48 h).
4.1.2. HL-60 HAX1 CRISPR Knockout
Plasmid design and molecular subcloning: two pairs (4 oligonucleotides) of small guide RNA (sgRNA) complementary to the
HAX1
gene were designed using the online bioinformatic tool (
https://CRISPR.mit.edu
, accessed on 15 August 2022). Each pair of sgRNA was introduced to the AIO-GFP plasmid that encodes the Cas9 nickase tagged with EGFP (D10A), as described in [
30
]. Briefly, each of the four oligonucleotides contained 5’ overhangs (forward: ACCG, reverse: AAAC) compatible with BbsI and BsaI restriction enzymes. The BbsI site present in AIO-GFP was utilized to introduce antisense (LC—left CRISPER) oligonucleotides and therefore generate AIO-GFP HAX1 LC1 and AIO-GFP HAX1 LC2 plasmids. To each respective plasmid, the second (sense, RC—right CRISPER) sgRNA of a given pair was introduced utilizing the BsaI site. As a result, two different constructs were generated, AIO-GFP HAX1 LCRC1 and AIO-GFP HAX1 LCRC2.
Cell line generation: HL-60 cell line was grown in RPMI1640 medium with L-glutamine (Biowest) and 10% Fetal Bovine Serum (Gibco) at 37 °C in a 5% CO
2
. Electroporation of 5 × 106 HL-60 cells was carried out with AIO-GFP HAX1 LCRC1 and AIO-GFP HAX1 LCRC2 using the CLB-Transfection™ Kit (Lonza, Austria) and the CLB-Transfection™ System (Lonza, Austria) with the default program 9 setting. Single transfected cells were sorted into separate wells of 96-well culture plate using BD FACSAria™ III (Becton Dickinson, Franklin Lakes, NJ, USA). Cells were cultured in RPMI for 14–21 days, colonies were propagated, and successful KO was validated by Western blot in four cell lines, two of which were used in experiments (
Figure S1
).
4.2. RIP-Seq
The HL-60 promyelocytic cell line (DSMZ, Braunschweig, Germany) was grown in RPMI1640 medium with L-glutamine (Biowest) and 10% Fetal Bovine Serum (Gibco) at 37 °C in a 5% CO
2
. Sample preparation: The experiment was carried out in five replicates. The EZ-Magna RIP RNA-Binding Protein Immunoprecipitation Kit (Millipore, 17–700 Sigma-Aldrich) was used according to the manufacturer’s protocol. A single freeze–thaw was employed to gently lyse the cells, as described by Keene et al. [
31
]. An amount of 30 × 106 cells per sample were collected by centrifugation at 966×
g
, 5 min at 4 °C, and washed two times with PBS containing protease inhibitors, resuspended in 200 μL of RIP lysis buffer (Millipore) containing protease and RNase inhibitors, incubated for 5 min on ice, snap-frozen in liquid nitrogen, and stored at −80 °C. Magnetic Beads Protein A/G (from Magna RIP Kit) were incubated overnight (4 °C) with 10 µg of anti-HAX1 rabbit polyclonal antibody (Thermo Fisher Scientific, Waltham, MA, USA; cat. PA5-27592) and Rabbit IgG (Millipore) as a negative control. The lysates from the previous step were quickly thawed, centrifuged at 14,000 rpm for 10 min at 4 °C, and 150 μL of supernatants were added to each antibody complex in the RIP Immunoprecipitation Buffer. The final volume of the immunoprecipitation reaction was 1.5 mL. A total of 10% of the sample was taken and stored as a total input. The lysate was incubated with antibody-coated beads for 4 h at 4 °C. After immunoprecipitation, the beads were washed 5 times with 1 mL of cold RIP Wash Buffer. The last, sixth wash was performed with 0.5 mL of wash buffer and 50 μL out of 500 μL of each beads’ suspension was taken to test the efficiency of immunoprecipitation by Western blotting. The remaining 450 μL of each suspension was collected with magnetic separator, immune complexes and input were eluted and treated with proteinase K (55 °C for 30 min). RNA was purified by extraction of phenol/chloroform followed by ethanol precipitation. The concentration of the precipitated RNA samples was checked using QuantiFluor RNA System (Promega), and the samples were used for library preparation and RIP-seq.
4.3. RNA-Seq
Sample preparation: HL-60 cell lines (WT and HAX1 KO#1 and #2) were grown to 3.5 × 106 cells in each culture (each cell line in four replicates). RNA was isolated using RNA PureLink Mini (Thermofisher, Waltham, MA, USA). Genomic DNA was removed from the samples using the TURBO DNA-free kit (Thermofisher, Waltham, MA, USA). RNA integrity was evaluated using Agilent RNA 6000 Nano Kit (Agilent Technologies, Waltham, MA, USA). RNA samples with a RIN score ≥ 9 were used for the preparation of cDNA libraries.
4.4. NGS Library Preparation and Sequencing (RIP-Seq, RNA-Seq)
The cDNA libraries were prepared using TruSeq™ Stranded Total RNA Library Prep Gold (Illumina, San Diego, CA, USA) according to the manufacturer’s procedure. The average size of the libraries was determined using the Agilent 2100 Bioanalyzer and High Sensitivity DNA Kit (Agilent Technologies, USA), while the concentration was assessed using the Qubit Fluorometer and dsDNA HS Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA). Uniquely indexed libraries were pooled, mixed with Illumina PhiX Control v3 Library (1% of the total amount), and sequenced on HiSeq 1500 (Illumina) in Rapid Run Mode. Single-read sequencing (1 × 50 bp) and paired-end sequencing (2 × 100 bp) were performed for RIP-seq and RNA-seq, respectively.
4.5. RIP-Seq and RNA-Seq Data Analysis
4.5.1. RIP-Seq
All experiments were performed in five replicates. Raw sequences were trimmed according to quality using Trimmomatic [ 32 ] (version 0.39) using default parameters, except MINLEN, which was set to 50. Trimmed sequences were mapped to the human reference genome provided by ENSEMBL (version grch38_snp_tran) using Hisat2 [ 33 ] with default parameters. Optical duplicates were removed using the MarkDuplicates tool from GATK [ 34 ] package (version 4.1.2.0) with default parameters, except OPTICAL_DUPLICATE_PIXEL_DISTANCE, which was set to 12000. The mapped reads were associated with transcripts from the grch38 database [ 35 ] (Ensembl, version 96) using HTSeq-count [ 36 ] (version 0.9.1) with default parameters, except for the stranded, which set to “reverse”. The variation was assessed by visual inspection of the first two components from the principal component analysis (PCA), which revealed correct clustering. FPKM was calculated with the fpkm function of the deseq2 package. Differentially expressed genes were selected using the DESeq2 package [ 37 ] (version 1.16.1). The fold change was corrected using apeglm. PCA, FPKM, and Deseq2 calculations were performed in the R environment (version 3.6).
4.5.2. RNA-Seq
All experiments were carried out in four replicates. The DEGs selection was performed as described above.
4.6. CRAC (Crosslinking and Analyses of cDNAs)
4.6.1. Sample Preparation
Stable established cell lines with HAX1 overexpression (coding protein tagged at the C or N terminal end, two replicates for each construct) were induced with 1 μg/mL doxycycline and incubated 18–48 h. After, the incubation cells were UV-crosslinked in Stratalinker 1800 (E = 400 mJ/cm
2
) at a wavelength 254 nm. Cells were lysed for 10 min on ice in lysis buffer (50 mM Tris-HCl pH 7.5, 300 mM NaCl, 1% NP-40, 5 mM EDTA, 10% glycerol, 5 mM β-mercaptoethanol). Lysates were spun at 4600 RPM, 4 °C for 5 min, and then filtered using syringe filter of 0.45 µm with PES membrane. IgG Sepharose was added to the lysates and incubated overnight at 4 °C with rotation. The beads were washed with IgG wash buffer (50 mM Tris-HCl pH 7.5, 800 mM NaCl, 0.5% NP-40, 5 mM MgCl
2
) and PNK wash buffer (25 mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1% NP-40, 1 mM MgCl
2
). RNAs were trimmed on beads using 1 unit of RNAce-IT in 0.4 of PNK buffer for 7 min at 37 °C. To stop the reaction, the supernatant with RNaceIT was removed and the beads were resuspended in the room temperature denaturing elution buffer Ni-WBI (50 mM Tris-HCl pH 7.5, 300 mM NaCl, 1.5 mM MgCl
2
, 10 mM Imidazole pH 8.0, 0.1% NP-40, and 6 M guanidine hydrochloride). The elution was repeated one more time, both fractions were combined, and the Ni-NTA beads were added for overnight incubation at 4 °C. The NI-NTA beads were washed and transferred to Pierce columns. RNA was dephosphorylated with 8 U of Thermosensitive Alkaline Phosphatase (Promega) in supplied MultiCore buffer with 80 U RNAsin for 30 min at 37 °C. Beads were washed with Ni-WBI and PNK wash buffer. The 3′ linker ligation was performed overnight at 16 °C with 1 μM 3′ linker, 800 U of truncated T4 RNA ligase 2 K227Q (New England Biolabs) in supplied PNK buffer with RNAsin (Promega), and 10% (PEG8000). The beads were washed with WBI and PNK wash buffer. The RNA–protein complexes were radioactively labeled with 32P-γ-ATP (20 μCi) using 40 U T4 Polynucleotide Kinase (New England Biolabs) in the supplied PNK buffer for 30 min at 37 °C. The 5′ linker ligation was performed in the same reaction mixture by addition of the 5′ linker to the final 2.5 mM, nonradioactive ATP to final 1.25 mM, and 40 U T4 RNA ligase 1 for 8 h at 16 °C. After washing the beads with the Ni-WBI and PNK wash buffer, the RNA–protein complexes were eluted with elution buffer (50 mM Tris-Hcl pH 7.8, 300 mM NaCl, 150 mM Imidazole pH 8.0, 0.1% NP-40, 5 mM 2-mercaptoethanol) at room temperature for 5 min. Protein–RNA complexes were precipitated with 80% acetone in the presence of GlycoBlue at −20 °C overnight and spun for 20 min with max speed at 4 °C. Pellets were resuspended in LDS sample buffer (ThermoFisher, Waltham, MA, USA), DTT, and EDTA and denatured for 3 min at 90 °C.
4.6.2. Autoradiography
Samples were resolved on 4–12% Bis-Tris NuPAGE gel at constant voltage (120 V) using NuPAGE MOPS SDS running buffer (Thermo Fisher Scientific, Waltham, MA, USA) and transferred to nitrocellulose membrane in NuPAGE transfer buffer using BioRad Protean wet transfer system at constant voltage (100 V) for 1 h. Exposition was performed at −80 °C overnight.
4.6.3. RNA Isolation from Membrane
Bands corresponding to RNA crosslinked to the HAX1 protein ( Figure 1 D) were cut out and incubated with 450 μL Proteinase K buffer (50 mM Tris-HCl pH 7.8, 50 mM NaCl, 10 mM imidazole pH 8.0, 0.1% NP-40, 1% SDS, 5 mM EDTA, 5 mM 2-mercaptoethanol) and 200 μg Proteinase K for 2 h at 55 °C. The 3M sodium acetate pH 5.2 was added to final 10% and the RNA was extracted with 500 µL phenol:chloroform:isoamyl alcohol. After 5 min spin with a maximum speed at 4 °C, the aqueous phase was collected to a new tube and the RNA was precipitated with 3 volumes of ethanol in the presence of GlucoBlue.
4.6.4. cDNA Library
Isolated RNA was incubated with SSIV reverse transcriptase (ThermoFisher) and a primer binding to 3′ linker. The cDNA was amplified using LA Takara Taq polymerase. PCR products were resolved on 3% Metaphor agarose gel (Lonza), and DNA fragments of sizes approximately 150–200 nt were isolated from the gel using Qiagen’s Gel Extraction Kit ( Figure 1 D). The cDNA library was sequenced on the Illumina MiSeq platform in Edinburgh Genomics (the University of Edinburgh).
4.7. CRAC Data Analysis
For CRAC experiments, all experiments (for N- and C-tagged protein) were performed in two replicates each. Fold change for each gene was calculated as a Log2 from the experiment/negative control ratio, normalized for total number of hits, and means from two replicates. NGS results were analyzed using algorithms: flexbar (preprocessing), tophat (genome mapping), and bedtools (analysis of genomic annotations). To identify HAX1 binding motifs, we extracted the coordinates of all HAX1 binding sites in mRNAs and created a control dataset by randomly placing the coordinates of these binding sites on the same mRNAs using shuffleBed. We then used the STREME sequence motif discovery algorithm (minimum motif length 4 nt, maximum length 8 nt) to identify enriched motifs [
38
] (
https://meme-suite.org/meme/doc/streme.html
, accessed on 15 August 2022).
Genomic position of HAX1 binding identification was done using UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19) Assembly.
4.8. Gene Ontology and Correlation Analysis
Enrichment plots for RNA-seq data were generated by GSEA (gene set enrichment analysis, [ 39 , 40 ]) software. Table of transcripts, identified during the RNA-seq experiment, with an associated number of counts per transcript (data obtained with HTSeq-count), was used as input data. Number of permutations was set to 1000 and permutation type was set to “gene_set”. Gene set database (version 7.2) used for analysis is included in the respective enrichment plots titles. The other gene ontology enrichment analyses were performed using packages: Gene Ontology resource ( http://geneontology.org , accessed on 15 August 2022); ([ 41 ] Gene Ontology 2021), DAVID Functional Annotation Tool, DAVID Bioinformatics Resources, NIAID/NIH ( https://david.ncifcrf.gov/home.jsp , accessed on 15 August 2022) [ 42 , 43 ], and String 11 Functional Enrichment Analysis for proteins with values/ranks ( https://string-db.org , accessed on 15 August 2022) [ 44 ]. Transcription factors were analyzed using Enrichr ENCODE and ChEA Consensus TFs from ChIP-X ( https://maayanlab.cloud/Enrichr/ , accessed on 15 August 2022) [ 45 , 46 ].
Correlation analysis with high-throughput data accumulated in TCGA (The Cancer Genome Atlas) database was performed using cBioPortal for Cancer Genomics, a platform for exploring multidimensional cancer genomic data [ 47 , 48 ] ( https://www.cbioportal.org/ , accessed on 15 August 2022 ).
4.9. Transcription In Vitro
Transcription in vitro was performed for 140 nt RPL19 fragment of CDS from exon 3 (primers: FW 5′-GGTGCATTATGCTTTCCCAGGTCAG-3′, REV 5′-CTATGCCCATGTGCCTGCCCTTC-3′) cloned into pGEM-T Easy vector in sense and antisense orientation. M13 fwd and rev primers were used in the PCR reaction for template generation. MEGAscript T7 transcription Kit (ThermoFisher Scientific) was used for in vitro transcription with T7 RNA polymerase, according to the manufacturers’ protocol. Transcripts were purified using MEGAclear Kit (ThermoFisher Scientific, Waltham, MA, USA).
4.10. Microscale Thermophoresis (MST)
MST experiments were performed using Monolith NT.115 (NanoTemper Technologies GmbH, Munich, Germany). Purified HAX1 protein (Proteintech, Ag27244, fused with His-tag) was labeled with RED-NHS 2nd Generation dye according to the supplied labeling protocol Monolith NT™ Protein Labeling Kit. A series of dilutions of ligand RNA (sense and antisense transcript) were prepared using buffer solution containing PBS with 0.2% Tween-20. The solution of labeled protein was mixed 1:1 with different concentrations of RNA strand, yielding a final concentration of 50 nM of the protein and the ligand in a range of final concentrations between 10.8 µM and 0.000328 µM. After 5 min of incubation, the NT.115 premium capillaries (NanoTemper Technologies, Munich, Germany) were filled with the RNA/protein solution and thermophoresis was measured at an LED power of 100% and an MST power of 60% at RT. Each operation was controlled using the MO control software. The Kd was determined by nonlinear fitting of the thermophoresis responses and EC50 was determined by Hill fitting model using the MO Affinity Analysis v2.3 for both types of the calculations.
4.11. Western Blot
Protein extracts were heat-denaturated (95 °C) in Laemmli buffer (50 mM Tris/HCl, 0.01% Bromophenol Blue, 1.75% 2-mercaptoethanol, 11% glycerol, 2% SDS) and separated by 10–12% SDS/PAGE electrophoresis. Proteins were transferred to Immobilon-P PVDF membrane (Merck Millipore, Burlington, MA, USA). The membranes were incubated for 1h using 5% low-fat milk solution in 1X TBS (50 mM Tris-Cl, pH 7.5, 150 mM NaCl) as a blocking buffer, and then overnight at 4 °C in the same blocking solution containing one of the following antibodies: anti-HAX1 (rabbit, Proteintech 11266-1-AP) or anti-RPL26 (rabbit, 1:5000, Abcam, ab59567). After washing (3 × 10 min in TBS), membranes were incubated for 2 h at room temperature with the adequate HRP-conjugated secondary antibody: goat anti-rabbit IgG (1:5000, Abcam, GB; cat. 97051) or goat anti-mouse IgG (1:10,000, Abcam, GB; cat. ab97023). Membranes were developed using HRP detection kit WesternBright Quantum (Advansta, San Jose, CA, USA; cat. K-12042).
4.12. qPCR
Quantitative PCR was performed as described [
11
]. Briefly, stable cell lines with HAX1 WT and HAX1 KO were subjected to Actinomycin D treatment (10 μg/mL). Cells were harvested in a designated time points and used for total RNA preparation (PureLink RNA mini kit; Invitrogen), followed by the treatment with recombinant DNase I (Roche). An amount of 1 μg of the obtained RNA was used for cDNA synthesis using Superscript III (Invitrogen). The cDNA was quantified by quantitative PCR on an ABI Prism 7500 real-time PCR system using Power SYBR Green PCR Master Mix (Applied Biosystems, Life Technologies, Carlsbad, CA, USA) and primers amplifying a fragment of DHX37 transcript (forward 5′- CCCGATATCGAGAAAGCCTGG-3′; reverse 5′-CGTCCAGCACGTGAGATGAA-3′), RRP7 transcript: (forward 5′- TTCTCGTCACAAGGCACAGG-3′; reverse 5′-GAAGGGCCACACCTAAGTCC-3′) and, as a reference, ACTB transcript (forward 5′-AGCCTCGCCTTTGCCGA-3′; reverse 5′-GCGCGGCGATATCATCATC-3′). The ΔΔ CT method was used for calculating mRNA expression levels.
4.13. Sucrose Gradient Centrifugation
HL-60 cell lines (WT and HAX1 KO#1 and #2) were grown and subcultured until achieving 6 T-75 or 3 T-175 flasks with cells at a density of 1 × 106/mL. Cells were treated with cycloheximide (100 μg/mL) at 37 °C for 10 min, harvested by centrifugation for 5 min at 500×
g
, 4 °C, and washed 3 times with ice-cold PBS supplemented with 100 μg/mL cycloheximide. After final wash and complete removal of PBS, the cell pellet was resuspended in 0.75 mL of lysis buffer A (10 mM Tris-HCl pH 7.4, 12.5 mM MgCl2, 100 mM KCl, 0.5% Triton X-100 reduced, 2 mM DTT, 100 µg/mL CHX, 200 units SUPERaseIn™ RNase Inhibitor (20 U/μL; ThermoScientific), and cOmplete EDTA-free protease inhibitor (Roche)). Cells were lysed by thorough pipetting and incubation for 15 min at 4 °C on a rotating wheel. Lysates were aspirated into 1 mL syringe, passed through a 26G needle seven times, and then centrifuged for 10 min at 16,000×
g
, 4 °C. RNA concentration in clarified cytoplasmic extracts thus obtained was measured using Nanodrop 2000c (ThermoScientific). A total of 14–20 OD260 units of cytoplasmic extract in 500 μL of lysis buffer was layered on top of 10–50% linear sucrose gradients, prepared using ÅKTA Purifier FPLC system and 0.22 µm-filtered sucrose solutions in polysome buffer (20 mM Hepes-KOH pH 7.4, 12.5 mM MgCl2, 100 mM KCl; 2 mM DTT, 100 µg/mL CHX, and cOmplete EDTA-free protease inhibitor), and ultracentrifuged for 3 h 15′ at 36,000 rpm, 4 °C in SW-41Ti rotor (Beckman Coulter). Subsequently, 0.5 mL fractions were collected from gradient by pumping 60% sucrose solution in polysome buffer to the bottom of tubes, and OD254 was monitored on an ÅKTA Purifier.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells11192943/s1 , Figure S1: HAX1 protein is not present in HAX1 KO cell lines used in analysis. Figure S2: Principal Component Analysis of five RIP-seq replicates shows correct clustering of data. Figure S3: Large ribosomal subunit rRNA with marked region of potential interaction site with HAX1. Figure S4: STREME analysis of CRAC data. Figure S5: The raw MST data for HAX1-RPL19mRNA interaction. Figure S6: Analysis of transcription factors detected in RIP-seq selected as regulating transcripts differently expressed in HAX1 KO. File S1: RIP-seq results; experimental data and analysis. File S2: CRAC results; experimental data and analysis. File S3: Overlap of RIP and CRAC results File S4: RNA-seq ( HAX1 KO/WT) results. File S5: Correlation of expression of HAX1 with other genes in different neoplasm (cBioPortal analysis)
Author Contributions
Conceptualization, E.A.G. and G.K.; methodology, G.K., R.T., M.W. (Marta Wisniewska) and M.R.; formal analysis, M.W. (Maciej Wakula); investigation, A.B., E.M.-K., M.W. (Maciej Wakula), M.C., F.L., M.S.-R., M.W. (Marta Wisniewska), R.T. and A.H.; data curation, G.K. and K.G.; writing—original draft preparation, E.A.G.; writing—review and editing, E.A.G., R.T., G.K., A.H. and D.T.; supervision, E.A.G.; project administration, E.A.G.; funding acquisition, E.A.G. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by Polish National Science Centre (grant numbers: 2014/14/M/NZ1/00437, 2015/17/N/NZ1/00668).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
HAX1 targets genomic position available at UCSC Genome Browser ( http://genome-euro.ucsc.edu/s/Grzegorz%20Kudla/Ewelina_HAX_MCPIP , accessed on 15 August 2022). Source data for the coverage of CRAC reads: gkudla@bifx-rta :/homes2/gkudla/Solexa/GK/Ewelina_Macech/20181219_Ola_sequencing/mapping/motifs_EMC1_EMC2_combined. NGS data have been deposited with the Gene Expression Omnibus (GEO) functional genomics data repository, accession numbers: GSE189611, GSE189609.
Acknowledgments
The authors are grateful to Alicja Trebinska-Stryjewska and Antek Laczkowski for helpful comments.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Experimental design of HAX1–RNA interactome studies. ( A ) HAX1 amino acid sequence with characteristic features and regions (acid box, PEST domain, structural elements predicted using PSIPRED (PSI-blast-based secondary structure PREDiction)). ( B ) CatRapid prediction of HAX1 RNA binding propensity classifies it as a putative RBP, but binding does not occur via classical elements. ( C ) Schematic of RIP experiments: no crosslink, single purification step with HAX1-specific antibody. ( D ) Schematic of CRAC experiments, sequential steps: UV crosslink of RNA targets, double purification with Sepharose and NiNTA resin, isotope labeling and extraction of the RNA–protein complexes from polyacrylamide gel, RNA extraction, reverse transcription, PCR, and next generation sequencing of the RNA targets.
Figure 2. Identification of HAX1-associated RNA targets by RIP-seq analysis in HL-60 cells. ( A ) Functional annotation enrichment of HAX1 target genes. Enriched gene ontology terms (DAVID: Biological Process) presented in bar plot, the length of each bar corresponds to statistical significance of the enrichment (−log10 p -value). The top twenty terms are presented. ( B ) Enriched Biological Process terms (Panther GO) plotted with fold enrichment (log2) against False Discovery Rate (−log10). The most reliable results are in the upper right corner. Categories associated with ribosome biogenesis, rRNA processing, and translation are marked red. Categories associated with RNA metabolism (other than rRNA) are marked light orange. Detailed description of GO terms in Supplementary File S1 . ( C ) Distribution of RNA classes among HAX1 RIP targets. ( D ) MA plot showing RIP targets counts (X-axis) calculated as fragments per kilobase per million (FPKM); Y-axis: log2FC(RIP_HAX1/RIP_IgG), red—significant, grey—not significant. The internal frame indicates positive log2 FC (physiologically relevant as possible binding targets).
Figure 3. Identification of HAX1-associated RNA targets by CRAC analysis (HEK293 cells). ( A ) Functional annotation enrichment of HAX1 target genes (results from the pooled N- and C-tagged protein approach). Enriched gene ontology terms (DAVID: Biological Process) presented in bar plot, the length of each bar corresponds to statistical significance of the enrichment (−log10 p -value). The top 20 terms are presented for each category. ( B ) Enriched Biological Process terms (Panther GO) plotted with fold enrichment (log2) against false discovery rate (−log10). The most reliable results are in the upper right corner. Terms associated with ribosome biogenesis, rRNA processing, and translation are marked red. Terms associated with RNA metabolism (other than rRNA) are marked in light orange. Detailed description of GO terms in Supplemental Data File S2 . ( C ) Distribution of RNA species in HAX1 targets. ( D ) Coverage of HAX1 CRAC reads along small (18S) and large (28S) ribosomal subunits. Reads for negative control shown below. ( E ) Consensus motif identified by STREME in the HAX1-targets dataset (combined experimental data from C- and N-tagged HAX1). The E-value is the p -value multiplied by the number of motifs reported by STREME. ( F ) Genomic position of HAX1 binding in CRAC-identified targets (269 targets overlapping in C- and N-tagged datasets) established using UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19) Assembly.
Figure 4. Characterization of the overlapping CRAC–RIP subset of HAX1 mRNA targets. ( A ) Overlapping targets in RIP and CRAC_C (629 mRNAs) represent, respectively, 13.7% and 38.5% of the overall results. Hypergeometric test for these overlap gives p -values of 9.8e–42 (total gene set: 15220). ( B ) Functional annotation enrichment of the RIP/CRAC overlap of HAX1 target genes (DAVID, top 20 terms) maintains a high enrichment in terms associated with translation, RNA and rRNA processing, and ribosome biogenesis (Biological Process) ( C ) Enriched Biological Process terms found for the overlap subset (Panther GO) plotted with fold enrichment (log2) against false discovery rate (−log10) reveal that terms associated with translation and ribosome biogenesis are the most probable. ( D ) Target validation by microscale thermophoresis (MST) performed for the RPL19 in vitro transcript (sense). From 33 transcripts encoding ribosomal proteins present in the overlapping RIP/CRAC target list, a fragment of the RPL19 coding sequence was selected for validation. The interaction with purified and the fluorescently labeled HAX1 protein was confirmed in 4 independent measurements by thermophoresis under different conditions (MST power medium to high). For each measurement, the dissociation constant (Kd) and half maximal effective concentration (EC50) were assigned. No interaction was observed with antisense transcript (negative control).
Figure 5. HAX1 KO affects the expression profile in HL-60 cells. ( A ) Enrichment plots generated by GSEA analysis for the chosen categories (translation, rRNA processing, respiratory electron transport) ( B ) Enrichment in GO Biological Process terms for genes differentially expressed in HAX1 KO vs. HAX1 WT (String 11 weighted analysis with log2[RNA-Seq_ HAX1 _KO/RNA-Seq WT] as values) indicates participation in translation (including mitochondrial translation), rRNA processing/ribosome biogenesis, and energy generation in mitochondria. Detailed description of GO terms in Supplementary Data File S4 . ( C ) Scatter plot showing differentially expressed genes in HAX1 KO. Of the total 1186 transcripts significantly downregulated in KO, 172 are associated with translation and 202 with energy generation, while from the 1158 transcripts significantly upregulated in KO, 13 and 58, respectively, are associated with these categories. The p -value cutoff: 0.05. A total of 14 outliers were omitted. The statistical significance of the downregulation of the transcripts involved in ribosome biogenesis and translation and cellular respiration was assessed by the Chi-Square test and was shown to be high ( p -value = 5.5 × 10 −20 and 1.2 × 10 −5 , respectively). For the other two groups (all mapped results and all DEGs), there was no statistical significance associated with downregulation.
Figure 6. The subset of genes whose expression correlates with HAX1 in the four different neoplasms exhibits enrichment in the same biological processes as shown for HAX1 KO. Correlation analysis was performed using cBioPortal Cancer Genomics. Clinical data obtained from the TCGA database. Enrichment analysis was performed using String 11 with correlation coefficients as values. ( A ) Acute myeloid leukemia (AML, 200 patients); ( B ) Diffuse large B-cell lymphoma (DLBCL, 48 patients); ( C ) Cervical cancer (297 patients); ( D ) Invasive breast cancer (1084 patients) C. Detailed description of genes, Spearman coefficients and GO terms in the Supplementary Data File S5 .
Figure 7. HAX1 binding to RNA targets may be responsible for changes in the expression profile ( A ). Comparison of the distribution of FC changes caused by HAX1 knockout (data obtained in RNA-seq) in the subset of transcripts present between targets identified by RIP (RIP target) and not identified by RIP (non-RIP target). Three different RIP target subsets were compared with cut-offs determined according to the decreasing FDR, showing a shift towards lower FC values (RIP_HAX1/RIP_IgG) in the subsets with lower FDR. Red line: a subset of transcripts involved in ribosome biogenesis, identified by String 11 weighted analysis for RIP-target transcripts (RIP_HAX1/RIP_IgG FC as values). Significance calculated by the Kolmogorov–Smirnov test ( B ). The fraction of transcripts involved in ribosome biogenesis increases with decreasing FDR for the subset of RIP targets. Pathway enrichment calculated in String 11 weighted analysis with FC values from RNA-seq (RNA-seq_ HAX1 _KO/RNA-seq_WT). ( C ) Enrichment in GO terms assessed by String 11 weighted analysis with FC values from RNA-seq for a subset of downregulated transcripts. Analogous analysis for the upregulated subset produced no results. ( D ) The degradation of DHX37 and RRP7 mRNAs is more dynamic in HAX1 KO cells. Cells were treated with Actinomycin D (10 μg/mL). Relative expression was quantified by qPCR at designated time points. The experiment was carried out in several biological repeats and evaluated by the t-test (DHX37, n = 4, p -value: 0.026, 6 h, RRP7A n = 3, p -value: 0.035, 3 h). Error bars: SEM.
Figure 8. HAX1 KO affects the subunit:monosome ratio. ( A ) Representative absorbance profiles at 254 nm of sucrose gradient (10–50%) sedimentation of HL-60 cell extracts. The three leftmost peaks include ribosomal subunits (40S and 60S) and nontranslating monosomes (80S). The remaining peaks represent polysomes. Western blots for HAX1 and RPL26 ribosomal protein (large subunit) performed for the corresponding fractions are presented under the profiles. ( B ) Quantitative analysis of sedimentation profiles indicates that free subunits are more abundant in HAX1 KO in relation to the monosome (upper graph: 40S:80S ratio, lower graph: subunits/monosome ratio). The area under each peak was quantified using ImageJ (n = 6 in each sample), statistical significance determined with an unpaired t -test. Analysis by one-way ANOVA and Tukey multiple comparison test also show statistically significant difference for the 40S:80S ratio ( p -value: 0.003 and 0.0486 for HAX1 KO #1 and #2, respectively) and for the subunits:monosome ratio ( p -value: 0.0296 for HAX1 KO #1, for HAX1 KO #2, p -value: 0.15).
| https://www.mdpi.com/2073-4409/11/19/2943/htm |
HYATT INDUSTRIAL MANUFACTURING CORP. v. LEY CONSTRUCTION
GR NO. 147143, (2006-03-10)
DIVISION
[ GR NO. 147143, Mar 10, 2006 ]
HYATT INDUSTRIAL MANUFACTURING CORP. v. LEY CONSTRUCTION +
DECISION
519 Phil. 272
FIRST DIVISION
[ G.R. NO. 147143, March 10, 2006 ]
HYATT INDUSTRIAL MANUFACTURING CORP., AND YU HE CHING, PETITIONERS, VS. LEY CONSTRUCTION AND DEVELOPMENT CORP., AND PRINCETON DEVELOPMENT CORP., RESPONDENTSD E C I S I O N
AUSTRIA-MARTINEZ, J.:
Before the Court is a petition for review on
certiorari
seeking the nullification of the Decision dated May 4, 2000 of the Court of Appeals' (CA) then Seventh Division in CA-G.R. CV No. 57119, which remanded Civil Case No. 94-1429 to the trial
court and directed the latter to allow the deposition-taking without delay;
[1]
and the CA Resolution dated February 13, 2001 which denied petitioners' motion for reconsideration.
[2]
The facts are as follows:
On April 8, 1994, respondent Ley Construction and Development Corporation (LCDC) filed a complaint for specific performance and damages with the Regional Trial Court of Makati, Branch 62 (RTC), docketed as Civil Case No. 94-1429, against petitioner Hyatt Industrial
Manufacturing Corporation (Hyatt) claiming that Hyatt reneged in its obligation to transfer 40% of the
pro indiviso
share of a real property in Makati in favor of LCDC despite LCDC's full payment of the purchase price of P2,634,000.00; and that Hyatt failed to
develop the said property in a joint venture, despite LCDC's payment of 40% of the pre-construction cost.
[3]
On April 12, 1994, LCDC filed an amended complaint impleading Princeton Development Corporation (Princeton) as additional defendant claiming that
Hyatt sold the subject property to Princeton on March 30, 1994 in fraud of LCDC.
[4]
On September 21, 1994, LCDC filed a second amended complaint adding as defendant, Yu He Ching (Yu), President of Hyatt, alleging that LCDC paid the purchase price of
P2,634,000.00 to Hyatt through Yu.
[5]
Responsive pleadings were filed and LCDC filed notices to take the depositions of Yu; Pacita Tan Go, Account Officer of Rizal Commercial Banking Corporation (RCBC); and Elena Sy, Finance Officer of Hyatt. Hyatt also filed notice to take deposition of Manuel Ley, President of
LCDC, while Princeton filed notice to take the depositions of Manuel and Janet Ley.
[6]
On July 17, 1996, the RTC ordered the deposition-taking to proceed.
[7]
At the scheduled deposition of Elena Sy on September 17, 1996, Hyatt and Yu prayed that all settings for depositions be disregarded and pre-trial be set instead, contending that the taking of depositions only delay the resolution of the case. The RTC agreed and on the same day
ordered all depositions cancelled and pre-trial to take place on November 14, 1996.
[8]
LCDC moved for reconsideration
[9]
which the RTC denied in its October 14, 1996 Order, portion of which reads:
This Court has to deny the motion, because: 1) as already pointed out by this Court in the questioned Order said depositions will only delay the early termination of this case; 2) had this Court set this case for pre-trial conference and trial thereafter, this case
would have been terminated by this time; 3) after all, what the parties would like to elicit from their deponents would probably be elicited at the pre-trial conference; 4) no substantial rights of the parties would be prejudiced, if pre-trial conference is held, instead of
deposition.
[10]
On November 14, 1996, the scheduled date of the pre-trial, LCDC filed an Urgent Motion to Suspend Proceedings Due to Pendency of Petition for
Certiorari
in the Court of Appeals.
[11]
The petition, which sought to annul the Orders of the RTC
dated September 17, 1996 and October 14, 1996, was docketed as CA-G.R. SP No. 42512
[12]
and assigned to the then Twelfth Division of the CA.
Meanwhile, pre-trial proceeded at the RTC as scheduled
[13]
and with the refusal of LCDC to enter into pre-trial, Hyatt, Yu and Princeton moved to declare LCDC non-suited which the RTC granted in its Order dated December 3, 1996, thus:
On September 17, 1996, this Court noticing that this case was filed as early (as) April 4, 1994
[14]
and has not reached the pre-trial stage because of several depositions applied for by the parties, not to mention that the records of this case
has reached two (2) volumes, to avoid delay, upon motion, ordered the cancellation of the depositions.
On September 24, 1996, plaintiff filed a motion for reconsideration, seeking to reconsider and set aside the order dated September 17, 1996, which motion for reconsideration was denied in an order dated October 14, 1996, ruling among others that "after all, what the parties
would like to elicit from these deponents would probably be elicited at the pre-trial conference", and, reiterated the order setting this case for pre-trial conference on November 14, 1996.
On the scheduled pre-trial conference on November 14, 1996, a petition for
certiorari
was filed with the Court of Appeals, seeking to annul the Order of this Court dated September 17, 1996 and October 14, 1996, furnishing this Court with a copy on the same
date.
At the scheduled pre-trial conference on November 14, 1996, plaintiff orally moved the Court to suspend pre-trial conference alleging pendency of a petition with the Court of Appeals and made it plain that it cannot proceed with the pre-trial because the issue on whether or not
plaintiff may apply for depositions before the pre-trial conference is a prejudicial question. Defendants objected, alleging that even if the petition is granted, pre-trial should proceed and that plaintiff could take deposition after the pre-trial conference, insisting that
defendants are ready to enter into a pre-trial conference.
This Court denied plaintiff's motion to suspend proceedings and ordered plaintiff to enter into pre-trial conference. Plaintiff refused. Before this Court denied plaintiff's motion to suspend, this Court gave Plaintiff two (2) options: enter into a pre-trial conference, advising
plaintiff that what it would like to obtain at the deposition may be obtained at the pre-trial conference, thus expediting early termination of this case; and, terminate the pre-trial conference and apply for deposition later on. Plaintiff insisted on suspension of the pre-trial
conference alleging that it is not ready to enter into pre-trial conference in view of the petition for certiorari with the Court of Appeals. Defendants insisted that pre-trial conference proceed as scheduled, manifesting their readiness to enter into a pre-trial
conference.
When plaintiff made it clear that it is not entering into the pre-trial conference, defendants prayed that plaintiff be declared non-suited. x x x
x x x x
In the light of the foregoing circumstances, this Court is compelled to dismiss plaintiff's complaint.
WHEREFORE, for failure of plaintiff to enter into pre-trial conference without any valid reason, plaintiff's complaint is dismissed. Defendants' counterclaims are likewise dismissed.
SO ORDERED.
[15]
LCDC filed a motion for reconsideration
[16]
which was denied however by the trial court in its Order dated April 21, 1997.
[17]
LCDC went to the CA on appeal which was docketed as CA-G.R. CV No. 57119 and assigned to the then Seventh
Division of the CA.
[18]
On July 24, 1997, the CA's then Twelfth Division,
[19]
in CA-G.R. SP No. 42512 denied LCDC's petition for
certiorari
declaring that the granting of the petition and setting aside of the September 17, 1996 and October 14, 1996 Orders are
manifestly pointless considering that the complaint itself had already been dismissed and subject of the appeal docketed as CA-G.R. CV No. 57119; that the reversal of the said Orders would have practical effect only if the dismissal were also set aside and the complaint
reinstated; and that the dismissal of the complaint rendered the petition for certiorari devoid of any practical value.
[20]
LCDC's motion for reconsideration of the CA-G.R. SP No. 42512 decision was denied on March 4, 1998.
[21]
LCDC
then filed with this Court, a petition for
certiorari,
docketed as G.R. No. 133145 which this Court dismissed on August 29, 2000.
[22]
On May 4, 2000, the CA's then Seventh Division issued in CA-G.R. CV No. 57119 the herein assailed decision, the fallo of which reads:
WHEREFORE, premises considered, finding the appeal meritorious, this case is remanded to the court a quo for further hearing and directing the latter to allow the deposition taking without delay.
SO ORDERED.
[23]
The CA reasoned that: LCDC complied with Section 1, Rule 23 of the 1997 Rules of Civil Procedure which expressly sanctions depositions as a mode of discovery without leave of court after the answer has been served; to unduly restrict the modes of discovery during trial would
defeat the very purpose for which it is intended which is a pre-trial device, and at the time of the trial, the issues would already be confined to matters defined during pre-trial; the alleged intention of expediting the resolution of the case is not sufficient justification to
recall the order to take deposition as records show that the delay was brought about by postponement interposed by both parties and other legal antecedents that are in no way imputable to LCDC alone; deposition-taking, together with the other modes of discovery are devised by
the rules as a means to attain the objective of having all the facts presented to the court; the trial court also erred in dismissing the complaint as LCDC appeared during the pre-trial conference and notified it of the filing of a petition before the CA; such is a legitimate
justification to stall the pre-trial conference, as the filing of the petition was made in good faith in their belief that the court
a quo
erred in canceling the deposition scheduled for no apparent purpose.
[24]
Hyatt and Princeton filed their respective motions for reconsideration which the CA denied on February 13, 2001.
[25]
Hyatt and Yu now come before the Court via a petition for review on
certiorari
, on the following grounds:
I
THE COURT OF APPEALS, SEVENTH DIVISION, COMMITTED GRAVE ABUSE OF DISCRETION, ACTUALLY AMOUNTING TO LACK OF JURISDICTION, IN HOLDING IN EFFECT INVALID THE ORDERS OF THE LOWER COURT DATED SEPTEMBER 17, 1996 AND OCTOBER 14, 1996 WHICH ARE NOT RAISED OR PENDING BEFORE
IT, BUT IN ANOTHER CASE (CA-G.R. SP. No. 42512) PENDING BEFORE ANOTHER DIVISION OF THE COURT OF APPEALS, TWELFTH DIVISION, AND WHICH CASE WAS DISMISSED BY THE SAID DIVISION OF THE COURT OF APPEALS AND FINALLY BY THE HONORABLE SUPREME COURT IN G.R. NO. 133145.
II
THE COURT OF APPEALS, SEVENTH DIVISION, COMMITTED GRAVE ABUSE OF DISCRETION AND SERIOUS ERRORS OF LAW IN REVERSING THE LOWER COURT'S ORDER DATED DECEMBER 3, 1996 AND APRIL 21, 1997 HOLDING RESPONDENT NON-SUITED FOR FAILURE TO ENTER INTO PRE-TRIAL.
[26]
Anent the first issue, petitioners claim that: the validity of the RTC Order dated September 17, 1996 which set the case for pre-trial, as well as its Order dated October 14, 1996 denying LCDC's motion for partial reconsideration are not involved in CA-G.R. CV No. 57119 but were
the subject of CA-G.R. SP No. 42512, assigned to the then Twelfth Division, which dismissed the same on July 24, 1997 and which dismissal was affirmed by this Court in G.R. No. 133145; in passing upon the validity of the Orders dated September 17, 1996 and October 14, 1996, the
CA's then Seventh Division in CA-G.R. CV No. 57119 exceeded its authority and encroached on issues taken cognizance of by another Division.
[27]
On the second issue, petitioners claim that: the CA's then Seventh Division should have outrightly dismissed the appeal of LCDC as the same did not involve any error of fact or law but pertains to a matter of discretion which is properly a subject of
certiorari
under Rule 65 of the Revised Rules of Court; conducting discovery thru deposition is not a condition
sine qua non
to the holding of a pre-trial and the fact that LCDC wanted to take the deposition of certain persons is not a valid ground to suspend the holding of
pre-trial and subsequently the trial on the merits; the persons whose depositions were to be taken were listed as witnesses during the trial; to take their depositions before the lower court and to present them as witnesses during the trial on the merits would result in
unnecessary duplicity; the fact that LCDC has a pending petition for
certiorari
with the CA's then Twelfth Division docketed as CA-G.R. SP No. 42512 is not a ground to cancel or suspend the scheduled pre-trial on November 14, 1996 as there was no restraining order
issued; LCDC's availment of the discovery procedure is causing the undue delay of the case; it is only after LCDC has filed its complaint that it started looking for evidence to support its allegations thru modes of discovery and more than two years has already passed after the
filing of the complaint yet LCDC still has no documentary evidence to present before the lower court to prove its allegations in the complaint.
[28]
Petitioners then pray that the Decision dated May 4, 2000 and the Resolution dated February 13, 2001 of the CA's then Seventh Division in CA-G.R. CV No. 57119 be annulled and set aside and the validity of the Orders dated December 3, 1996 and April 21, 1997 of the RTC of Makati,
Branch 62 in Civil Case No. 94-1429 be sustained.
[29]
In its Comment, LCDC argues that the petitioners erred in claiming that the CA's then Seventh Division overstepped its authority as this Court has ruled in G.R. No. 133145 that the issue of whether LCDC has been denied its right to discovery is more appropriately addressed in
the appeal before the then Seventh Division in CA-G.R. CV No. 57119 below rather than by the then Twelfth Division in the
certiorari
proceeding in CA-G.R. SP No. 42512; and while the appeal of the final Order of the RTC dated December 3, 1996 also questioned the
Orders dated September 17, 1996 and October 14, 1996, it does not render the appeal improper as this Court in G.R. No. 133145 held that the subsequent appeal constitutes an appropriate remedy because it assails not only the Order dated December 3, 1996, but also the two earlier
orders.
[30]
On the second issue, LCDC contends that: the mere fact that a deponent will be called to the witness stand during trial is not a ground to deny LCDC the right to discovery and does not cause"unnecessary duplicity", otherwise no deposition can ever be taken; a deposition is for
the purpose of "discovering" evidence while trial is for the purpose of "presenting" evidence to the court; if petitioners' concern was the delay in the disposition of the case, the remedy is to expedite the taking of the depositions, not terminate them altogether; petitioners
have nothing to fear from discovery unless they have in their possession damaging evidence; the parties should be allowed to utilize the discovery process prior to conducting pre-trial since every bit of relevant information unearthed through the discovery process will hasten
settlement, simplify the issues and determine the necessity of amending the pleadings; the trial court erred in not suspending the pre-trial conference pending the petition for
certiorari
before the then Twelfth Division of the CA since considerations of orderly
administration of justice demanded that the trial court accord due deference to the CA; not only was LCDC's petition for
certiorari
filed in good faith, the CA found it meritorious, vindicating LCDC's insistence that the pre-trial be suspended; the undue delay in
the disposition of the case was not attributable to LCDC's deposition-taking but to the flurry of pleadings filed by defendants below to block LCDC's depositions and prevent it from gaining access to critical evidence; the critical evidence that LCDC needs to obtain through
discovery is evidence that is totally within the knowledge and possession of petitioners and defendant Princeton and is not available elsewhere.
[31]
On September 17, 2001, the Court required the parties to file their respective memoranda.[32] Hyatt and Yu on the one hand and LCDC on the other filed their respective memoranda reiterating their positions.
[33]
On January 2, 2002, Princeton filed a "Comment" which this Court considered as its Memorandum in the Resolution dated January 30, 2002.
[34]
In said memorandum, Princeton averred that: it is not true that Princeton failed to comply with any discovery orders as all information requested of Princeton was duly furnished LCDC and there are no pending discovery orders insofar as Princeton is concerned; LCDC is seeking to
dictate its procedural strategies on the RTC and the opposing parties; LCDC was not deprived due process as it was given all the opportunity to prepare for its case and to face its opponents before the court; LCDC admits to the probability of forum shopping as it filed a
petition for certiorari with the then Twelfth Division of the CA and later an appeal with the then Seventh Division of the CA; the RTC did not bar LCDC from presenting witnesses or discovering any evidence, as all it did was to transfer the venue of the testimony and discovery
to the courtroom and get on with the case which LCDC did not want to do; that discovery proceedings need not take place before pre-trial conference; trial court judges are given discretion over the right of parties in the taking of depositions and may deny the same for good
reasons in order to prevent abuse; the trial court did not err in not granting LCDC's motion to suspend proceedings due to the pendency of a petition for certiorari with the CA since there was no order from said court and there was no merit in the petition for certiorari as
shown by the dismissal thereof by the then Twelfth Division; there was proper and legal ground for the trial court to declare LCDC non-suited; appearance at the pre-trial is not enough; there is no evidence to support LCDC's claim that Hyatt surreptitiously transferred title to
Princeton.
[35]
The Court is in a quandary why Hyatt and Yu included Princeton as respondent in the present petition when Princeton was their co-defendant below and the arguments they raised herein pertain only to LCDC. With the failure of petitioners to raise any ground against Princeton in
any of its pleadings before this Court, we shall treat Princeton's inclusion as respondent in the present petition as mere inadvertence on the part of petitioners.
Now to the merits. The issues that need to be resolved in this case may be simplified as follows: (1) Whether the CA's then Seventh Division exceeded its authority in ruling upon the validity of the Orders dated September 17, 1996 and November 14, 1996; and (2) Whether the CA
erred in remanding the case to the trial court and order the deposition-taking to proceed.
We answer both questions in the negative.
Petitioners assert that the CA's then Twelfth Division in CA-GR SP No. 42512 and this Court in G.R. No. 133145 already ruled upon the validity of the Orders dated September 17, 1996 and November 14, 1996, thus the CA's then Seventh Division in CA G.R. CV No. 57119 erred in
ruling upon the same.
A cursory reading of the decisions in CA-GR SP No. 42512 and G.R. No. 133145, however, reveals otherwise. The CA's then Twelfth Division in CA-G.R. SP No. 42512 was explicit in stating thus:
x x x Any decision of ours will not produce any practical legal effect. According to the petitioner, if we annul the questioned Orders, the dismissal of its Complaint by the trial [court] will have to be set aside in its pending appeal. That assumes that the division
handling the appeal will agree with Our decision. On the other hand, it may not. Also other issues may be involved therein than the validity of the herein questioned orders.
We cannot pre-empt the decision that might be rendered in such appeal. The division to [which] it has been assigned should be left free to resolve the same. On the other hand, it is better that this Court speak with one voice.
[36]
This Court in G.R. No. 133145 also clearly stated that:
x x x
First
, it should be stressed that the said Petition (CA-G.R. SP No. 42512) sought to set aside only the two interlocutory RTC Orders, not the December 3, 1996 Resolution dismissing the Complaint. Verily, the Petition could not have assailed the
Resolution, which was issued after the filing of the former.
Under the circumstances, granting the Petition for
Certiorari
and setting aside the two Orders are manifestly pointless, considering that the Complaint itself had already been dismissed. Indeed, the reversal of the assailed Orders would have practical effect only if
the dismissal were also set aside and the Complaint reinstated. In other words, the dismissal of the Complaint rendered the Petition for
Certiorari
devoid of any practical value.
Second, the Petition for Certiorari was superseded by the filing, before the Court of Appeals, of a subsequent appeal docketed as CA-G.R. CV No. 57119, questioning
the Resolution and the two Orders.
In this light, there was no more reason for the CA to resolve the
Petition for
Certiorari.
x x x x
In this case, the subsequent appeal constitutes an adequate remedy. In fact, it is the appropriate remedy, because it assails not only the Resolution but also the two Orders.
x x x x
WHEREFORE, the Petition is DENIED and the assailed Resolutions AFFIRMED. x x x.
[37]
With the pronouncements of the CA in CA-G.R. SP No. 42512 and by this Court in G.R. No. 133145 that the subsequent appeal
via
CA-G.R. CV No. 57119 constitutes as the adequate remedy to resolve the validity of the RTC Orders dated September 17, 1996 and November 14,
1996, the arguments of petitioners on this point clearly have no leg to stand on and must therefore fail.
On the second issue, the Court finds that the CA was correct in remanding the case to the RTC and ordering the deposition-taking to proceed.
A deposition should be allowed, absent any showing that taking it would prejudice any party.
[38]
It is accorded a broad and liberal treatment and the liberty of a party to make discovery is well-nigh unrestricted if the matters inquired into are otherwise
relevant and not privileged, and the inquiry is made in good faith and within the bounds of law.
[39]
It is allowed as a departure from the accepted and usual judicial proceedings of examining witnesses in open court where their demeanor could be observed by
the trial judge, consistent with the principle of promoting just, speedy and inexpensive disposition of every action and proceeding;
[40]
and provided it is taken in accordance with the provisions of the Rules of Court,
i.e.,
with leave of court
if summons have been served, and without such leave if an answer has been submitted; and provided further that a circumstance for its admissibility exists (Section 4, Rule 23, Rules of Court).
[41]
The rules on discovery should not be unduly restricted,
otherwise, the advantage of a liberal discovery procedure in ascertaining the truth and expediting the disposal of litigation would be defeated.
[42]
Indeed, the importance of discovery procedures is well recognized by the Court. It approved A.M. No. 03-1-09-SC on July 13, 2004 which provided for the guidelines to be observed by trial court judges and clerks of court in the conduct of pre-trial and use of deposition-discovery
measures. Under A.M. No. 03-1-09-SC, trial courts are directed to issue orders requiring parties to avail of interrogatories to parties under Rule 45 and request for admission of adverse party under Rule 26 or at their discretion make use of depositions under Rule 23 or other
measures under Rule 27 and 28 within 5 days from the filing of the answer. The parties are likewise required to submit, at least 3 days before the pre-trial, pre-trial briefs, containing among others a manifestation of the parties of their having availed or their intention to
avail themselves of discovery procedures or referral to commissioners.
[43]
Since the pertinent incidents of the case took place prior to the effectivity of said issuance, however, the depositions sought by LCDC shall be evaluated based on the jurisprudence and rules then prevailing, particularly Sec. 1, Rule 23 of the 1997 Rules of Court which provides
as follows:
SECTION 1.
Depositions pending action, when may be taken.
By leave of court after jurisdiction has been obtained over any defendant or over property which is the subject of the action, or without such leave after an answer has been served, the
testimony of any person, whether a party or not, may be taken, at the instance of any party, by deposition upon oral examination or written interrogatories.
The attendance of witnesses may be compelled by the use of a subpoena as provided in Rule 21. Depositions shall be
taken only in accordance with these Rules. The deposition of a person confined in prison may be taken only by leave of court on such terms as the court prescribes. (Emphasis supplied).
As correctly observed by the CA, LCDC complied with the above quoted provision as it made its notice to take depositions after the answers of the defendants have been served. LCDC having complied with the rules then prevailing, the trial court erred in canceling the previously
scheduled depositions.
While it is true that depositions may be disallowed by trial courts if the examination is conducted in bad faith; or in such a manner as to annoy, embarrass, or oppress the person who is the subject of the inquiry, or when the inquiry touches upon the irrelevant or encroaches
upon the recognized domains of privilege,
[44]
such circumstances, however are absent in the case at bar.
The RTC cites the delay in the case as reason for canceling the scheduled depositions. While speedy disposition of cases is important, such consideration however should not outweigh a thorough and comprehensive evaluation of cases, for the ends of justice are reached not only
through the speedy disposal of cases but more importantly, through a meticulous and comprehensive evaluation of the merits of the case.
[45]
Records also show that the delay of the case is not attributable to the depositions sought by LCDC but was caused by
the many pleadings filed by all the parties including petitioners herein.
The argument that the taking of depositions would cause unnecessary duplicity as the intended deponents shall also be called as witnesses during trial, is also without merit.
The case of
Fortune Corp. v. Court of Appeals
[46]
which already settled the matter, explained that:
The availability of the proposed deponent to testify in court does not constitute "good cause" to justify the court's order that his deposition shall not be taken. That the witness is unable to attend or testify is one of the grounds when the deposition of a witness
may be used in court during the trial. But the same reason cannot be successfully invoked to prohibit the taking of his deposition.
The right to take statements and the right to use them in court have been kept entirely distinct. The utmost freedom is allowed in taking depositions; restrictions are imposed upon their use. As a result, there is accorded the widest possible opportunity for knowledge by both
parties of all the facts before the trial. Such of this testimony as may be appropriate for use as a substitute for viva voce examination may be introduced at the trial; the remainder of the testimony, having served its purpose in revealing the facts to the parties before trial,
drops out of the judicial picture.
x x x [U]nder the concept adopted by the new Rules, the deposition serves the double function of a method of discovery - with use on trial not necessarily contemplated - and a method of presenting testimony. Accordingly, no limitations other than relevancy and privilege have
been placed on the taking of depositions, while the use at the trial is subject to circumscriptions looking toward the use of oral testimony wherever practicable.
[47]
Petitioner also argues that LCDC has no evidence to support its claims and that it was only after the filing of its Complaint that it started looking for evidence through the modes of discovery.
On this point, it is well to reiterate the Court's pronouncement in
Republic v. Sandiganbayan
[48]
:
What is chiefly contemplated is the discovery of every bit of information which may be useful in the preparation for trial, such as the identity and location of persons having knowledge of relevant facts; those relevant facts themselves; and the existence,
description, nature, custody, condition, and location of any books, documents, or other tangible things. Hence, "the deposition-discovery rules are to be accorded a broad and liberal treatment. No longer can the time-honored cry of "fishing expedition" serve to preclude a party
from inquiring into the facts underlying his opponent's case. Mutual knowledge of all the relevant facts gathered by both parties is essential to proper litigation. To that end, either party may compel the other to disgorge whatever facts he has in his possession. The
deposition-discovery procedure simply advances the stage at which the disclosure can be compelled from the time of trial to the period preceding it, thus reducing the possibility, of surprise.
[49]
It also does not escape this Court's attention that the trial court, before dismissing LCDC's complaint, gave LCDC two options: (a) enter into a pre-trial conference, advising LCDC that what it would like to obtain at the deposition may be obtained at the pre-trial conference,
thus expediting early termination of the case; and (b) terminate the pre-trial conference and apply for deposition later on. The trial court erred in forcing LCDC to choose only from these options and in dismissing its complaint upon LCDC's refusal to choose either of the
two.
The information LCDC seeks to obtain through the depositions of Elena Sy, the Finance Officer of Hyatt and Pacita Tan Go, an Account Officer of RCBC, may not be obtained at the pre-trial conference, as the said deponents are not parties to the pre-trial conference.
As also pointed out by the CA:
x x x To unduly restrict the modes of discovery during trial, would defeat the very purpose for which it is intended, as a pre-trial device. By then, the issues would have been confined only on matters defined during pre-trial. The importance of the modes of
discovery cannot be gainsaid in this case in view of the nature of the controversy involved and the conflicting interest claimed by the parties.
[50]
Deposition is chiefly a mode of discovery, the primary function of which is to supplement the pleadings for the purpose of disclosing the real matters of dispute between the parties and affording an adequate factual basis during the preparation for trial.
[51]
Further, in
Republic v. Sandiganbayan
[52]
the Court explained that:
The truth is that "evidentiary matters" may be inquired into and learned by the parties before the trial.
Indeed, it is the purpose and policy of the law that the parties before the trial if not indeed even before the pre-trial should discover or inform
themselves of all the facts relevant to the action, not only those known to them individually, but also those known to their adversaries; in other words, the desideratumis that civil trials should not be carried on in the dark
; and the Rules of Court make
this ideal possible through the deposition discovery mechanism set forth in Rules 24 to 29. The experience in other jurisdictions has been the ample discovery before trial, under proper regulation, accomplished one of the most necessary ends of modern procedure; it not only
eliminates unessential issues from trials thereby shortening them considerably, but also requires parties to play the game with the cards on the table so that the possibility of fair settlement before trial is measurably increased.
As just intimated, the deposition-discovery procedure was designed to remedy the conceded inadequacy and cumbersomeness of the pre-trial functions of notice-giving, issue-formulation and fact revelation theretofore performed primarily by the pleadings.
The various modes or instruments of discovery are meant to serve (1) as a device, along with the pre-trial hearing under Rule 20, to narrow and clarify the basic issues between the parties, and (2) as a device for ascertaining the facts relative to those issues. The evident
purpose is, to repeat, to enable the parties, consistent with recognized privileges, to obtain the fullest possible knowledge of the issues and facts before civil trials and thus prevent that said trials are carried on in the dark.
[53]
(emphasis
supplied)
In this case, the information sought to be obtained through the depositions of Elena and Pacita are necessary to fully equip LCDC in determining what issues will be defined at the pre-trial. Without such information before pre-trial, LCDC will be forced to prosecute its case in
the dark the very situation which the rules of discovery seek to prevent. Indeed, the rules on discovery seek to make trial less a game of blind man's bluff and more a fair contest with the basic issues and facts disclosed to the fullest practicable extent. [54]
Considering the foregoing, the Court finds that the CA was correct in remanding the case to the trial court and ordering the depositions to proceed.
WHEREFORE
, the petition is denied for lack of merit.
Costs against petitioner.
SO ORDERED.
Panganiban, C.J., (Chairperson), Ynares-Santiago, Callejo, Sr.,
and
Chico-Nazario, JJ.,
concur.
[1]
Rollo, pp. 40-49, penned by Associate Justice Corona Ibay-Somera and concurred in by Associate Justices Portia Aliño-Hormachuelos and Elvi John S. Asuncion.
[2]
Id. at 51-52.
[3]
Records, pp. 1-6.
See also
CA Decision in CA G.R. CV No. 57119,
rollo,
p. 41.
[4]
Id. at 40-46.
[5]
Id. at 133-140.
[6]
Id. at 553-557, 567, 613.
[7]
Id. at 745-747.
for Elena C. Sy, (by plaintiff) on September 17, 1996 at 2:00 o'clock in the afternoon;
for Manuel Ley (by defendant Hyatt) on September 24, 1996 at 2:00 o'clock in the afternoon.
for Yu He Ching (by plaintiff) on September 26, 1996 at 2:00 p.m.
for Manuel Ley and Janet Ley (by defendant Princeton) on October 1, 1996 at 2:00 p.m.
for Pacita Tan Go (by plaintiff) on October 3, 1996 at 2:00 p.m.
[8]
Id. at 785.
The
fallo
of which reads:
"WHEREFORE, in order not to delay the early termination of this case, all depositions set for hearing are hereby cancelled and set this case for Pre-trial on November 14, 1996 at 2:00 o'clock in the afternoon."
[9]
Id. at 790-796.
[10]
Id. at 808.
[11]
Id. at 815-818.
[12]
Ley Construction & Development Corp. v. Hyatt Industrial Manufacturing Corp.,
393 Phil. 633, 636-638 (2000).
See also
Petition,
rollo,
pp. 13-14.
[13]
Records, at 836, December 3, 1996 RTC Order.
[14]
Should be "April 8, 1994."
[15]
Records, pp. 835-837.
[16]
Id. at 838-847.
[17]
Id. at 872-873.
[18]
Rollo,
p. 40.
[19]
Penned by Justice Hector L. Hofileña, with the concurrence of Justices Artemon D. Luna and Artemio G. Tuquero.
[20]
Ley Construction v. Hyatt,
supra note 12, at 640.
[21]
Id. at 636.
[22]
Ley Construction v. Hyatt,
supra note 12.
[23]
Rollo, pp. 48-49.
[24]
Id. at 44-49.
[25]
Id. at 51-52.
[26]
Id. at 16-17.
[27]
Id. at 17-20.
[28]
Id. at 20-24.
[29]
Id. at 24.
[30]
Id. at 60-63.
[31]
Id. at 63-77.
[32]
Id. at 82-83.
[33]
Id. at 97-110; 112-168.
[34]
Id. at 187.
[35]
Id. at 170-186.
[36]
Ley Construction v. Hyatt,
supra note 12, at 638-639.
[37]
Id. at 640-643.
[38]
Jonathan Landoil International Co. Inc. v. Mangudadatu,
G.R. No. 155010, August 16, 2004, 436 SCRA 559, 575.
[39]
Ayala Land, Inc. v. Tagle,
G.R. No. 153667, August 11, 2005, 466 SCRA 521, 532;
Jonathan Landoil v. Mangudadatu,
supra, at 573.
[40]
Jonathan Landoil v. Mangudadatu,
supra, at 574.
[41]
Id.,
See also
Secs. 1 & 4 of Rule 23 of the Rules of Court.
[42]
Ayala Land, Inc. v. Tagle,
supra at 531.
[43]
A.M. No. 03-1-09-SC, pars. I.A. 1.2; 2(e).
[44]
Jonathan Landoil v. Mangudadatu,
supra, at 573.
[45]
Dulay v. Dulay,
G.R. No. 158857, November 11, 2005.
[46]
G.R. No. 108119, January 19, 1994, 229 SCRA 355.
[47]
Id. at 376-377.
[48]
G.R. No. 90478, November 21, 1991, 204 SCRA 212.
[49]
Id. at 224.
[50]
Rollo,
pp. 45-46.
[51]
Dulay v. Dulay,
supra;
Ayala Land v. Tagle,
supra at 530;
Jonathan Landoil v. Mangudadatu,
supra, at 573.
[52]
Supra note 48.
[53]
Id. at 222-223.
[54]
Fortune Corp. v. Court of Appeals,
supra at 363.
tags
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Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Journal Paper
Themes
Assistive & Accessible Technology
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Giulia Barbareschi, Wesley Teerlink, Josepg Gakunga Njuguna, Purity Musungu, Mary Dama Kirino, andCatherine Holloway
According to estimates from the World Health Organization, in 2010, there were more than 30 million people in need of prosthetic and orthotic devices across Africa, Asia, and Latin America. 1This number is likely to have grown significantly in the past decade, in line with trends recorded for the general need of assistive technology. 2For many people who undergo a lower limb amputation, access to an appropriate prosthesis is essential to restore functional mobility and ensure good quality of life. 3Ultimately, an appropriate lower-limb prosthesis (LLP) can enable people with amputation to fulfill their desired role in their family, work, and community life. 4
Prosthetic and Orthotics International; 2022
Abstract
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Background:
Many people with amputations who live in low-resourced settings struggle to access the workshops where qualified prosthetists provide appropriate care. Novel technologies such as the thermoplastic Confidence Socket are emerging, which could help facilitate easier access to prosthetic services.
Objectives:
The objective of this study was to evaluate the satisfaction and the performance of transtibial prosthesis featuring the Confidence Socket.
Study design:
This is a longitudinal repeated-measures design study.
Methods:
A convenience sample of 26 participants who underwent transtibial amputation were fitted with the Confidence Socket. The performance of the socket was evaluated after a follow-up period between 1 month and 6 months using the L test of functional mobility and the amputee mobility predictor. Satisfaction with the prosthesis was measured using the Trinity Amputation and Prosthetic Experience Scales and purposefully designed 7-point Likert scales.
Results:
Ten of the 26 participants returned for follow-up. Perceived activity restriction and L test times improved significantly at follow-up, but the self-reported satisfaction with the Confidence Socket was lower at follow-up compared with that after fitting.
Conclusions:
The Amparo Confidence Socket represents a potentially viable alternative to improve access to appropriate prosthesis in Kenya, but some aspects of users’ self-reported satisfaction should be further investigated.
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Barbareschi G, Teerlink W, Njuguna JG, Musungu P, Kirino MD, Holloway C. Evaluating the use of a thermoplastic socket in Kenya: A pilot study. Prosthet Orthot Int. 2022 Oct 1;46(5):532-537. doi: 10.1097/PXR.0000000000000130. Epub 2022 Mar 25. PMID: 35333813; PMCID: PMC9554758.
Evaluating the use of a thermoplastic socket in Kenya: A pilot study
Assistive & Accessible Technology
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Jamie Danemayer, Andrew Young, Siobhan Green, Lydia Ezenwa, Michael Klein
This study synthesizes learnings from three distinct datasets: innovator applications to the COVIDaction data challenges, surveys from organizers from similarly-aimed data challenges, and a focus group discussion with professionals who work with COVID-19 data. Thematic and topic analyses were used to analyze these datasets with the aim to identify gaps and barriers to effective data use in responding to the pandemic.
Data & Policy; 2023
Abstract
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Innovative, responsible data use is a critical need in the global response to the coronavirus disease-2019 (COVID-19) pandemic. Yet potentially impactful data are often unavailable to those who could utilize it, particularly in data-poor settings, posing a serious barrier to effective pandemic mitigation. Data challenges, a public call-to-action for innovative data use projects, can identify and address these specific barriers. To understand gaps and progress relevant to effective data use in this context, this study thematically analyses three sets of qualitative data focused on/based in low/middle-income countries: (a) a survey of innovators responding to a data challenge, (b) a survey of organizers of data challenges, and (c) a focus group discussion with professionals using COVID-19 data for evidence-based decision-making. Data quality and accessibility and human resources/institutional capacity were frequently reported limitations to effective data use among innovators. New fit-for-purpose tools and the expansion of partnerships were the most frequently noted areas of progress. Discussion participants identified building capacity for external/national actors to understand the needs of local communities can address a lack of partnerships while de-siloing information. A synthesis of themes demonstrated that gaps, progress, and needs commonly identified by these groups are relevant beyond COVID-19, highlighting the importance of a healthy data ecosystem to address emerging threats. This is supported by data holders prioritizing the availability and accessibility of their data without causing harm; funders and policymakers committed to integrating innovations with existing physical, data, and policy infrastructure; and innovators designing sustainable, multi-use solutions based on principles of good data governance.
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Danemayer, J., Young, A., Green, S., Ezenwa, L., & Klein, M. (2023). Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges. Data & Policy, 5, E11. doi:10.1017/dap.2023.6
Responding to the coronavirus disease-2019 pandemic with innovative data use: The role of data challenges
Type
Conference Paper
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Editorial
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Disability design and innovation in computing research in low resource settings
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Secondary school students’ perceptions of a mobile application design for smoking prevention
Introduction: Our research was based on the BUS model, which provides guidelines for developing mobile applications for health. This model is supported by theories of behavior change, user-centered design, and social marketing. This study aimed to determine secondary school students’...
Secondary school students’ perceptions of a mobile application design for smoking prevention
,
María del Carmen Gogeascoechea-Trejo 2
,
María de Lourdes Mota-Morales 3
,
Christian Soledad Ortiz-Chacha 3
,
Betzaida Salas-García 2
,
Enrique Romero-Pedraza 4
,
María Cristina Ortiz-León 3
1 Public Health Institute, Master’s in Public Health, University of Veracruz, Veracruz, Mexico 2 Health Sciences Institute, University of Veracruz, Veracruz, Mexico 3 Public Health Institute, University of Veracruz, Veracruz, Mexico 4 Psychological Research Institute, University of Veracruz, Veracruz, Mexico
CORRESPONDING AUTHOR
María Cristina Ortiz-León Public Health Institute, Master’s in Public Health, University of Veracruz, Av. Dr. Luis Castelazo Ayala s/n, Col. Industrial Animas, 91190 Xalapa-Enríquez, Veracruz, Mexico
Submission date: 2020-08-03
Final revision date: 2020-12-10
Acceptance date: 2021-01-31
Publication date: 2021-03-31
Tob. Prev. Cessation 2021;7(March):24
DOI: https://doi.org/10.18332/tpc/132965
Article (PDF)
Supplementary files
References (31)
KEYWORDS
prevention
tobacco control
education–youth prevention
mobile application prototype
TOPICS
Behavioral counselling
Education
Prevention of tobacco use
Youth
ABSTRACT
Introduction: Our research was based on the BUS model, which provides
guidelines for developing mobile applications for health. This model is supported by theories of behavior change, user-centered design, and social marketing. This study aimed to determine secondary school students’ perceptions of a mobile application design for smoking prevention. Methods: In 2018, qualitative research was conducted in three secondary
schools located in the central part of the state of Veracruz, Mexico. Focus groups were established to explore beliefs about smoking and mobile phone use. The sketch technique was used to identify the characteristics for the mobile application. Results: The students’ perception of smoking allowed us to determine behaviors that can be changed: 1) associating cigarettes with a distraction from problems can be prevented; 2) peer and family pressure as a trigger to starting smoking can be avoided; and 3) tobacco use can be disassociated from being popular. Regarding the design of the mobile application prototype, an entertaining game with levels to help teenagers stay active was proposed. Conclusions: Games for health can help modify user behavior and even
positively influence their values. The final product was the prototype for the ‘No le entres’ (don’t jump in) application. An important finding was that adolescents living in both urban and rural settings use mobile phones similarly.
INTRODUCTION
In Mexico, 1.1 million active adolescent smokers have been reported to exist. Such a figure represents 7.8% of the population, where, according to the National Survey on Alcohol, Drugs and Tobacco Consumption 1, the age of onset and daily consumption are 13.7 and 14.3 years, respectively. Therefore, further efforts are essential to prevent and reduce smoking in this age group, since by 2030 more than 8 million smoking-related deaths per year are expected to occur 2.
Engaging in healthy behaviors and easy access to quality information are the fundamentals of health promotion 3. Engaging in healthy behavior is an individual decision; therefore, the individual behaviors of a given population group represent a behavior collective that has an impact on public health. Tobacco use is an unhealthy behavior, so individualized information, considering the characteristics of everyone such as age, sex, and type of consumption, among others, plays a key role when people choose whether to smoke or not. In this sense, Information and Communications Technologies (ICTs) have enhanced and even created new ways to perceive healthcare 3. Within ICTs, mobile phones deliver a means of communication easily adaptable to these needs, since they are communication devices with a high rate of penetration for a large part of the population, particularly adolescents 4.
Additionally, smartphones combine several features; they allow for communication, and many applications deliver immediate access to different content or entertainment 5. The entry of these devices into people’s daily lives can be exploited for their benefit. For example, developing applications gives rise to opportunities to promote health and make education more dynamic, interactive, and individual, and this can occur on a large scale, since the targeted population can be so easily reached. In addition, they are more profitable than other types of interventions 6.
Article 12 of the Framework Convention for Tobacco Control establishes that available communication tools must be used to carry out interventions to prevent tobacco consumption. If we consider that adolescents are mobile phone users and make up a population where most users have access to mobile applications, then mobile phones could be used as a tool for smoking prevention in this age group 7.
Digital objects, including mobile applications (apps), should be designed considering the specific needs of both the context and the community 8. The BUS model considers these aspects. Its name is derived from three different concepts: B comes from Behavior Change Theories, U from User-Centered Design (UCD), and S from Social Marketing. BUS considers six stages: 1) situation analysis, 2) concept generation and prototype design, 3) prototype development, 4) pilot test, 5) launch campaign, and 6) assessment. In this model, it is critical that users are involved while the application is being designed in all stages, from the conceptual design to the final assessment. Behavior Change Theories and UCD are both used in all the stages, while Social Marketing only in five 9.
Regarding the Behavior Change Theories to develop interventions for adolescents, the following theories stand out: Health Belief Model 10, the Theory of Reasoned Action 11, and the Social Learning Theory 12. Thus, we considered them when designing our app. The Health Belief Model predominated, which refers to the use of rewards for adherence to indications provided by health professionals to improve quality of life and prevent complications to their health state. The Theory of Reasoned Action points out that the influence of peers affects adolescent behavior. The Social Learning Theory stresses the importance of external influences on behavior since people learn by observing and learning about the experiences of others.
There is a history of UCD to study adolescents’ perceptions of the features that smart applications should have with respect to health in the United States and Europe. We found that no studies like these have been conducted in the Latino or Spanish-speaking adolescent population. In most, the qualitative approach and focus groups to determine the characteristics necessary to design feasible and usable mobile applications for health predominate. Smoking cessation 13, providing sexual education 14, diabetes control 15, asthma 16 , 17, and increasing physical activity 18are some of the health problems to be solved. We found no studies on developing UCD-based applications for smoking prevention in adolescents.
When designing mobile apps, it is necessary to identify the target population and document the design process to determine the ideal features by considering their perspective as potential users to encourage their use. For the abovementioned reasons, this project aimed to determine secondary school students’ perception of the characteristics of a mobile application for preventing tobacco use.
METHODS
Study design
We conducted a user-centered design qualitative approach 19. We implemented the first two phases of the BUS model: 1) situation analysis, and 2) concept generation and prototype design.
Context
We recruited students from three secondary schools located in the central part of the state of Veracruz, Mexico. Schools were identified as School 1, School 2, and School 3.
Sampling strategy
We selected the three schools and students by convenience. We included schools located in communities with different levels of marginalization and population centers. We included female and male public secondary school students in first, second, and third grade, aged 12–15 years. Students were both smokers and non-smokers, and all students were mobile application users.
Data collection methods
Two focus groups were held between October and November 2018 and another in February 2019. They consisted of three students per school grade, female and male, and both a moderator and a rapporteur took part. Before holding the focus groups, participants wrote their school grades and groups, sex, full name, and phone type (Android or iPhone) on the attendance list.
We used the same guide at the beginning of each focus group to standardize data collection, so we structured it as follows: a presentation to generate empathy among the participants and establish the rules for participation was shown. After this, the students received a brief introduction about health mobile applications, their purpose, and some examples. The next sections of the guide explored beliefs about tobacco use and mobile phone use in everyday life. To obtain the attributes, design, and contents of an app designed to prevent tobacco consumption, we used the sketch technique, where students were told to express themselves through drawings on white sheets with colored pencils. In the final part of the guide, we thanked participants for taking part in the sessions.
We reminded them that the information given in the group was exclusively for academic purposes and that it would be handled confidentially. We created an attendance list that included school grade, group, sex, age, and phone type. Since the participants were minors, informed consent forms were signed by the participants’ parents. Students gave us their informed approval. This project was approved by the Technical Council of Instituto de Salud Pública (Public Health Institute), part of the University of Veracruz, which is empowered to issue both ethical and methodological opinions on research and is also the body empowered by the regulations with force in the university.
The sessions were recorded, with the consent of the participants, using a MacBook Air computer and a smartphone. RDUM and MCOL held the focus groups, as they have experience working with these groups.
Processing and analyzing information
We considered the following category analysis for data collected by the focus groups: 1) beliefs about tobacco use, with subcategories – health, family, friends, and status; 2) mobile phone use in everyday life, with the following usability subcategories – internet access, mobile applications, social networks, costs, rewards, and usage time; and 3) attributes of mobile applications, with the following subcategories – avatar, rewards, health behavior, color, type of application, and use of other elements.
BSG, MCGT and MLMM, which previously have done analysis, considered category analysis and manually transcribed and codified data collected by the focus groups. We then performed both a content analysis using segmentation and an iconic memory analysis to process visual information.
CSOC and MCOL, which have experience with qualitative research, verified transcribed data after codification was finished and if a segment matched the category analysis identified by at least two of the codifiers, then it was kept. Once identifying category analysis was analyzed and verified, results from the analysis were presented to the research team. ERP, RDUM and MCOL then selected eligible behaviors to be improved by developing a smart application, so they were able to generate the concepts that gave rise to our application.
After we generated the concepts, we then designed a low-fidelity prototype of our application to prevent smoking.
RESULTS
Situation analysis
Relevant characteristics of participants
School 3 is located in a rural town with a high level of marginalization, and internet access is limited. School 3 and School 2 were those with a greater number of participants (Table 1). In all the three groups, male participation predominated. In the focus groups of Schools 1 and 2 (Focus Groups 1 and 2, respectively), all participants had a mobile phone while the research was being conducted. In the focus group of School 3 (Focus Group 3), some participants had no mobile phones for unspecified family reasons. In all the three focus groups, Android-based mobile phones predominated, while in Focus Group 2 some students had IOS-based mobile phones.
Table 1
Characteristics of both schools and participants taking part in the focus groups
Characteristics School 1 School 2 School 3 Name of the town Tlaltetela Xalapa Cantaranas Type of town Urban Urban Rural Level of marginalization High Very low High Total number of students 267 1500 113 Participants per school 6 10 10 Sex Female 1 6 1 Male 5 4 9 School grade First 0 4 4 Second 2 6 2 Third 4 0 4 Type of mobile OS Android 6 7 5 IOS 0 3 0 Does not have one 0 0 5
Beliefs about tobacco use during the adolescent stage
Secondary school participants knew about the health damage caused by tobacco use. They recognized that such a habit leads to death. A participant pointed out that:
‘Smoking damages and contaminates your body, causing death.’(School 3, Male student)
They also identified substances contained in cigarettes that can affect their health. In turn, they stated that smoking not only damages the smoker, but also those around him or her.
‘Mom taught me that smoking causes a lot of physical pain, like cirrhosis, and affects your liver. It is also bad for people living around you … as tobacco smoke is in your clothes, you can make them sick and your lungs can get sick.’(School 2, Male student)
They have also heard or seen other people smoking, from which they had received positive messages about this habit, and they conceived this activity as pleasant, stress-relieving, and fun (because smoke comes out of your mouth). Some stated that flavored and colored cigarettes are an incentive to start smoking.
‘When I smoke, I think of several flavored and colored cigarettes - those are not so strong.’(School 1, Male participant)
According to participants, their decision to start smoking is influenced by family. They emphasized that family problems affect them and cause them to smoke. They felt that, if a family member smokes, it is an invitation to experience and start smoking.
‘[Family] influences start smoking for several reasons. Problems at home is one of them and you try to find something to kill time or a family member smokes and he or she somehow convinces you, influences you or makes you try to smoke.’(School 2, Male participant)
However, some participants assigned their parents the role of counselors because they often give advice. Nevertheless, participants themselves stay away from counselling sessions and make decisions without taking them into account.
‘Parents often give advice because they want to help you, but you don't listen, you don't give a f… damn.’(School 3, Male participant)
They believe that friendship plays a key role in decision-making, particularly when starting to smoke. In the three schools, young smokers are visible and put pressure on others to start smoking. To do so, they use challenging phrases such as:
‘You are a man, men smoke, are you a pussy or what?’(School 1, Male participant)
The belief that smoking brings popularity, importance and power stood out in the focus groups:
‘Smoking makes you popular, the others see you as an older and a mature guy and you become important for them, they want to be like you, they start admiring you for an unknown reason.’(School 2, Female participant)
‘You smoke because you want to imitate artists, singers, if they smoke and just do fine, why can't you?’(School 1, Male participant)
Mobile phones in everyday life
Mobile phones are used to play games, competition games as well as violent or war games. Participants from both urban and rural environments play the same games. They also use mobile phones to communicate with their friends through social networks or instant messaging services.
‘I use my mobile phone for chatting or checking Facebook and catching up with gossips about other classmates. I like playing either Free Fire or Fortnite because we can kill people.’(School 2, Female participant)
‘I use more Facebook, Messenger and games like Free Fire or that one … Fortnite, they are so cool. Besides, they have a lot of levels and their graphics are so f… cool.’(School 3, Male participant)
In addition, mobile phones are useful for them to keep themselves informed about sports as well as watch and download videos.
‘I use my mobile phone for Messaging my friends and parents and watching and listening to musical videos. For watching porn. For playing Free Fire. It's so cool!’(School 3, Male participant)
In a single group, it was mentioned that mobile phones were used to do homework.
‘I use it [the mobile phone] for doing homework or researching topics.’(School 1, Male participant)
We observed that social networks are part of the daily life of young people. Social networks have become essential for them, regardless of whether they come from communities with low or high levels of marginalization.
‘I check Facebook and YouTube. I also play Fortnite or Free Fire, as you can meet people and chat with others.’(School 2, Male participant)
Participants only download free apps that provide them with prizes or rewards to keep their interest.
‘I like that games and apps are free, as I can download them. I prefer playing on PC, it is easier and free … using the keyboard is pretty cool, as my mobile phone freezes and you can't play very well.’(School 2, Male participant)
We observed that they are constantly close to their phones so that they can spend more time on them. Participants living in rural environments spend fewer hours on their mobile phones because of the quality of the signal – not because of a lack of desire or interest.
‘At school you are not allowed to check your phone in classes, but I am virtually checking my apps all day. Sometimes I only want to watch what time it is, when I realize I already have notifications about my apps and I stay hours looking at them … all day I have an urge to be checking notifications.’(School 2, Female participant)
‘Well, I spent about 4 hours checking my apps, because my Internet is unstable.’(School 3, Male participant)
Attribute coding for app design
According to participants’ perception, designing an application to prevent tobacco use must be governed by an avatar (Figure 1a). Games must be developed, for example, to kill cigarettes, answer questions, and earn points to improve the appearance of the avatar (Figure 1b).
Figure 1
Sketches drawn by focus group participants
Regarding the prevention of tobacco use, they stated that it is important to be informed and aware of the risks of smoking by using audiovisual tools, which would reinforce their knowledge and provide motivational messages. They also pointed out that, at the end of each level of the game, they should be told how important it is not to start smoking. They said that it should be emphasized that not smoking is beneficial for their health and for maintaining a high quality of life and that they save money when they do not buy cigarettes (Figure 1c).
Use of vibrant and bright colors prevailed in the designs of the three groups. There was a preference to developing war-based games with weapons. However, there were variants where the user was a caregiver that prevented the person they are looking after from starting to smoke. They also said that a game to strengthen their thinking skills with questions to assess their knowledge and learning should be developed. Moreover, they also proposed a decision-making game where, if the player decides not to smoke, then the player can move on to the next level (Figure 1d).
Participants said that watching educational videos on YouTube was important for them to stay informed about tobacco risks (Figure 2a). A chat was also proposed whereby participants can meet other participants who have smoked and, through interaction, learn from their experience. They also stated that health professionals should be included so that participants can learn more about the consequences of tobacco use from an expert’s perspective. Another interesting suggestion was to link the app with associations that fight tobacco use and addictions, and the money collected when playing the app should be given to these associations (Figure 2b). All groups proposed to link the app with other social networks such as Facebook, Instagram, and WhatsApp (Figure 2c), in addition to relying on games like Free Fire(Figure 2d).
Figure 2
Sketches drawn by focus group participants
Concept generation and app design to smoking prevention
With the information collected, we proceeded to target behaviors that could be feasibly modified by an app:
Regarding cigarettes as a distraction for participants’ problems.
Being pressured from friends and family.
Regarding tobacco use as popular.
Table 2shows the behaviors to be modified, the way to intervene, and the elements that can be easily incorporated into our app.
Table 2
List of behaviors to be changed, how to intervene and elements to be incorporated into our app
Behaviors to be changed How to intervene Element to be incorporated into our appPrevent associating the cigar as a distraction for problems.Leisure and entertaining activities.A three-level game as a positive distraction to avoid tobacco use.Prevent pressure from peers and family to start smoking.Strengthening the autonomy of teenagers with positive messages and information on the damage caused by tobacco use during the adolescent stage, so that they can recognize harmful behaviors.Short videos with positive non-smoking messages, infographics, illustrations and memes will contain 'Did you know that' … information, supported by data and statistics. According to the Theory of Reasoned Action that emphasizes the influence of peers on behavior, YouTubers and influencers, who are popular among teenagers, will be invited to participate in the short videos.Do not associate tobacco use with being popular.Stimulating talents, skills and interests to benefit their health. Prevent relating tobacco use with acceptance to social groups in their environment.Answering questions. According to the Model of Health Beliefs, if answers are correct, teenagers will receive rewards, either a gift coupon or accessories for the avatar, in addition to moving on to the next level.A decision-making level, where teenagers will put into practice what they have learned and choose between two situations (one that puts them at risk and another that keeps them healthy). Thus, teenagers will reinforce their selfesteem and confidence in themselves and avoid associating tobacco use with the need to being accepted by the social groups around them and achieve a popularity status.
Prototype design
Our app prototype was called ‘No le entres’ (don’t jump in), as a warning against starting smoking.Figure 3shows the navigation map. It starts with application access through three social networking sites: Facebook, Twitter, and Gmail. After that, the privacy notice pops up and provides information about data protection. The next few lines briefly describe our app and provide instructions on how to play each of the three levels.
Figure 3
Navigation map of ¡No le entres! (Don´t jump in) app
In the next screen, the player will choose the gender of the avatar. The player will interact with this avatar throughout the entire game and be able to customize her or him according to personal taste by selecting clothes, shoes, and style.
The first level is trivia, answering questions about tobacco use, physical and social damage, as well as the benefits of not smoking. If the player answers questions correctly, then the player can move on to the next level, but if the player does not, then the app will provide pieces of information such as short videos, infographics, pictures and memes, which will dispel doubts about the correct answer. The level will aim to inform participants, based on scientific evidence, about tobacco use to prevent classmates and family members from inducing them to smoke by giving them false information.
The second level is a rally that will be designed using augmented reality. The player will travel around the city he or she is living in when accessing our app to find two graphical elements: smokers and cigarette butts, which will be collected by clicking on. Then, on the screen the adolescent will see a question about what to do with that element. The player will have to choose wisely to move on to the next level.
The more elements caught by the player, the more points the player gets. This level aims to develop abilities for searching and recreation so that adolescents can perceive themselves as skillful and useful people who are able to make the best decisions on their health.
The third level is an obstacle game where the player using his or her avatar has to dodge cigarettes, while collecting water balloons to throw at smokers. It is a time-trial level whose objective is to reinforce in adolescents that smoking is harmful and they must avoid cigarette smoke.
Once players beat the three levels correctly and satisfactorily, they receive rewards consisting of discounts at movie theaters, clothing stores, bookstores, music stores, and entertainment as well as accessories for their avatars.
DISCUSSION
Our research was based on the BUS methodology, whereby three focus groups were held. We used User-Centered Design and Behavior Change Theories, resulting in the prototype for the ‘No le entres’ (don’t jump in) mobile application, which aims to prevent smoking among adolescents. It is innovative in that we found no evidence of mobile applications being developed to prevent smoking among the Latino adolescent population.
In the participants’ discourse, the Health Belief Model predominated, since they recognized the effects of smoking as a very serious issue. However, smoking is still a source of satisfaction for them. Thus, it is necessary for people not only to determine the risks of smoking, but also the benefits of not using tobacco 10. We also used this model to design our app, since it considers that the player will receive prizes once all three levels of the game are beaten.
The Theory of Reasoned Action was another theory that was made visible in the participants’ discourse, since participants frequently mentioned that friends usually induce them to smoke. However, if we replace a ‘negative peer’ with a peer with positive behavior, it will be easier to prevent young people from starting to smoke 11. Considering this theory, we will include YouTubers and influencers to send positive messages.
Since participants mentioned that chatting with people, who have already gone through tobacco use disorder to determine the negative consequences, had positive effects 12, we considered the Social Learning Theory to enhance the talent and ability of the user by asking him or her to make a correct decision.
When we explored mobile phone usage, the penetration of this device and the internet were both confirmed in different contexts. Although the three schools are located in towns with different levels of marginalization, the activities carried out by adolescents using this device did not differ. Therefore, at least for this population group, there are no technological gaps, since, regardless of whether they live in urban or rural areas, mobile phone usage is the same. This is consistent with Ferras et al. 20who claim that mobile phone usage seems to be resolving the lack of communication and isolation among adolescents living in rural contexts, which is also in line with what UNESCO stated in 2013, as regards the fact that an increasing number of people, including those from impoverished areas, own and use mobile devices 21.
The results showed that adolescents spend around eight hours a day using their mobile phones. On weekends, usage increases, and this may be a problem. However, several authors recognize that, due to the time intended for this device, mobile phones can be used as a tool for adolescents to engage in healthy behaviors, especially prevention of drug use 22 - 24.
Adolescents think that avatars they designed should be used to design our app and that the app should include chats to communicate with other young people. This is similar to the results obtained by Whittaker et al. 13, since according to these authors an application is attractive for adolescents if there is music for relaxation, interaction with others, and exposure to ‘real’ and ‘honest’ role models with credible stories and animations.
Young people stated that informational videos should include information on how tobacco damages health. This is consistent with a study carried out in 2017 by Park et al. 25who evaluated the effectiveness of videos made to prevent tobacco use.
Finally, adolescents feel more empathy and pleasure for game-type applications that provide them with features that encourage them to continue playing, such as abilities to improve avatar characteristics and to buy items on the internet. The same results were reported by Pope et al. 18who demonstrated that a game-type application needs to have rewards, competences, and accessibility to be attractive to young people.
The prototype design was based on a game with levels that help adolescents to stay active and enhance their skills. This game for health has been proven to help change user behavior 26 , 27, and it can even influence one’s values positively 28.
The BUS methodology allowed adolescents, as the target population, to be involved in the application design since the beginning of the process, because, as has been demonstrated, for an application to be successful, the end user must be considered in the design. The sketch technique allowed adolescents to exercise their creativity and increase their confidence when expressing their ideas about the app, achieving completely user-centered results.
Few apps are aimed at preventing tobacco use 8, including the Smokerface app. However, our ‘No le entres’ app is different, because in the initial conception Smokerface used the Mirroring 29approach, so end users were not involved. Most applications available on the market are aimed at treating it 30.
Within the MPOWER plan to reverse the smoking epidemic, MPOWER stresses that adolescents who receive effective messages through television are less likely to become smokers. Such a plan was elaborated in 2008, a time when mobile phone use was not as popular as it is today. Thus, it is believed that using mobile phones to deliver these messages could be as effective as television 31. Therefore, it is advisable for public health authorities to include in their traditional programs for adolescents to promote health, prevent diseases, and encourage the use of ICTs, since, as this study has shown, mobile phones are popular, and adolescents spend a substantial amount of time on them.
Limitations
Regarding limitations in this study, we mention that most participants were male, which possibly influenced the development of a war-type game. Another limitation was that we only applied the first two stages of the BUS model due to the resources available for the study. Therefore, it is important to continue to develop this app to evaluate its use and effect among adolescents; data on use frequency and the effectiveness of the theories of behavior change need to be obtained.
CONCLUSIONS
Guidelines for digital content design are provided to prevent tobacco consumption in the adolescent population. An important finding was that adolescents living in both urban and rural settings use mobile phones similarly. Thus, developing applications for this population group has a great potential to grow still further for m-Health strategies. Games for health can help modify user behavior and even positively influence their values. The final product was the prototype for the ‘No le entres’ (don’t jump in) application.
ACKNOWLEDGEMENTS
We thank Miguel Alejandro Cámara Arciga for helping us design the prototype. We also thank the education authorities of the three schools and students who took part in the focus groups.
CONFLICTS OF INTEREST
The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported.
FUNDING
This research received internal funding, in coordination with the Master’s in Public Health of the University of Veracruz.
PROVENANCE AND PEER REVIEW
Not commissioned; externally peer reviewed
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Chemopreventive effect of apple and berry fruits against colon cancer
Chemopreventive effect of apple and berry fruits against colon cancer
Citation of this article
Corresponding Author of This Article
Research Domain of This Article
Journal Information of This Article
Publication Name
World Journal of Gastroenterology
ISSN
1007-9327
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Chemopreventive effect of apple and berry fruits against colon cancer
Saravana Kumar Jaganathan, Muthu Vignesh Vellayappan, Gayathri Narasimhan, Eko Supriyanto, Dyah Ekashanti Octorina Dewi, Aqilah Leela T Narayanan, Arunpandian Balaji, Aruna Priyadarshini Subramanian, Mustafa Yusof
Saravana Kumar Jaganathan, Eko Supriyanto, Dyah Ekashanti Octorina Dewi, Aqilah Leela T Narayanan, Mustafa Yusof, IJN-UTM Cardiovascular Engineering Centre, Faculty of Bioscience and Medical Engineering, Universiti Teknologi Malaysia, Johor Bahru 81310, Malaysia
Muthu Vignesh Vellayappan, Arunpandian Balaji, Aruna Priyadarshini Subramanian, Department of Research and Development, PSNA College of Engineering and Technology, Kothandaraman Nagar, Tamil Nadu, Dindigul 624622, India
ORCID number: $[AuthorORCIDs]
Author contributions : Jaganathan SK designed the research; Jaganathan SK, Vellayappan MV, Narasimhan G, Balaji A and Subramanian AP collected the literature; Vellayappan MV and Narasimhan G wrote the review in consultation with Jaganathan SK; Narasimhan G, Supriyanto E, Octorina Dewi DE, Narayanan ALT, Arunpandian B and Subramanian AP participated in editing of manuscript by providing suggestions; Yusof M had checked the overall integrity of manuscript during revision by providing suggestions; all the authors verified the final manuscript.
Supported by (in part) Ministry of Higher Education Malaysia with the Grant Vot, No. R.J130000.7809.4F444 and the Ref No. PY/2014/03167; Part of the grant with the Vot, No. 04H93, Ministry of Education was also used for this study
Correspondence to
: Saravana Kumar Jaganathan, Senior Lecturer, IJN-UTM Cardiovascular Engineering Centre, Faculty of Bioscience and Medical Engineering, Universiti Teknologi Malaysia, Skudai, Johor Bahru 81310, Malaysia.
[email protected]
Telephone : +60-7-5558563 Fax: +60-7-5558553
Received: April 11, 2014 Revised: June 16, 2014 Accepted: August 13, 2014 Published online: December 7, 2014
Abstract
Colon cancer arises due to the conversion of precancerous polyps (benign) found in the inner lining of the colon. Prevention is better than cure, and this is very true with respect to colon cancer. Various epidemiologic studies have linked colorectal cancer with food intake. Apple and berry juices are widely consumed among various ethnicities because of their nutritious values. In this review article, chemopreventive effects of these fruit juices against colon cancer are discussed. Studies dealing with bioavailability, in vitroand in vivoeffects of apple and berry juices are emphasized in this article. A thorough literature survey indicated that various phenolic phytochemicals present in these fruit juices have the innate potential to inhibit colon cancer cell lines. This review proposes the need for more preclinical evidence for the effects of fruit juices against different colon cancer cells, and also strives to facilitate clinical studies using these juices in humans in large trials. The conclusion of the review is that these apple and berry juices will be possible candidates in the campaign against colon cancer.
Key Words: Apple , Berry , Chemoprevention , Colon cancer , Fruit juices , Phytochemicals
Core tip:Colon cancer is one of the leading causes of death worldwide. Chemoprevention of colon cancer using various dietary agents is an area of current interest. This manuscript reviews the chemopreventive potential of apple and berry juices against colon cancer. This work will further promote the importance of dietary fruit juices in colon cancer prevention.
Citation: Jaganathan SK, Vellayappan MV, Narasimhan G, Supriyanto E, Octorina Dewi DE, Narayanan ALT, Balaji A, Subramanian AP, Yusof M. Chemopreventive effect of apple and berry fruits against colon cancer. World J Gastroenterol 2014; 20(45): 17029-17036
URL: https://www.wjgnet.com/1007-9327/full/v20/i45/17029.htm
DOI: https://dx.doi.org/10.3748/wjg.v20.i45.17029
INTRODUCTION
Current statistics from the American Cancer Society indicate that in 2014, there will 1665540 new cancer cases in the United States and 585720 cancer deaths, corresponding to 1600 deaths per day. Colon cancer is the second most prevalent cause of cancer death in men and women after lung cancer. Recently, there has been tremendous growth in understanding the fundamentals of carcinogenesis leading to the new mode of cancer prevention known as “chemoprevention.” Chemoprevention is defined as the intake of foreign agents in order to restrain induction, to prevent or slow the progression of cancer, or reversal of carcinogenesis at a premalignant stage[1]. Chemoprevention makes use of either suitable pharmacologic or dietary agents that are consumed in various forms such as macronutrients, micronutrients, or nonnutritive phytochemicals[2]. Various dietary agents have been explored for their chemopreventive effects against cancers[3,4]. There is always an increasing interest for how these agents are linked with colon cancer, as unlike other cancer cells, colon cancer cells are exposed directly. Various epidemiologic studies demonstrated that the oral consumption of fruits and vegetables is inversely associated with the risk of cancer development[5]. In addition, fruits consumed in liquid form as juices also exhibit similar chemopreventive effects against colon cancer[6,7]. Digestive tract cancers, especially colon cancer, are amenable to dietary modification. Recent research works show that almost 75% of all the sporadic cases of colorectal cancer are directly affected by dietary intake. Thus, dietary modification is probably one of the best ways for alleviating the risk of developing colon cancer[8].
Apple and berry fruits have long been widely consumed by various ethnicities because of their beneficial values. Fruit juice intake is gaining in popularity among younger generations due to the comparative ease of consumption. Moreover, the quantity of fruit intake can also be incremented by the intake of juice. In addition to this, fruit juices are available in most retail stores and the various benefits of intake have encouraged many to consume them. The protective nature of fruits against colon cancer may be attributed to the presence of compounds such as dietary fiber, minerals, vitamins and phytochemicals[9]. Phytochemicals are biologically active non-nutrient components present in fruits that can be divided into alkaloids, carotenoids, polyphenols and other nitrogen-containing components[10]. The phytochemicals have a chemopreventive property due to their antioxidant activity viainactivation of reactive oxygen species, which plays a vital role in the initiation and progression of colon cancer[11]. Hence adequate intake of these phytochemicals may hinder cancer by enhanced DNA repair and thereby reduce the damage to DNA viaoxidative stress[12].
We recently reviewed the role of pomegranate and citrus juices in colon cancer prevention[4]. As a fair amount of research has been conducted using apple and berry juice phytochemicals as a chemopreventive agent against cancer, we chose to further delineate the chemopreventive effects of these juices against colon cancer as well. For this purpose, studies examining the effects of apple and berry juices in colon cancer cell lines and animal models, as well as their bioavailability, are discussed.
APPLE JUICE
The botanical name of the apple is Malus domestica. It is the one of the most commonly cultivated tree fruits. Apple juice is the consumable fluid or liquid that is obtained by crushing the apple. The apple juice contains various beneficial polyphenols such as hydroxycinnamic acids, flavan-3-ols/procyanidins, flavonols, dihydrochalcones, and anthocyanins (red peel).
Bioavailability and metabolism of apple juice in colon cancer
In order to determine the protective effect of apple juice on colon cancer, we first must understand the bioavailability of apple products. Research on determination of absorption in ileostomy patients by Feskanich et al[13] showed that nearly 67%-100% of apple phenolics were digested almost completely in the small intestine itself, while only 0%-33% reached the colon. These authors showed the level of metabolization of the polyphenolic components of the apple juice after digestion and absorption. Other studies have demonstrated the extensive cleavage, isomerization and conjugation of the native polyphenolic compounds occurring during the process. It was observed that 12.7% of the cloudy apple juice compounds get as far as the intestine, however, 22.3% of the apple juice compounds are recovered as metabolites. These studies shed light on the importance of the compounds in the metabolized apple products and indicate the need for the determination of the biologic activity of metabolites of the phytochemicals in vivo[13]. In general, only the native polyphenolic compounds are commonly tested, though they are subjected to substantial metabolic modification. Thus, under physiologic conditions of the tissues, the ingested polyphenolic compounds may be present in a very small quantity or absent. The ingested polyphenols are metabolized by colonic microflora. Hence, it is vital to examine the breakdown products produced at the stomach along with the various metabolites in the blood[13].
In vitro studies of apple juice using colon cancer cell lines
For the study of in vitroeffects of apple juice on cancer related processes, various experiments were conducted using cultured colonic cells and cancer-derived cell lines at different developmental stages. Schaefer et al[14] crushed and extracted apple juice to obtain several polyphenolic mixtures from cider and table apples harvested in Germany, including one extract from apple pomace. A comparison was made among four preparations differing in relative percentages of 14 phytochemicals in apple juice and their effects on oxidative markers in cell lines such as Caco-2 and HT29. HT29 is a well-developed cell line of colon adenocarcinoma and Caco-2 cells are from human colon cancer cells. It was found that all the extracts reduced the oxidative damage and the presence of butyl hydroperoxide-induced reactive oxygen species. Even though there is difference in the effectiveness observed in the different extract preparations, their efficacy against cancer is similar to the efficacy of phytochemicals identified in the apple juice. In addition, antioxidant capacity determined by Trolox equivalent antioxidant capacity differed for the various extracts with similar chemical compositions. This indicates that there are unknown compounds that account for the antioxidant effects in apple juice. Moreover, prolonged exposure of apple juice results in even greater antioxidant properties for some compounds. From this, it can be deduced that metabolic products obtained over time may have enhanced antioxidant capacity compared to the parent phytochemicals.
A recent study examined the effect of apple juice on cell proliferation. An experiment was done with MCF-7 cells, a breast cancer cell line, and HT29 cells for the study of effect of extracts of ten fruits, including apple peels[15]. Moreover, a proportion of anthocyanidin-rich parts of the fruit juices were tested. It was found that apple peel extract exhibited the property of significant dose reduction in HT29, but not MCF-7 cells; the MCF-7 cells were less responsive to extract exposure. Thus, there was a differential outcome in the inhibitory effect of anthocyanidin-rich fraction of apple juice in HT29 cells.
Gossé et al[16] conducted a study to determine whether polymeric or monomeric apple polyphenols are more effective in attenuating the proliferation of SW620 adenocarcinoma-derived metastatic colon cancer cells. This study revealed that larger polymeric molecules are absorbed in a higher segment of the intestine, which reduces their effectiveness in attenuating colon cancer. The absorbed polymeric molecules result in increased residual concentration in the colon. When the SW620 cells are incubated with the procyanidins (polymeric molecules), dose-dependent inhibition of cell growth was observed; 50% inhibition was observed at 45 mg/mL, and total inhibition at 70 mg/mL. Moreover, this extract induced downregulation of various signaling pathways involved in cell proliferation and differentiation, including protein kinase C (PKC), and enzymes involved in polyamine biosynthesis. The polyamines are regulators of cell function and have a significant impact on cancer vianurturing cell proliferation or cell death based on the cell type. Finally, flow cytometric experiments revealed that the apple extract increased the number of apoptotic cells and interrupted the cell cycle. In an extension of the above study, the procyanidins found in apple juice have dual effects of downregulating polyamine biosynthesis and stimulating the catabolism or breakdown of these compounds. In addition, the apoptotic effect of apple procyanidins is improved by a compound that disables the activity of polyamine oxidase. Hence, the authors concluded that apple procyanidins are a potential chemopreventive agent for treating colon cancer.
Some other works have described the molecular mechanisms and cell signaling response to apple juice exposure. A recent work by Kern et al[17] in 2007 showed that after 24-h exposure at a high concentration (403 mg/mL) of apple juice, PKC activity was decreased by 50% in HT29 cells. When the duration of exposure was longer, extracts in the apple juice targeted the signaling elements upstream of PKC. However, when each compound was segregated from the apple extract, they were ineffective in altering any of the markers under study. Thus, it may be concluded that only the composite mixture of the apple extracts are more important in mediating the observed effects due to the synergy or interaction between different compounds.
The effects of apple juice products on particular enzymes involved in colon carcinogenesis have also been studied. Cytochrome P450 1A1 is one of the most prominent enzymes responsible for activating the chemical carcinogens in the colon. In a study using Caco-2 cells, apple juice without or with reduced levels of acids, carbohydrates, and other native compounds induced the expression of cytochrome P450 1A1 as well as inhibited its catalytic activity. The major phenolics isolated from the apple juice, such as phlorizin, rutin, quercetin and their two glucoside forms, and phloretin, exhibited significant inhibition. It was found that the other types of enzymes relevant to cancer etiology also were favorably affected by apple products[18]. In a study, polyphenols were extracted from cider apple and a variety of juices. Moreover, an artificial mixture mimicking the natural polyphenolic profile was developed, and its effect on cultured HT29 cells was studied. Cells incubated with the apple juice extract for 24, 48, or 72 h had a decreased growth rate. Furthermore, inhibition of cell growth by the synthetic mixture was less efficient than the natural polyphenolic profile. The isolated components were less effective than both mixtures. Treatment with apple juice triggered an increase in the expression of some vital genes, which includes phase 2 enzymes. These enzymes are associated with chemoprevention (glutathione S-transferases and sulfotransferases). Even though more study is needed, it is intriguing that the apple products have the potential to alter the genetic profiles in a protective manner. All the observed results clearly show that individual isolated components are less effective than the complete mixture of the juice polyphenols.
In 2007, Veeriah et al[19] examined the effects of apple extracts fermented in vitrowith human fecal flora on cultured HT29 and LT97 cells. LT97 is a colon adenoma cell line representing the early stage of malignant tumor development. It was found that 99.9% of the parent polyphenols, with the exception of complex structures, were degraded due to fecal fermentation. Furthermore, the short-chain fatty acids (SCFA) increased 1.5-fold in the fermented samples compared to non-fermented samples. Even though a correlation between growth inhibition and SCFA was not assessed, it is known that SCFA stimulates apoptosis, differentiation, and growth arrest pathways. Hence, it can be concluded that the fermented apple juice extracts have an antiproliferative effect on both types of cells lines, especially LT97 cells.
In vivo effect of apple juice on colon cancer
To determine the impact of apple juice on colon cancer, Barth et al[20] utilized a rat model of chemically induced colonic damage (using 1,2-dimethylhydrazine). The rats were fed daily with two preparations of apple juice, a clear juice preparation and “cloudy” (higher content of pectin and procyanidin) preparation, obtained from a combination of apples, for seven weeks. The daily consumption of this apple juice protected the mucosa from colonic damage. As there is a possibility for the progression of early lesions into malignancies, the presence of hyperproliferative and aberrant crypts indicated the potential pathogenesis in this rat model. The two methods of apple juice preparation decreased the number of large aberrant crypt foci in the distal colon, DNA damage and hyperproliferation. The same authors further studied the effects of segregated fractions on the various markers and concluded that the juice in the original form has a better efficacy compared to the unique components, which include the polyphenolic-rich extracts[21]. The work done by Soyalan et al[22] demonstrated the potential of polyphenol-rich apple juices in stimulating the redox-sensitive gene expression in rats for colon cancer prevention. They also elucidated that the cloudy apple juice has better efficacy as a cancer chemopreventive agent compared to the clear apple juice and smoothie apple juice. In another independent experiment, Koch et al[23] explored the efficacy of apple juice in obese rats, and found no cancer preventive bioactivity. Although obesity and colon cancer formation are directly linked, they did not rule out the role of chemopreventive effects of apple juices and suggested future trials with obese or diabetic human individuals[23].
In another study, rats were injected with the chemical carcinogen azoxymethane, which results in various morphologic changes such as carcinoma. It was found that apple extracts given along with the animals’ drinking water for 6 wk had colon cancer protective effects[16]. Preneoplastic lesions in the rats fed with apple phytochemicals were reduced as result of apple intake. There were 50% fewer aberrant crypts observed compared to the non-fed group. The authors predicted that this effect is extendable to humans who are consuming two apples per day. This would provide a sufficient amount of procyanidin (4-10 mg/kg body weight) to attain similar results in humans.
BERRY JUICE
The botanical name of chokeberry is Aronia meloncarpaand that of bilberry is Vaccinium myrtillus. These fruits are grown in North America, Europe, Asia, and Africa. Anthocyanin-rich extracts (AREs) derived from berries are prepared by certain quantization methods to maximize pigment recovery. The berry extracts contain anthocyanin, β-carotene, a carotenoid and tangeretin, a flavonoid. Berry juices are prepared by crushing various berries and bottled for marketing.
Bioavailability and metabolism of berry juice in colon cancer
Anthocyanins in chokeberry extract pass into the large intestine and are degraded by bacteria. Detecting and measuring the trace levels of anthocyanins in urine, plasma, excretion and metabolism is very difficult[24]. Approximately 66% of anthocyanins derived from cyanidine-3-galactoside were detected in urine and serum samples of volunteers who consumed 20 g of chokeberry extract consisting of 1.3 g cyanidin-3-glycosides. Metabolites such as oxidized and methylated derivatives of cyanidin-3-galactoside, cyanidin glucuronide and glucuronide conjugates, were present at levels of 0.011 to 0.013 nmol/L in urine samples. The cumulative total serum concentration of anthocyanins and their metabolites was 591.7 nmol/L[25]. Wu et al[26] reported similar results, showing that cyanidine-3-galactoside accounted for 60.7% of the total anthocyanin-based compounds in the urinary excretion of chokeberry-fed pigs. The peak anthocyanin concentration of 2.9 nmol/L in plasma at 1 h and 18 min, including a total renal excretion of 0.02% of ingested anthocyanins over 24 h, which are metabolites of cyanidin, was observed in healthy volunteers as depicted by Wiczkowski et al[27] in 2010. As flavonols are present in very small quantities in chokeberry extracts, there is not much information on its bioavailability. However, a study with rats by Kida et al[28] in 2000 showed that the monomers of flavan-3-ol were eliminated in the liver from the bloodstream and returned to the small intestine. Flavan-3-ols are highly excreted in urine and recovered in ileal fluid from ileostomy patients[29]. Biosorption studies revealed that biologic uptake of anthocyanin extracts depends on the structure of anthocyanin. However, Koide et al[30] demonstrated that HCT-15 cancer cell growth inhibition was affected by various anthocyanin sources and glycosylation modifications. In addition, anthocyanins in bilberry extracts are non-acylated glucoside derivatives, but are cyanidin derivatives in chokeberry extracts.
In vitro studies of berry juice using colon cancer cell lines
Growth of human intestinal carcinoma HCT-15 cells in vitrowas inhibited efficaciously by anthocyanin fractions extracted from different cherry and berry extracts in comparison to that of flavonoid fractions[31]. Berry extracts including cowberry, strawberry, blueberry, and bilberry extracts that contain anthocyanins inhibited the growth of HCT-116 colon cancer cells[32]. Growth of HT29 and HCT-116 cell lines were also inhibited by tart cherry anthocyanins and their aglycon, cyanidin[33]. Cyanidin-3-galactoside is the predominant anthocyanin in commercialized chokeberry ARE that is available as a mixture of phenolic compounds. Chokeberry AREs rendered 65% growth inhibition and cell viability of HT29 cells within 24 h of exposure, suggesting a cytostatic inhibition. In the presence of the chokeberry extract, NCM460 cells, which are epithelial cells from normal colon, were found to grow normally[34].
Cell cycle progression is regulated by the interaction between cyclins and cyclin-dependent kinases (CDKs). Cyclin-dependent kinase inhibitors (CDKIs) negatively regulate the activity of CDKs and play an important role in controlling cell cycle progression. CDKIs, such as p21WAF1 and p27KIP1, bind to cyclin-CDK complexes and halt the G1 phase of the cell cycle. HT29 cell percentage after exposure to chokeberry was increased, and a block in the cell cycle checkpoint in the G1/G0 phase was observed[35]. Depending on the time of exposure to AREs, an increase in p21WAF1 and p27KIP1 gene expression was in agreement with ARE-induced G1/G0 cell cycle arrest. Phytochemicals, such as β-carotene and tangeretin, mediate cell cycle arrest in colon cancer cells by upregulating the expression of p27KIP1 and p21WAF1, which can block the cell cycle by inhibiting both G1 and G2-phase cyclin-CDK complexes[35]. Although blocking of cell cycle at both G1/G0 and G2/M phases after exposure of HT29 cells to chokeberry AREs was demonstrated, chokeberry AREs neither affected the cell cycle nor altered the expression of cell cycle genes in normal colon cells. This evidence supports the notion that AREs prevent cancer cell growth through the inhibition of cell cycle events.
Cyclooxygenase (COX) enzymes are involved in prostaglandin formation through the catalysis of arachidonic acid oxygenation. Carcinomas and colorectal adenomas show an increase in COX-2 mRNA compared to normal mucosa[36]. COX-2 is also upregulated or induced in response to inflammation, whereas COX-1 is expressed in all body tissues and performs a “housekeeping” role. In the NCM460 cell line, derived from normal colon mucosa, expression of COX-2is low in comparison to the constitutively expressed COX-1. In contrast, high expression of COX-2is seen in HT29 cells. Hence, chemoprevention of colon cancer is possible by inhibiting COXgenes. A plausible method is to use non-steroidal anti-inflammatory drugs to inhibit the COX-2 enzyme, thereby delaying or preventing cancer of the colon. Recent studies revealed that anthocyanin fractions isolated from various berries show an inhibitory effect on COX enzyme activities in vitro[37]. Seeram et al[37] demonstrated that COX-1 and COX-2 enzymes were inactivated by cyanidin-3-rutinoside and cyanidin-3-glucosylrutinoside anthocyanins extracted from sweet cherries and raspberries. The basal level of COX-2 mRNA after exposure to chokeberry ARE was not altered in NCM460 cells. In contrast, the levels of COX-2 mRNA derived from colon adenocarcinoma were high. It is supposed that the difference in growth response of the two cell lines after exposure to chokeberry extracts may be through a COX-dependent mechanism, as evidenced by the variable expression levels of COX enzymes. However, further experimentation revealed that with an increase in chokeberry extract exposure time, there was an increase in COX-2expression levels in HT29 cells. The cells treated with ARE showed an increase in COX-2 protein and prostaglandin E2, indicating that growth inhibition was not ascribed to COX-2 inhibition. HT29 cell growth inhibition after exposure to chokeberry AREs is not mediated through the suppression of COX-2 activity, though the activity of COX enzymes was inhibited by anthocyanins in vitro. It may be a COX-independent growth inhibition. A COX-independent effect in growth was also observed in colorectal cancer cells treated with celecoxib[37]. Furthermore, the mechanism of growth inhibition may involve the NF-κB pathway inhibition, peroxisome proliferator-activated receptors, or expression of the cell cycle genes[38]. Thus, it can be concluded that chokeberry AREs upregulated p21WAF1 and p27KIP1 and downregulated cyclin A and cyclin B1 to inhibit colon carcinoma cell growth, with very limited effects on the growth of normal colon cells. This ensures that AREs can be used for treating human colorectal cancers without affecting normal cells significantly.
In vivo effect of berry juice on colon cancer
Hagiwara et al[33] demonstrated that rats fed with purple corn color extract, which is rich in anthocyanin, showed a decrease in the prevalence of aberrant crypt foci and early colon cancer lesions. This experiment demonstrates that 2-amino-1-methyl-6-phenylimidazol(4,5- b) pyridine-induced colon carcinogenesis was abated by anthocyanin-rich fractions[33]. In another report, oral administration of lyophilized black raspberries containing anthocyanins to rodents produced inhibitory effects on colorectal cancer and/or polyp tissue. In addition, biomarkers of proliferation and angiogenesis were significantly reduced by the berry treatment, while apoptosis was greatly enhanced[39].
Mirtocyan is an anthocyanin-rich standardized bilberry extract. It causes pharmacodynamic changes commensurate with colorectal cancer chemopreventive efficacy and generates measurable anthocyanin levels in urine, blood and target tissues. Low doses of mirtocyan showed a significant reduction in the levels of circulating insulin-like growth factor-1, which possesses a procarcinogenic property[40]. Hence, further studies on the pharmacodynamic effects of bilberry anthocyanins at various doses are essential to demonstrate them as potential colorectal cancer chemopreventive agents.
CONCLUSION
The objectives of this review were to document the chemopreventive effects of apple and berry fruit juices against colon cancer and to discuss preclinical and clinical effects of these juices. Furthermore, bioavailability and metabolism of these fruit extracts were highlighted. Summaries of in vitroand in vivostudies of apple and berry juice against colon cancer represented in Tables1and2, respectively.
Table 1 In vitro and in vivo effects of apple extracts against colon cancer.
Apple juice and its Components Models (cell line/animal) Observation/result Ref. Apple extracts HT29 and LT97 colon adenoma cell line SCFA increased 1.5 fold in fermented samples [19] SCFA stimulates apoptosis, differentiation and growth arrest Composite mixture of apple extracts HT29 cells PKC activity was decreased by 50% after 24 h exposure of 403 mg/mL [17] Upstream signaling elements targeted after longer duration of exposure Polyphenolic mixtures from cider, table apples and apple pomace; Phenolics such as phlorizin, rutin, quercetin and phloretin Caco-2 cells and HT29 colonic cell lines Reduced oxidative damage [14] Reduced the presence of butyl hydroperoxide-induced ROS Caco-2 cells Induction of p450 1A1 expression and inhibition of catalytic activity of the enzyme Anthocyanidin-rich fraction of apple juice HT29 and MCF-7 breast cancer cell line Significant dose reduction in HT29 cells and not in MCF-7 cells [15] MCF-7 cells are less responsive to extract exposure Procyanidins of apple juice (polymeric polyphenols) SW620 adenocarcinoma-derived metastatic cells of colon cancer Dose-dependent inhibition of cell growth [16] 50% of inhibition at 45 mg/mL and total inhibition at 70 mg/mL Downregulation of signaling pathway such as cell proliferation and differentiation, PKC and enzymes involved in polyamine biosynthesis and stimulation of catabolism Increased number of apoptotic cells and interruption in cell cycle Apple phytochemicals Rats injected with azoxymethane Reduction in preneoplastic lesions and 50% fewer aberrant crypts Apple juice extract; Synthetic mixture, isolated components HT29 cells Decreased growth rate efficiently for 24, 48 and 72 h [18] Increased the expression of genes which include phase-2 enzymes, including glutathone-s-transferases and sulfotransferases, which are involved in chemoprevention Growth rate inhibition was less efficient comparatively Lesser effectiveness than either mixture Two preparation methods of apple juice: clear and cloudy (higher content of pectin and procyanidin) Rat model (induced with 1,2-dimethylhydrazine) Protection from dimethylhydrazine-induced genotoxic damage [20] Important markers were reduced including decreased number of large aberrant crypt foci in the distal colon, reduced DNA damage and reduced hyper-proliferation Polyphenolic-rich extracts Rat model (induced with 1,2-dimethylhydrazine) Juice fractions were found to be more effective in protecting from damage compared to isolated fractions [21]
PKC: Protein kinase C; ROS: Reactive oxygen species; SCFA: Short-chain fatty acids.
Table 2 In vitro and in vivo effects of berry extracts against colon cancer.
Berry juice and its Components Models (cell line/animal) Observation/result Ref. Anthocyanin fractions of berry juice HCT-15 cells Inhibited growth of human intestinal carcinoma cells [31,33] HCT-116 cells Inhibited the growth of colon cancer cells Chokeberry ARE HT29 cells Percentage of cells increased and blockade in G1/G0 phase of cell cycle [32,33] Increased expression of p21WAF1 and p27KIP1 genes Decreased percentage of cells in S phase indicating that cells moved to G2/M phase [35] Predominant anthocyanin: cyanidin-3-galactoside HT29 cells 65% growth inhibition after 24 h exposure [34] High cell viability observed indicating cytostatic inhibition Inactivation of COX-1 and COX-2 enzymes Anthocyanins (cyanidin-3-glucosylrutinoside and cyanidin-3-rutinoside) HT29 cells Growth inhibition of cells may occur in a COX-independent manner [37] Phytochemicals of berry juice; Carotenoid (β-carotene) and flavonoid (tangeritin) HT29 cells Upregulation of p21WAF1 and p27KIP1 expression [35] p21WAF1 CDKI blocks G1 and G2 phase cyclin-CDK complexes Anthocyanin-rich purple corn color of berry juice Rats injected with PhIP Decrease in incidence of early colon cancer lesions, decrease in aberrant crypt foci and a protective effect against PhIP-induced colon carcinogenesis [33] Anthocyanin-rich black raspberries Rodents with colorectal cancer/polyp tissue Biomarkers of proliferation and angiogenesis were significantly reduced while apoptosis of cancer cells was enhanced Mirtocyan of bilberry extract Patients with colorectal adenocarcinoma and colorectal liver metastases Significant reduction in IGF-1 levels thereby reducing carcinogenesis [40]
ARE: Anthocyanin-rich extract; CDK: Cyclin-dependent kinase; CDKI: CDK inhibitor; COX: Cyclooxygenase; IGF-1: Insulin-like growth factor-1; PhIP: 2-amino-1-methyl-6-phenylimidazol(4,5-b) pyridine.
This review justifies the need for additional preclinical studies with these juices and extracts. In order to bolster the anticancer effect of these juices/extracts against colon cancer in vitro, experiments using additional cell lines are crucial. Further, in vivostudies using Apc Min/+mouse models may provide some valuable insights about the mechanism of action of these juices. The purpose of this work is to highlight the importance of establishing clinical trials in human subjects. It will be noteworthy to perform clinical trials in patients with colon cancer, in which the effects produced by the oral consumption of these fruit juices can be outlined. For instance, colorectal cancer patients must be administered a measured quantity of fruit juices on a regular basis for a specific duration of time. Then, chemopreventive effects produced by these fruit juices against colon cancer may be documented. Hence, conducting human clinical trials may validate the potency of these fruit juices in the fight against colon cancer.
ACKNOWLEDGMENTS
Authors acknowledge University Industry Research Laboratory (UPMU) of UTM for their support.
Footnotes
P- Reviewer: Paydas S, Pessi T S- Editor: Qi Y L- Editor: AmEditor E- Editor: Wang CH
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Furosemide Use to Fill the Bladder of Pediatric Females Awaiting Pelvic Ultrasound - Full Text View - ClinicalTrials.gov
Furosemide Use to Fill the Bladder of Pediatric Females Awaiting Pelvic Ultrasound
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ClinicalTrials.gov Identifier: NCT05098366 Recruitment Status :
Recruiting First Posted : October 28, 2021 Last Update Posted : May 12, 2023 See Contacts and Locations
Sponsor:
Connecticut Children's Medical Center
Candice Jersey, Connecticut Children's Medical Center
Study Details
Study Description
Brief Summary:
The purpose of this study is to investigate whether or not furosemide causes the bladder to fill faster than IV fluids alone so that a pelvic ultrasound exam can be performed.
Condition or disease Intervention/treatment Phase Ovarian Torsion Drug: Furosemide Drug: Normal saline Early Phase 1
Detailed Description:
Trans-abdominal pelvic ultrasound is the standard imaging modality for diagnosis of ovarian torsion in the pediatric population, however this requires that the patient have a full bladder at the time of imaging. This study will investigate whether low dose furosemide in addition to IV fluid boluses may provide a fast, effective, and non-invasive means to fill the bladder of pediatric females awaiting pelvic US. The target population are females age 8 to 18 years seen in the emergency room at Connecticut Children's Medical Center who are undergoing a trans-abdominal pelvic ultrasound to assess for ovarian torsion. Enrolled patients will be randomized to the control (IVF bolus only) group vs. the intervention (IVF bolus + furosemide) group and will undergo point-of-care US (POCUS) and bladder scanner evaluation of the bladder every 30 minutes until the bladder is determined to be full.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Estimated Enrollment : 100 participants Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Randomized controlled trial Masking: Single (Participant) Primary Purpose: Diagnostic Official Title: Utilization of Furosemide to Expedite Bladder Filling in Pediatric Females With Suspected Ovarian Torsion Awaiting Pelvic Ultrasound Actual Study Start Date : May 29, 2021 Estimated Primary Completion Date : April 2024 Estimated Study Completion Date : April 2024
U.S. FDA Resources
Arms and Interventions
Arm Intervention/treatment Experimental: Furosemide Participants will receive a 20mL/kg (max 1000mL) IV fluid bolus and a 0.1mg/kg (max 5mg) furosemide dose Drug: Furosemide 0.1mg/kg (max 5mg) of IV furosemide Other Name: Lasix Placebo Comparator: IV fluids Participants will receive a 20mL/kg (max 1000mL) IV fluid bolus and an IV fluid flush Drug: Normal saline 20mL/kg (max 1000mL) normal saline bolus plus a normal saline flush Other Names: Intravenous fluids IV fluids
Outcome Measures
Primary Outcome Measures
:
The time from initiation of the intervention to the time that the bladder reaches large, ovoid shape on POCUS exam [ Time Frame: Through study completion, about 3 hours ]
Initiation of the intervention is defined as administration of furosemide vs. normal saline flush.
Secondary Outcome Measures
:
The correlation between bladder volume as calculated on POCUS exam of a large, ovoid bladder and bladder volume as reported by bladder scanner [ Time Frame: Through study completion, about 3 hours ]
Measurements will be completed every 30 minutes through study completion
Number and nature of all reports of adverse events related to furosemide administration [ Time Frame: From time of intervention until final disposition, about 6 hours ]
Adverse events include signs of severe dehydration, allergic reaction, and electrolyte abnormality
The time from initiation of the intervention to the time of completion of successful radiology-performed pelvic US [ Time Frame: About 3 hours ]
The time from initiation of intervention to the time of admission or discharge order placement [ Time Frame: From time of intervention until final disposition, about 6 hours ]
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Layout table for eligibility information Ages Eligible for Study: 8 Years to 18 Years (Child, Adult) Sexes Eligible for Study: Female Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Females age 8-18yrs seen in the ED at CCMC who are undergoing a trans-abdominal pelvic ultrasound to assess for ovarian torsion
Ability of patient (if 18yrs) or parent/legal guardian to sign a written informed consent
Exclusion Criteria:
History of renal, genitourinary, or pelvic anomalies
a. Eg: Chronic kidney disease, anuria, vesicoureteral reflux, ureteral obstruction, urologic reconstructive surgery, suprapubic or pelvic surgery, indwelling urethral catheter, oophorectomy, bicornate uterus
Patients with multiple chronic illnesses or systemic neurologic abnormality
a. Eg: Bronchopulmonary dysplasia, tracheostomy, gastrostomy tube dependence, cerebral palsy, severe developmental delay, mitochondrial disorder, congenital heart disease, cardiomyopathy, chronic kidney disease, diabetes
Patients with known pregnancy
Patients deemed to be critically ill
a. Mental status changes, signs of end organ damage, hypotension
Contraindication to giving Furosemide
a. Allergy to sulfonamide medications, severe dehydration, hypotension, underlying electrolyte abnormality, underlying renal disease
History of previous diuretic use within the past year
Patients who self-report their bladder as being full at the time of enrollment
Contacts and Locations
Information from the National Library of Medicine
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05098366
Contacts
Layout table for location contacts Contact: Candice Jersey, D.O. (860) 837-5596 [email protected] Contact: Lynn-Ann Sorbol (860) 837-5596
Locations
Layout table for location information United States, Connecticut Connecticut Children's Medical Center Recruiting Hartford, Connecticut, United States, 06106 Principal Investigator: Candice Jersey, D.O. Sub-Investigator: Henry Chicaiza, M.D. Sub-Investigator: Andrew Heggland, M.D.
Sponsors and Collaborators
Connecticut Children's Medical Center
Investigators
Layout table for investigator information Principal Investigator: Candice Jersey, D.O. Connecticut Children's Medical Center
Publications of Results:
Prieto JM, Kling KM, Ignacio RC, Bickler SW, Fairbanks TJ, Saenz NC, Nicholson SI, Lazar DA. Premenarchal patients present differently: A twist on the typical patient presenting with ovarian torsion. J Pediatr Surg. 2019 Dec;54(12):2614-2616. doi: 10.1016/j.jpedsurg.2019.08.020. Epub 2019 Aug 30.
Guthrie BD, Adler MD, Powell EC. Incidence and trends of pediatric ovarian torsion hospitalizations in the United States, 2000-2006. Pediatrics. 2010 Mar;125(3):532-8. doi: 10.1542/peds.2009-1360. Epub 2010 Feb 1.
Childress KJ, Dietrich JE. Pediatric Ovarian Torsion. Surg Clin North Am. 2017 Feb;97(1):209-221. doi: 10.1016/j.suc.2016.08.008.
Naffaa L, Deshmukh T, Tumu S, Johnson C, Boyd KP, Meyers AB. Imaging of Acute Pelvic Pain in Girls: Ovarian Torsion and Beyond☆. Curr Probl Diagn Radiol. 2017 Jul-Aug;46(4):317-329. doi: 10.1067/j.cpradiol.2016.12.010. Epub 2016 Dec 21.
Karaman E, Beger B, Cetin O, Melek M, Karaman Y. Ovarian Torsion in the Normal Ovary: A Diagnostic Challenge in Postmenarchal Adolescent Girls in the Emergency Department. Med Sci Monit. 2017 Mar 15;23:1312-1316. doi: 10.12659/msm.902099.
Dessie A, Steele D, Liu AR, Amanullah S, Constantine E. Point-of-Care Ultrasound Assessment of Bladder Fullness for Female Patients Awaiting Radiology-Performed Transabdominal Pelvic Ultrasound in a Pediatric Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2018 Nov;72(5):571-580. doi: 10.1016/j.annemergmed.2018.04.010. Epub 2018 Jul 3.
Stranzinger E, Strouse PJ. Ultrasound of the pediatric female pelvis. Semin Ultrasound CT MR. 2008 Apr;29(2):98-113. doi: 10.1053/j.sult.2007.12.002.
Guerra LA, Keays MA, Purser MJ, Wang SY, Leonard MP. Pediatric cystogram: Are we considering age-adjusted bladder capacity? Can Urol Assoc J. 2018 Dec;12(12):378-381. doi: 10.5489/cuaj.5263.
Koff SA. Estimating bladder capacity in children. Urology. 1983 Mar;21(3):248. doi: 10.1016/0090-4295(83)90079-1. No abstract available.
Ross M, Selby S, Poonai N, Liu H, Minoosepehr S, Boag G, Eccles R, Thompson G. The Effect of a Full Bladder on Proportions of Diagnostic Ultrasound Studies in Children with Suspected Appendicitis. CJEM. 2016 Nov;18(6):414-419. doi: 10.1017/cem.2016.23. Epub 2016 Apr 4.
Shapira-Zaltsberg G, Fleming NA, Karwowska A, Trejo MEP, Guillot G, Miller E. Non-visualization of the ovaries on pediatric transabdominal ultrasound with a non-distended bladder: Can adnexal torsion be excluded? Pediatr Radiol. 2019 Sep;49(10):1313-1319. doi: 10.1007/s00247-019-04460-y. Epub 2019 Jul 9.
Ljungberg A, Segelsjo M, Dahlman P, Helenius M, Magnusson M, Magnusson A. Comparison of quality of urinary bladder filling in CT urography with different doses of furosemide in the work-up of patients with macroscopic hematuria. Radiography (Lond). 2021 Feb;27(1):136-141. doi: 10.1016/j.radi.2020.07.002. Epub 2020 Jul 26.
Helenius M, Segelsjo M, Dahlman P, et al. Comparison of four different preparation protocols to achieve bladder distension in patients with gross haematuria undergoing CT urography. Radiography 2012;18:206-11.
Van Der Molen AJ, Cowan NC, Mueller-Lisse UG, Nolte-Ernsting CC, Takahashi S, Cohan RH; CT Urography Working Group of the European Society of Urogenital Radiology (ESUR). CT urography: definition, indications and techniques. A guideline for clinical practice. Eur Radiol. 2008 Jan;18(1):4-17. doi: 10.1007/s00330-007-0792-x. Epub 2007 Nov 1.
Eades SK, Christensen ML. The clinical pharmacology of loop diuretics in the pediatric patient. Pediatr Nephrol. 1998 Sep;12(7):603-16. doi: 10.1007/s004670050514.
Oh SW, Han SY. Loop Diuretics in Clinical Practice. Electrolyte Blood Press. 2015 Jun;13(1):17-21. doi: 10.5049/EBP.2015.13.1.17. Epub 2015 Jun 30.
Layout table for additonal information Responsible Party: Candice Jersey, Pediatric Emergency Medicine Fellow, Connecticut Children's Medical Center ClinicalTrials.gov Identifier: NCT05098366 History of Changes Other Study ID Numbers: 21-008 First Posted: October 28, 2021 Key Record Dates Last Update Posted: May 12, 2023 Last Verified: May 2023 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: Undecided
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Product Manufactured in and Exported from the U.S.: No
Keywords provided by Candice Jersey, Connecticut Children's Medical Center:
Pediatric Point-of-care Ultrasound Bladder volume
Layout table for MeSH terms Ovarian Torsion Ovarian Diseases Adnexal Diseases Genital Diseases, Female Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases Genital Diseases Gonadal Disorders Endocrine System Diseases Torsion Abnormality Pathological Conditions, Anatomical Furosemide Diuretics Natriuretic Agents Physiological Effects of Drugs Sodium Potassium Chloride Symporter Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action
For Patients and Families
For Researchers
| https://clinicaltrials.gov/ct2/show/NCT05098366 |
What's causing this man's pruritic rash? | Consultant360
A 40-year-old East Indian man presented with a chronic, recurrent, erythematous rash limited to the inguinal and axillary areas for the past 3 years.
Psoriasis
What's causing this man's pruritic rash?
A 40-year-old East Indian man presented with a chronic, recurrent, erythematous rash limited to the inguinal and axillary areas for the past 3 years. The rash was pruritic and at times slightly macerated, and there was no scaling. He treated himself with some over-the-counter medications recommended by his pharmacist, but it was of minimal benefit. Medical history was significant for diabetes mellitus. He did not consume alcohol or smoke. His 65-year-old father had psoriasis.
PHYSICAL EXAMINATION
On examination, there were well-demarcated, thin erythematous plaques in the inguinal and axillary regions. The skin surface was smooth, atrophic, non-scaly, and slightly shiny. He also had pitting of the fingernails. The rest of the physical examination was unremarkable.
What's Your Diagnosis?
A.Extra-mammary Paget diseaseB. Fungal intertrigoC.Glucagonoma syndromeD.Inverse psoriasisE.Langerhans cell histiocytosisF.Seborrheic dermatitis
(Answer and discussion on next page)
Answer: Inverse Psoriasis
Diagnosis of inverse psoriasis is usually clinical, based on the characteristic features, and family history of psoriasis and typical psoriatic lesions in other areas may aid in the diagnosis. A mycologic examination of skin scraping using potassium hydroxide may at times be necessary to differentiate it from fungal intertrigo. A skin biopsy should be considered if the diagnosis is in doubt. In this case, the patient’s presentation was consistent with histological findings of inverse psoriasis, also known as flexural or intertriginous psoriasis.
An anatomic variant of psoriasis, “inverse psoriasis” is characterized by the involvement of skin-fold areas such as the inguinal folds, axillary folds, inframammary folds, retroauricular area, and gluteal cleft rather than the more common psoriatic involvement of the trunk, extensor surfaces of the extremities, and scalp. 1Histologic examination of a classic lesion shows confluent parakeratosis with a loss of the granular layer, epidermal hyperplasia, elongation of rete ridges with thinning of the suprapapillary plates, and dilated capillaries in the dermal papillae with perivascular lymphocytic infiltration. 2,3Munro microabscesses (intracorneal deposits of neutrophils) and Kogoj micropustules (neutrophil deposits in the stratum spinosum), if present, are diagnostic. 2
EPIDEMIOLOGY
Estimates of prevalence of psoriasis range from 1% to 2%. 2Inverse psoriasis presents in 3% to 7% of psoriatic patients. 1,4The condition most commonly manifests between 15 and 30 years of age. 3Both sexes are affected equally. 3The condition is more common in Caucasian individuals than in black or Asian individuals. 2The prevalence is greatest in northern, colder climates, and the disease is often more severe in the colder months. A family history of psoriasis in a first-degree relative is present in about 30% of patients with childhood-onset psoriasis. 5The concordance rate in monozygotic twins is approximately 70%, compared with 20% in dizygotic twins. 5
ETIOPATHOGENESIS
Like plaque-type psoriasis, inverse psoriasis is characterized by hyperproliferation of epidermal keratinocytes and hyperkeratosis as well as a lymphocytic infiltration that consists mainly of T lymphocytes. Activation of T lymphocytes, migration of T lymphocytes to the skin, and T lymphocyte-mediated production of cytokines such as interferon gamma, interleukin-2 (IL-2), and tumor necrosis-factor alpha (TNF-alpha) are important in the pathogenesis. 5Interferon gamma inhibits apoptosis of keratinocytes, IL-2 stimulates growth of T lymphocytes, and TFN-alpha increases proliferation of proinflammatory cytokines and adhesion molecules. The adhesion molecules further stimulate T lymphocytes to produce cytokines. Psoriasis is associated with various histocompatibility antigens, especially HLA-Cw6. Predisposing factors include the use of chloroquine, lithium, or beta blockers, withdrawal of corticosteroid in a susceptible individual, emotional stress, alcohol or tobacco consumption, trauma (Köebner phenomenon), friction, obesity, and infection. 2,3,5,6
CLINICAL MANIFESTATIONS
Inverse psoriasis is characterized by smooth, sharply demarcated erythematous plaques with minimal or no scales. 3In contrast to the common plaque form, the lesion tends to be shiny and moist due to the ambient humidity of the inverse location. 2The lesions are usually symmetrically distributed. Some lesions may also have fissures, maceration, and rhagades. They often itch, sting, and/or burn. 3,4Typically, inverse psoriasis affects the skin-fold areas such as the inguinal folds, axillary folds, inframammary folds,genital folds, retroauricular area, and gluteal cleft. 4
Inverse psoriasis has a significant negative impact on the quality of life. The lesions are cosmetically unsightly and socially embarrassing for some patients and can cause emotional distress in more severely affected individuals. 2This form of psoriasis is more prone to maceration and secondary bacterial and/or fungal infection.
TREATMENT
Precipitating and exacerbating factors should be minimized or avoided. Optimal skincare requires constant attention to hydration and lubrication, and efforts to minimize itching. Low- to mid-potency topical corticosteroids are the first-line, short-term treatment of choice. 7Local adverse effects such as skin atrophy, striae, and telangiectasia, occur with increased frequency which prevent the prolonged use of topical corticosteroids in the skin-fold areas. 7Topical medications such as, calcipotriol or calcipotriene, and immunomodulators such as tacrolimus and pimecrolimus, while more expensive and not as rapid or efficacious as topical corticosteroids, are associated with fewer adverse effects and are recommended in the maintenance phase of treatment. 1,2,5,7Application of irritant topical agents should be avoided. Narrowband UVB phototherapy or photochemotherapy psoralen UVA, either alone or in combination with other topical remedies, should be considered for widespread or severe psoriasis. 2,4,5Systemic treatment is usually reserved for moderate to severe and generalized forms of psoriasis that are resistant to other therapies. 5Combination, sequential, or rotational systemic therapy, with methotrexate, acitretin, or cyclosporine, can achieve additive or synergistic efficacy at lower dosages and with less risk of adverse events. 2,5Medications such as adalimumab, apremilast, etanercept, infliximab, and ustekinumab which block molecular steps in the pathogenesis, have less potential for side effects but are more expensive. 1,2Preliminary studies have shown some efficacy of botulinum toxin A in the treatment of inverse psoriasis 6,8; further large-scale studies are necessary to confirm their findings.
OUTCOME OF THE CASE
Upon diagnosis by his dermatologist, the patient was treated with betamethasone valerate 0.1% cream nightly for 1 week, followed by topical tacrolimus 0.1% twice per week indefinitely. This treatment cleared up his psoriasis and resolved the associated itch, and appeared to keep the psoriasis at bay. ■
Alexander K.C. Leung, MD , is clinical professor of pediatrics at the University of Calgary and pediatric consultant at the Alberta Children’s Hospital in Calgary, Alberta, Canada.
References:
1. Jese R, Perdan-Pirkmajer K, Dolenc-Voljc M, Tomsic, M. A case of inverse psoriasis successfully treated with adalimumab. Acta Dermatovenerol. 2014;23(1):21-23.
2. Syed ZU, Khachemoune A. Inverse psoriasis: case presentation and review. Am J Clin Dermatol.2011;12(2):143-146.
3. Chen JF, Liu YC, Wang WM. Dermcase. Can you identify this condition? Inverse psoriasis. Can Fam Physician.2011;57(8):901, 903-904.
4. Wang G, Li C, Gao T, Liu, Y. Clinical analysis of 48 cases of inverse psoriasis: a hospital-based study. Eur J Dermatol.2005;15(3):176-178.
5. Leung AK, Robson WL. Psoriasis. In: Lang F, ed. The Encyclopedia of Molecular Mechanisms of Disease. Berlin, Germany: Springer-Verelag; 2009:1750-1751.
6. Zanchi M, Favot F, Bizzarini M, et al. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol.2008;22(4):431-436.
7. Kalb RE, Bagel J, Korman NJ, et al. Treatment of intertriginous psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol.2009;60(1):120-124.
8. Saber M, Brassard D, Benohanian A. Inverse psoriasis and hyperhidrosis of the axillae responding to botulinum toxin type A. Arch Dermatol.2011;147(5):629-630.
| https://www.consultant360.com/articles/whats-causing-mans-pruritic-rash?page=1%3FID=8pat&page=3%3FID=8pat |
Machines | Free Full-Text | Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms
The systematic kinematic analysis method for planar link mechanisms based on their unique procedures can clearly show the analysis process. The analysis procedure is expressed by a combination of many kinds of conversion functions proposed as the minimum calculation units for analyzing a part of the mechanism. When it is desired to perform this systematic kinematics analysis for a specific linkage mechanism, expert researchers can accomplish the analysis by searching for the procedure by themselves, however, it is difficult for non-expert users to find the procedure. This paper proposes the automatic procedure extraction algorithm for the systematic kinematic analysis of closed-loop planar link mechanisms. By limiting the types of conversion functions to only geometric calculations that are related to the two-link chain, the analysis procedure can be represented by only one type transformation function, and the procedure extraction algorithm can be described as a algorithm searching computable 2-link chain. The configuration of mechanism is described as the “LJ-matrix”, which shows the relationship of connections between links with pairs. The algorithm consists of four sub-processes, namely, “LJ-matrix generator”, “Solver process”, “Add-link process”, and “Over-constraint resolver”. Inputting the sketch of the mechanism into the proposed algorithm, it automatically extracts unique analysis procedure and generate a kinematic analysis program as a MATLAB code based on it. Several mechanisms are analyzed as examples to show the usefulness of the proposed method.
Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms
by Tatsuya Yamamoto * , Nobuyuki Iwatsuki and Ikuma Ikeda
Department of Mechanical Engineering, School of Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Author to whom correspondence should be addressed.
Machines 2020 , 8 (3), 41; https://doi.org/10.3390/machines8030041
Received: 30 April 2020 / Revised: 25 June 2020 / Accepted: 26 June 2020 / Published: 23 July 2020
(This article belongs to the Special Issue Selected Papers from Advances of Japanese Machine Design )
Abstract
The systematic kinematic analysis method for planar link mechanisms based on their unique procedures can clearly show the analysis process. The analysis procedure is expressed by a combination of many kinds of conversion functions proposed as the minimum calculation units for analyzing a part of the mechanism. When it is desired to perform this systematic kinematics analysis for a specific linkage mechanism, expert researchers can accomplish the analysis by searching for the procedure by themselves, however, it is difficult for non-expert users to find the procedure. This paper proposes the automatic procedure extraction algorithm for the systematic kinematic analysis of closed-loop planar link mechanisms. By limiting the types of conversion functions to only geometric calculations that are related to the two-link chain, the analysis procedure can be represented by only one type transformation function, and the procedure extraction algorithm can be described as a algorithm searching computable 2-link chain. The configuration of mechanism is described as the “LJ-matrix”, which shows the relationship of connections between links with pairs. The algorithm consists of four sub-processes, namely, “LJ-matrix generator”, “Solver process”, “Add-link process”, and “Over-constraint resolver”. Inputting the sketch of the mechanism into the proposed algorithm, it automatically extracts unique analysis procedure and generate a kinematic analysis program as a MATLAB code based on it. Several mechanisms are analyzed as examples to show the usefulness of the proposed method.
Keywords:
;
mechanism
;
linkage
;
analysis procedure
;
kinematic pair
1. Introduction
Motion analysis of mechanical linkage is one of the most essential tasks required when we design products with them. For some famous and popular mechanisms, they have been already accomplished by expert researchers. However, the analysis of many other obscure mechanisms has not been accomplished yet. It is not realistic for the researcher to comprehensively investigate the motion analysis for all of these mechanisms for the user’s use. Therefore, if product designers consider the use of several types of mechanisms, they must do their own kinematic analysis. There are some kinematic analysis methods for the closed-loop mechanism, such as solving the closed-loop equation of this mechanism, calculating the posture algebraically using geometry, and the systematic analysis.
In general, the closed-loop equation of closed-loop mechanisms becomes a system of transcendental equations that cannot be solved easily. Wamper [ 1 ] and Nielsen and Roth [ 2 ] introduced the calculation method based on the Dixon determinant [ 3 ] in order to make the problem into an eigenvalue problem and derived the numerical solution. The numerical solutions were obtained by the iterative calculation. However, solutions included the dimensions with the imaginary number or unnecessary solutions, such that the mechanism took impossible configuration. Additionally, such an extensive iterative calculation generally requires enough computer resources and computing time. The computer aided design software, such as SolidWorks [ 4 ], Autodesk Fusion360 [ 5 ], and Open Cascade [ 6 ], which are often used for developing mechanical products actually perform multi-body kinematic analysis with the iterative calculation. However, because the calculation is just a numerical operation and hidden in the black-box, the user cannot explicitly grasp the analysis process and, unfortunately, the calculation result may converge to a value that indicates the different mechanism posture from user’s required.
If the mechanism is a simple single loop chain, the output can be described as a function of input value by geometric analysis algebraically. The books written by JSME [ 7 ] and McCarthy [ 8 ] show the geometric analysis of four-bar linkage. Because the output is described as the algebraic expression, it is calculated directly, and the iterative calculation is not needed. However, in many cases, the output of a multi-loop linkage cannot be described as an algebraic expression.
Many researchers have worked on displacement analysis for kinematic chains that are classified into the Assur group [ 9 , 10 , 11 , 12 ]. Assur group is a set of kinematic chains developed by Leonid Assur whose degree-of-freedom is zero. A complex structure can be constructed by extending the assure kinematic chain, in other words, the complex linkage mechanism can be regarded as originating from some assure kinematic chains [ 13 ]. Therefore, it is expected that the analysis of the general linkage mechanisms will be possible by achieving the analysis of the kinematic chains belonging to the Assur group. However, it is impossible to analyze all of the innumerable Assur kinematic chains. Besides, it is necessary to figure out which Assur kinematic chain constitutes the link mechanism to be analyzed, and this method requires a huge database of the Assur group.
Funabashi [
14
] and the books [
7
,
15
] introduced the systematic analysis method. On this method, mechanisms are regarded as consisting of several types of basic open chain, and their displacements are calculated by the transformation functions. The transformation function can compute the displacement and the time derivation of each type of basic open chain without iterative calculations. Even for a mechanism with a complex configuration, the displacement of the entire mechanism is finally obtained by dividing it into some basic open chains and calculating them sequentially with transformation functions. Calculations of the chains are performed according to a prepared procedure consisting of the complex combination of transformation functions. Therefore, by referring to the procedure, the status of the mechanism and the process of analysis can be explicitly revealed. However, the analysis procedures differ for each mechanism type, and it is difficult for non-expert engineers to find the procedure.
Müller, Mannheim, Hüsing, and Corves developed the linkage and cam design software, namely Mechanism Developer (MechDev), which supports the machine design engineer during the design process [ 16 ]. Its kinematic analysis Plug-Ins is based on the combination of analytical and numerical computation methods. Although this software is a user-friendly design, the detailed procedure of the analysis process is not clear for users.
In this paper, the algorithm that automatically extracts the procedure for the systematic kinematic analysis method for planar linkage mechanisms is proposed. The procedure extraction algorithm is simplified to a simple two-link chain searching algorithm by reducing the types of transformation functions. By describing the configuration of the link mechanism in a new matrix format notation, it makes it possible to automatically search for two-link chains with a computer program. In order to test this algorithm, analysis procedures for two closed-loop plane link mechanisms are extracted. Additionally, it is proposed the way to choose the proper procedure from some available candidates. Our approach realizes automatic procedure extraction that is difficult for the previous method while maintaining the advantage of systematic analysis methods, which is, it can clearly show the process of analysis that cannot be grasped by other software. The motion of a mechanism can be calculated analytically without numerical iterative calculations that are done on other software, except for mechanisms that satisfy the particular condition. This is the expanded version of the conference paper in the 25th Jc-IFToMM Symposium [
17
]. The main expanded contents are (i) the implemented algorithm of Solver process; (ii) the example of analysis for the mechanism including a prismatic joint; and, (iii) the way to choose appropriate temporal constraints to be applied to the mechanism so that the analysis will be achieved.
2. General Matrix Representation of Linkages
The mechanisms are described as the general form that represents topological configurations of mechanisms. There are several kinds of representation the two-dimensional (2D) graph [
18
,
19
], the adjacency matrix [
20
,
21
], and so on. In automating the extraction of the analysis procedure, the configuration of the mechanism should be expressed in a matrix for handling on a computer. Additionally, it is necessary to describe which joint is connected to which link, in order to search for a two-link chain described later. Hence, in this paper, the configurations of mechanisms are described as the matrix form, "LJ-matrix", which is based on an incidence matrix that denotes the relationship between links and joints. LJ-matrix is proposed, as follows.
M
=
{
m
i
,
j
}
⊂
R
N
J
×
N
L
(1)
m
i
,
j
=
0
(
J
i
not
on
L
j
)
a
(
J
i
on
L
j
)
(2)
where
J
i
is the
i
-th pair and
L
j
is the
j
-th link for
i
= 1, 2, …,
N
J
and
j
= 1, 2, …,
N
L
.
N
J
and
N
L
are the numbers of pairs and links.
a
is defined on
Table 1
.
Table 1.
The element
a
of LJ-matrix is determined depending on types and known/unknown of
J
i
.
Known pairs mean fixed pairs or pairs that have been calculated their position already. Unknown pairs mean not calculated pairs.
Afterwards, in order to simplify the discussion regarding the extraction process of the analysis procedure that will be introduced later, the mechanisms are simplified under the following three preprocessing rules. (i) All of th links are represented as binary links or structures composed of them. The multiple-pairs link is rewritten as the truss component consisting of binary links ( Figure 1 ). (ii) The active pair is rewritten as the link whose length is a function of the input of the active pair. This link connects both ends of links connecting to the active pair ( Figure 2 ). (iii) Overlapped multiple pairs are recognized as a single pair.
Figure 1. A pentagonal link rewritten as a truss consisting of binary links.
Figure 2.
An active pair rewritten as an additional binary link in length
ℓ
(
θ
)
.
All the links and pairs of the simplified mechanism are given indices of
L
1
,
L
2
,
L
3
,
⋯
and
J
1
,
J
2
,
J
3
,
⋯
, respectively. In the following discussion, the mechanism to be analyzed will be treated as if it has already been simplified with these rules.
3. Procedure Extraction Algorithm
3.1. Systematic Analysis Based on Two-Link Chains
Funabashi’s systematic analysis method [
14
] achieves displacement analysis by means of a combination of some simple geometric calculation functions, “Transformation functions”. Funabashi proposed seven types of transformation functions. They input the calculated positions of pairs or angles of links and output position of another pair. In this paper, the systematic analysis method is only based on a single transformation function that focuses on two-link chains. A two-links chain is the simplest planar Assur kinematic. For the 0 DoF planar kinematic chains which contain 1 DoF kinematic pairs, the Grübler’s equation
F
=
3
N
−
2
J
−
3
=
0
can take the smallest number of links
N
=
2
and pairs
J
=
3
that compose a two-links chain. The link mechanism to be analyzed is considered to be regarded as originating from two-links chains belonging to the Assur group. The shape of a two-link chain whose both ends are known is computable and the pair that connects two links of it can be calculated.
Figure 3
,
Figure 4
and
Figure 5
show three types of planar two-link chains treated in this paper. A 3R link chain is a two-link chain consisting of three revolute joints. A 2R1P link chain is a two-link chain that consists of two revolute joints and one prismatic joint. A 1R2P link chain is a two-link chain consisting of one revolute joint and two prismatic joints. In this paper, the middle pair of them is a revolute joint.
Figure 3. 3R link chain.
Figure 4. 2R1P link chain.
Figure 5. 1R2P link chain.
The position and velocity of revolute joint
J
p
are calculated from the known position of
J
q
and
J
r
with dimensions of links, where
p
,
q
, and
r
are assumed as the position of
J
p
,
J
q
, and
J
r
, respectively.
(i)
3R link chain
p
and
p
˙
are calculated from
q
and
r
with the link length
a
,
b
, and time derivatives of them.
p
=
q
+
a
cos
α
a
sin
α
(3)
p
˙
=
q
˙
+
a
˙
cos
α
−
a
α
˙
sin
α
a
˙
sin
α
+
a
α
˙
cos
α
(4)
where
α
=
β
±
arccos
a
2
+
c
2
−
b
2
2
a
c
,
β
=
atan
2
(
Δ
Y
,
Δ
X
)
,
c
=
|
|
r
−
q
|
|
,
[
Δ
X
,
Δ
Y
]
T
=
r
−
q
,
α
˙
=
β
˙
±
b
b
˙
−
a
a
˙
−
c
c
˙
+
(
a
˙
c
+
a
c
˙
)
cos
α
a
c
sin
α
,
β
˙
=
Δ
Y
˙
Δ
X
−
Δ
Y
Δ
X
˙
Δ
X
2
+
Δ
Y
2
,
c
˙
=
(
r
˙
−
q
˙
)
T
(
r
−
q
)
/
c
, and
[
Δ
X
˙
,
Δ
Y
˙
]
T
=
r
˙
−
q
˙
. Each of
p
and
p
˙
has two solutions. They are symmetric about line connecting
J
q
and
J
r
on the
X
Y
-plane.
(ii)
2R1P link chain
p
and
p
˙
are calculated from
q
and
r
with the link direction
α
, the link length
b
, and time derivatives of them by Equations (
3
) and (4), where
a
=
c
cos
ϕ
±
b
2
−
c
2
sin
2
ϕ
,
ϕ
=
α
−
β
,
a
˙
=
c
˙
cos
ϕ
−
c
ϕ
˙
sin
ϕ
±
b
b
2
, and
ϕ
˙
=
α
˙
−
β
˙
. Each of
p
and
p
˙
has two solutions. They are symmetric about a line perpendicular to the direction of
J
q
passing through
J
r
on the
-plane.
(iii)
1R2P link chain
p
and
p
˙
are calculated from
q
and
r
with the pair direction
α
1
,
α
2
, and time derivatives of them.
p
=
q
cos
α
1
a
sin
α
1
p
˙
=
q
˙
+
a
˙
cos
α
1
−
a
α
1
˙
sin
α
1
a
˙
sin
α
1
+
a
α
1
˙
cos
α
1
where
a
=
sin
φ
sin
θ
c
,
θ
=
π
−
ϕ
−
φ
,
ϕ
=
α
1
−
β
,
φ
=
π
−
By simplifying the mechanism according to preprocessing rules, the position and velocity of every pair are calculated with only transformation function for two-link chains. Figure 6 shows the mechanism whose pair position is calculated by the transformation function for two-link chains. The analysis is achieved with the same procedure, even if the dimensions of each link change.
Figure 6. The mechanism analyzed by the transformation function for two-link chains: ( a ) The target mechanism ( b ) The active pair is rewritten as a new link. ( c – f ) The position of pair(red) is calculated by the transformation function for two-link chains.
3.2. Two-Link Chain Searching Algorithm
On LJ-matrix, computable two-link chains are described, as shown in Figure 7 .
Figure 7. A two-link chain described on LJ-matrix.
If an unknown pair
J
p
is connected to two known pairs
J
q
and
J
r
by links
L
a
and
L
b
, the
a
-th column and the
b
-th column have a positive element and a negative element. The positive elements are on the
p
-th row and the negative elements are on the
q
-th row or
r
-th row.
The algorithm that extracts the analysis order of two-link chains is proposed. Algorithm 1 is the algorithm that searches computable two-link chains and calculates the position and velocity of unknown pairs one by one. This algorithm is named “Solver”. Algorithm 1: Solver algorithm. LJ-matrix: M = { m i , j } while p ← Repetition of counting up from 1 to N J (condition: ∃ m < 0 if ∃ a , ∃ b such that m p , n ≥ 0 ∩ m k , n < 0 ( { n , k } ∈ { { a , q } , { b , r } } , a ≠ b , q , r = 1 , ⋯ , N J ) % Calculate position and velocity of p -th joint with transformation function f % { J p , J p ˙ } ← f ( J q , J q ˙ , J r , J r ˙ , L a , L a ˙ , L b , L b ˙ ) m p , a l l ← − m p , a l l end end
The Limitation of Solver Algorithm
The Solver algorithm calculates an unknown joint position that is based on the transformation function for the two-link chain. The transformation function is available for computable two-link chains whose both ends are known. Therefore, if a mechanism doesn’t have any computable two-link chain during the Solver process, analysis cannot be completed. This means that the linkage mechanism includes Assur kinematic chains other than the two-links chain. In this paper, such a Solver ineffective mechanisms are named “unsolvable mechanism”, and others are named “solvable mechanism”. Even if a mechanism has the same link chain as a solvable mechanism, it can be an unsolvable mechanism depending on how the active pair is designated. The mechanism presented in Figure 8 a is an unsolvable mechanism, as we can recognize that no computable two-link chain exists in Figure 8 d.
Figure 8. Analysis procedure for an unsolvable mechanism: ( a – c ) Same as Figure 6 . ( d ) No computable two-link chain exists. ( e ) Add-link(green) is installed. ( f – h ) Same as Figure 6 . ( i ) The distance between joints(blue) should be equal to link length. ( j ) Add-link length is optimized.
3.3. Auxiliary Process for Dealing with an Unsolvable Mechanism
3.3.1. Additional Temporal Constraint Link
In order to deal with unsolvable mechanisms, additional constraints are temporarily installed into the mechanism. The constraint is described as an additional link that does not exist in the original mechanism ( Figure 8 e). The additional link makes up a two-link chain, and Solver starts the analysis of mechanism from it ( Figure 8 f). In this paper, the additional link is named “Add-link”. The length of Add-link is temporarily determined to any value. On LJ-matrix, Add-link is described as a new column according to the definitions of LJ-matrix. The requirement of Add-link is that it makes up a computable two-link chain. It means that (i) Add-link connects any known joint and an unknown joint that has been connected to another known joint already and (ii) Add-link does not overlap with existing links. In many cases, there are some Add-link candidates that meet the requirement. Section 5 shows the difference of run time depending on the choices of Add-link candidates.
3.3.2. Resolving Over-Constraint
Add-links gives a new constraint. The degree of freedom is reduced and the mechanism becomes over-constrained. By executing Solver, the positions of each joint are calculated. Because the mechanism contains excess links for installed Add-links, if n Add-links are installed, Solver completes the calculation for all joints without reference to n original links ( Figure 8 h).
Subsequently, the distance between calculated joints which are on the not referred link is determined independently of link length (
Figure 8
i). The joints distance depends on the length of Add-links. Therefore, Add-links length has to be optimized, so that the joints distance is equal to the original link length. The optimization of the length of Add-links is realized by the Newton–Raphson method. The evaluation function is given as a system of transcendental equations
f
=
[
f
1
,
f
2
,
f
3
,
⋯
,
f
n
]
T
,
f
n
=
d
n
−
ℓ
n
, where
ℓ
n
is the length of the
n
-th not referred to original link by Solver, and
d
n
is the distance between joints. The new length of Add-link is calculated by iterative calculations of the following equation.
ℓ
a
k
+
1
=
ℓ
a
k
−
J
−
1
f
(7)
where
ℓ
a
=
[
ℓ
a
1
,
ℓ
a
n
J
a
n
.
(8)
∂
f
n
/
∂
ℓ
a
n
means the infinitesimal change in
f
n
when the infinitesimal change in the Add-link length is given. It is calculated by the transformation function (Equations (
3
) and (4) or Equations (
5
) and (6)).
4. Flowchart
Figure 9 shows the flowchart of the proposed algorithm that extracts the systematic kinematic analysis procedure. The algorithm consists of four sub-processes, namely, “LJ-matrix generator”, “Solver process”, “Add-link process”, and “Over-constraint resolver”.
Figure 9. Systematic kinematic analysis algorithm for planar linkage.
Every time the sub-process ends, what the sub-process did is recorded as the analysis procedure logs.
First, the LJ-matrix generator automatically generates the LJ-matrix of the mechanism to be analyzed. Input the schematic diagram of the mechanism drawn by users freely and defining active pairs and fixed links on the GUI ( Figure 10 ), they are automatically converted into the LJ-matrix by this process. Subsequently, the LJ-matrix generator makes the procedure logs about generated LJ-matrix, fixed links, and active pair.
Figure 10. GUI for LJ-matrix generator.
The generated LJ-matrix is input into the Solver process, which computes the joint position and velocity with Solver ( Section 3.1 ). In the position calculation, the two-link chains solver (i) or (ii) ( Section 3.1 ) can take two symmetrical position solutions. It is automatically determined according to the input schematic diagram that the solution adopted. Afterwards, the Solver process makes the procedure logs about the target joint to be calculated, dimensions of the two-link chain, and updating LJ-matrix.
In case, the Solver process failed to complete procedure extraction, that is, the target mechanism is unsolvable, Add-link process installs Add-links into the mechanism and its LJ-matrix. Figure 11 shows the flowchart of the Add-link process.
Figure 11. Flowchart of Add-link process.
Subsequently, the Add-link process makes the procedure logs about the installed Add-link.
The modified LJ-matrix is input into the Solver process again. If Solver process complete procedure extraction, the Over-constraint resolver re-calculates the length of Add-links based on iterative calculation ( Section 3.3.2 ). Afterwards, the Over-constraint resolver makes the procedure logs about re-calculated Add-links and evaluation function. The convergence of calculations on the Over-constraint resolver means that the kinematic analysis and procedure extraction is completed. After the algorithm is finished, the readable procedure manual and kinematic analysis MATLAB program are generated.
5. Results
5.1. Problem 1: A Slider-Crank Mechanism
Figure 12
a is the schematic diagram of the slider-crank mechanism and
Figure 12
b is the LJ-matrix of the mechanisms automatically converted from the sketch.
J
2
is a prismatic joint, and others are revolute joints. On this mechanism,
L
1
is fixed and the active pair is
J
1
. This mechanism is a solvable mechanism.
Listing 1
is the finally generated analysis procedure. By means of the procedure, the motion of the mechanism is automatically drawn when it is given any active pair input by users.
Figure 13
shows the motion simulation when the active pair input is linearly increasing.
Figure 12. The schematic diagram of Slider-crank mechanism ( a ) and generated LJ-matrix ( b ).
Figure 13. The motion simulation of slider-crank mechanism according to the extracted procedure.
Listing 1. Generated procedure manual.
1 lj_mat = fixed_link(lj_mat,link1); 2 joint3 = RRR_links(link2,link5,joint1,joint2); 3 joint4 = PRR_links(link3,link4,joint3,joint2);
5.2. Problem 2: A Six-Bar Linkage Mechanism
Figure 14
is the schematic diagram of the six-bar linkage mechanism and the LJ-matrix of the mechanisms automatically converted from the sketch. Every joint is a revolute joint. On this mechanism, the bottom link is fixed and the active pair is
J
7
. This mechanism is an unsolvable mechanism, as shown in
Figure 8
. In this case, the Add-link was installed into the mechanism as
L
12
connecting
J
1
and
J
4
(
Figure 14
).
Listing 2
is the finally generated analysis procedure. By means of the procedure, the motion of the mechanism is automatically drawn when it is given any active pair input by users.
Figure 15
shows the motion simulation when the active pair input is linearly increasing.
Figure 14. 6-bar linkage mechanism drawn on LJ-matrix generator GUI and installed Add-link.
Figure 15. The motion simulation of 6-bar linkage mechanism according to the extracted procedure.
Listing 2. Generated procedure manual.
1 lj_mat = fixed_link(lj_mat,link8,link9,link10); 2 joint6 = RRR_links(link7,link11,joint7,joint3); 3 additional_link(joint1,joint4); 4 joint4 = RRR_links(link2,link12,joint3,joint1); 5 joint2 = RRR_links(link1,link3,joint1,joint4); 6 joint5 = RRR_links(link4,link5,joint2,joint4); 7 add_link_optimizer(target_link[ 6 ],add-link[ 12 ]);
6. Processing Time of the Algorithm Depending on Add-Link Choice
There are some choices of Add-link that will be installed into the mechanism in order to help the Solver process, as mentioned in Section 3.3.1 . Because the proposed analysis algorithm treats installed Add-links like one of the original links in the mechanism, the mechanisms that different Add-links are installed into, but were originally the same link chain are processed as distinctly different mechanisms in the algorithm. Therefore, the configuration of two-link chains and the order of calculations, which are found out by Solver process from each mechanism is diverse. It means that each Add-link candidates finally derive different analysis procedures.
The six-bar linkage mechanism referred in
Section 5.2
has nine available candidates for Add-link
L
12
, including the adopted one connecting
J
1
and
J
4
. They satisfy the required condition for Add-link that they configure computable two-link chains with an original link of the mechanism.
Table 2
shows all candidates for Add-link
L
12
and connected joints at both ends of them, and they will derive nine types of different analysis procedures.
Table 2.
Candidates of
L
12
and their connecting joints for 6-bar linkage mechanism.
The best choice is defined as the candidate that minimizes the processing time of the analysis in order to choose one Add-link from the candidates. Of course, the processing time of the analysis algorithm depends on the analysis procedure, and it leads to suitable Add-links.
Figure 16 shows the scatter plot for the processing time of the analysis program. Data of the plot are given by running an actual analysis program for the six-bar linkage mechanism that is shown in Figure 14 , where the active pair angle takes the integer value in the range of −10 degrees to 10 degrees from the initial angle. One hundred times of measurements of processing time are carried out for every input value and Add-link candidates, and the average time of them is calculated as the data for plot. This graph suggests that there is a strong positive correlation between processing time and the number of iterative calculations in the Over-constraint resolver.
Figure 16. The relation between the processing time and the number of iterative calculations in Over-constraint resolver.
Because the number of the calculation is unique for a combination of the choice of Add-link and the active pair angle, the required situation for best Add-link is to minimize the number of iterative calculations.
Figure 17
shows the number of iterative calculations and the norm of function values,
f
, of distance between pairs, which is used to obtain the lengths of Add-links mentioned in
Section 3.3.1
, for each Add-link candidate listed in
Table 2
. The former is represented as ranges for input displacements
−
10
degree
<
Δ
θ
<
10
degree
and their average with bars. The latter is represented as “x”. In addition, the norm of
f
is calculated before executing the Over-constraint resolver, and the input displacement is +5 degrees from initial displacement. It is recognized that, around the initial input, these graphs almost resemble, and when an Add-link candidate which makes the norm of
f
minimum is adopted, the number of iterative calculations also takes the minimum value.
Figure 17. Iterative calculations and the norm of function values to obtain lengths of Add-links.
Therefore, in order to choose the best Add-link that minimize the processing time of the analysis procedure, (i) get all candidate that satisfy the required condition for Add-link; (ii) for each candidate, execute Solver process and compute the shape of the mechanism just until running Over-constraint resolver; (iii) calculate the norm of f , and find the best candidate that minimizes the norm; and, (iv) adopt this candidate as an Add-link.
7. Conclusion and Future Works
7.1. Conclusions
An algoriththat automatically extracts the procedure for the two-link chains based systematic kinematic analysis of planar linkage mechanisms has been proposed. The main results obtained in this paper are summarized, as follows.
(1)
LJ-matrix that represents the relationship between links and joints, classification of pairs which are known or unknown has been proposed.
(2)
An algorithm for automatically searching two-links chains and extracting the analysis procedure has been established.
(3)
This method does not require many kinds of transformation function but is based only on one transformation function.
(4)
For a mechanism not analyzed by only the two-links chain based calculations, the analysis is achieved by installing temporally over-constraints as additional links.
(5)
The proposed algorithm generates the procedure manual and MATLAB program for the analysis.
(6)
The generated procedure manual explicitly reveals the process of analysis.
(7)
For several mechanisms, their analysis procedures are extracted and their motions are analyzed with the extracted procedures.
(8)
It is shown that the best Add-link candidate that minimizes the processing time of the analysis program is found by assessing the norm of function values to obtain proper Add-links before executing the Over-constraint resolver.
7.2. Future Works
We discussed a method for extracting the analysis procedure for kinematics analysis for a general planar linkage mechanism with revolute pairs and prismatic pairs. This method is based on the characteristic of planar linkage mechanisms that the position/orientation of a two-link chain composed of one-degree-of-freedom kinematic pairs and links is determined by the position/direction at both ends. Therefore, even if the linkage mechanism has a planar higher kinematic pair with one degree of freedom such as a plane cam & roller or gear, it is expected that the method introduced in this paper can be used for the analysis of the mechanism. When you add a new type kinematic pair into this algorithm, the next classification number of the kinematic pair shown in Table 1 is inserted. Besides, it will be required the calculation components of the two-links chain such as Equation ( 3 )–(6) which are based on the kinematic pair combinations shown in Figure 3 , Figure 4 and Figure 5 . It is expected that these formulas will become complicated in the case of higher kinematic pairs. In some cases, the iterative calculation may be required in the calculation unit, however, since they are completed in the unit, they do not affect the calculation of the other two-links chains.
In the case of the extension of this method to the spatial linkage mechanism, since the mechanism moves spatially and has multiple DoF kinematic pairs, general two-links chains do not always belong to the Assur group. The Assur group for spatial linkage mechanisms satisfies the Grübler’s equation
F
=
6
(
N
−
J
−
1
)
∑
i
=
1
J
f
i
=
0
f
i
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Figure 1. A pentagonal link rewritten as a truss consisting of binary links.
Figure 2.
ℓ
(
θ
)
.
Figure 3. 3R link chain.
Figure 4. 2R1P link chain.
Figure 5. 1R2P link chain.
Figure 6. The mechanism analyzed by the transformation function for two-link chains: ( a ) The target mechanism ( b ) The active pair is rewritten as a new link. ( c – f ) The position of pair(red) is calculated by the transformation function for two-link chains.
Figure 7. A two-link chain described on LJ-matrix.
Figure 8. Analysis procedure for an unsolvable mechanism: ( a – c ) Same as Figure 6 . ( d ) No computable two-link chain exists. ( e ) Add-link(green) is installed. ( f – h ) Same as Figure 6 . ( i ) The distance between joints(blue) should be equal to link length. ( j ) Add-link length is optimized.
Figure 9. Systematic kinematic analysis algorithm for planar linkage.
Figure 10. GUI for LJ-matrix generator.
Figure 11. Flowchart of Add-link process.
Figure 12. The schematic diagram of Slider-crank mechanism ( a ) and generated LJ-matrix ( b ).
Figure 13. The motion simulation of slider-crank mechanism according to the extracted procedure.
Figure 14. 6-bar linkage mechanism drawn on LJ-matrix generator GUI and installed Add-link.
Figure 15. The motion simulation of 6-bar linkage mechanism according to the extracted procedure.
Figure 16. The relation between the processing time and the number of iterative calculations in Over-constraint resolver.
Figure 17. Iterative calculations and the norm of function values to obtain lengths of Add-links.
Table 1.
of LJ-matrix is determined depending on types and known/unknown of
J
i
.
J i Is Revolute Pair Prismatic Pair Known a = −1 a = −2 Unknown a = 1 a = 2
Table 2.
Candidates of
L
12
and their connecting joints for 6-bar linkage mechanism.
L 12 ( 1 ) L 12 ( 2 ) L 12 ( 3 ) L 12 ( 4 ) L 12 ( 5 ) L 12 ( 6 ) L 12 ( 7 ) L 12 ( 8 ) L 12 ( 9 ) J 1 , J 4 J 1 , J 5 J 2 , J 3 J 3 , J 5 J 2 , J 6 J 4 , J 6 J 2 , J 7 J 4 , J 7 J 5 , J 7
Yamamoto T, Iwatsuki N, Ikeda I. Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms. Machines. 2020; 8(3):41.
https://doi.org/10.3390/machines8030041
Chicago/Turabian Style
Yamamoto, Tatsuya, Nobuyuki Iwatsuki, and Ikuma Ikeda. 2020. "Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms" Machines8, no. 3: 41.
https://doi.org/10.3390/machines8030041
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Yamamoto, T.; Iwatsuki, N.; Ikeda, I. Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms. Machines 2020, 8, 41.
https://doi.org/10.3390/machines8030041
Yamamoto T, Iwatsuki N, Ikeda I. Automated Kinematic Analysis of Closed-Loop Planar Link Mechanisms. Machines. 2020; 8(3):41.
https://doi.org/10.3390/machines8030041
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Acute Myeloid Leukemia Clinical Trial: Liposome-encapsulated Daunorubicin-Cytarabine, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Acute Myeloid Leukemia - A Phase 1/2 Study of CPX-351 (NSC# 775341) Alone Followed by Fludarabine, Cytarabine, and G-CSF (FLAG) for
Acute Myeloid Leukemia Clinical Trial
Clinical Trial Finder Acute Myeloid Leukemia Trials
Liposome-encapsulated Daunorubicin-Cytarabine, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Summary
This phase I/II trial studies the side effects and best dose of liposome-encapsulated daunorubicin-cytarabine when given with fludarabine phosphate, cytarabine, and filgrastim and to see how well they work in treating younger patients withacute myeloid leukemiathat has come back after treatment (relapsed) or is not responding to treatment (is refractory). Liposome-encapsulated daunorubicin-cytarabine is made up of two chemotherapy drugs, cytarabine and daunorubicin hydrochloride, and works to stop cancer cell growth by blocking the cells from dividing. Drugs used in chemotherapy, such as fludarabine phosphate and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Filgrastim may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving liposome-encapsulated daunorubicin-cytarabine followed by fludarabine phosphate, cytarabine, and filgrastim may be a better treatment for patients with relapsed acute myeloid leukemia and may cause fewer side effects to the heart, a common effect of other chemotherapy treatments for acute myeloid leukemia.
Full Description
PRIMARY OBJECTIVES:I. To determine a recommended phase 2 dose (RP2D) and the toxicities associated with liposome-encapsulated daunorubicin-cytarabine (CPX-351) in pediatric and young adult patients with relapsed/refractory acute myeloid leukemia (AML).II. To estimate the response rate (complete remission [CR] plus complete remission with partial platelet recovery [CRp]) after CPX-351 (cycle 1) followed by fludarabine phosphate, cytarabine, and filgrastim (FLAG) (cycle 2) in children with AML in first relapse.SECONDARY OBJECTIVES:I. To estimate the response rate (CR + CRp + complete remission with incomplete blood count recovery [CRi]) after one cycle of CPX-351.II. To describe the pharmacokinetics of plasma cytarabine and daunorubicin after CPX-351 administration to pediatric and young adult patients with relapsed/refractory AML.TERTIARY OBJECTIVES:I. To describe the response in biomarkers of cardiac injury to a single cycle of CPX-351.II. To explore the effect of CPX-351 on novel biochemical and imaging markers of cardiotoxicity, including plasma micro ribonucleic acid (RNAs) (miRNA) and myocardial deformation.III. To explore the role of rare coding variants as risk factors for anthracycline-induced cardiomyopathy.OUTLINE:COURSE 1: Patients receive cytarabine intrathecally (IT) on day 0 and at day 28-30 or up to 7 days prior to day 1 of course 2, and liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5. Patients without evidence of central nervous system (CNS) disease (CNS1) receive no further CNS-directed therapy in course 1. Patients with < 5 white blood cells per microliter of blood with blast cells (CNS2) disease may receive additional 4-6 doses of cytarabine IT twice weekly starting 48 hours after the third dose of liposome-encapsulated daunorubicin-cytarabine until CNS is clear at the discretion of the investigator. Patients meeting criteria for CR, CRp, and CRi may proceed to course 2.COURSE 2: Patients receive filgrastim on days 1-5 and then on day 15 until blood count recovery, and fludarabine phosphate IV over 30 minutes and high-dose cytarabine IV over 1-3 hours once daily (QD) on days 1-5.After completion of study treatment, patients are followed up periodically for 12 months, and then yearly for 5 years.
Eligibility Criteria
Inclusion Criteria:Patients must have had histologic verification of AML at original diagnosisPatient must have one of the following:Recurrent disease with >= 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease.Recurrent disease with an absolute blast count greater than 1,000 per microliter in the peripheral blood with or without extramedullary diseaseTo be eligible for the dose-finding phase: (the dose-finding phase completed in 12/2016)Relapsed patientsPatients must be in first relapse, andPatients must not have received prior re-induction therapyRefractory patientsPatients must not have received more than one attempt at remission induction, which may consist of up to two different therapy courses; Children Oncology Group (COG) AAML1031 de novo therapy including induction I and induction II is an exampleTreatment-related AML (t-AML)Patients must be previously untreated for secondary AMLTo be eligible for the phase 2 efficacy phase:Relapse patients:Patients must be in first marrow relapse, andPatients must not have received prior re-induction therapy; donor lymphocyte infusion (DLI) is considered a re-induction attemptPatients must have the status of CNS1 or CNS2 only, and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsyPatients must have a performance status corresponding to an Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance scorePatients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,stem cell transplantor radiotherapy prior to entering this study; all prior treatment-related toxicities must have resolved to =< grade 2 prior to enrollmentMyelosuppressive chemotherapy: must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (excluding hydroxyurea)Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of CPX-351Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent such as steroids, retinoids; Note: for agents that have known adverse events occurring beyond 7 days after administration (i.e. monoclonal antibodies), this period must be extended beyond the time during which acute adverse events are known to occurRadiation therapy (RT): >= 2 weeks for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation; Note: patients must have received =< than 13.6 Gray (Gy) prior radiation to the mediastinumStem cell transplant (SCT): no evidence of active graft vs. host disease for at least 4 weeks; for allogeneic SCT patients, >= 3 months must have elapsed since transplantMust have received no more than 1 prior autologous orallogeneic stem cell transplant.Patients must be off all systemic immunosuppressive therapy for at least 2 weeks, excluding hydrocortisone for physiologic cortisol replacementIntrathecal cytotoxic therapy:No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisoneAt least 14 days must have elapsed since receiving liposomal cytarabine (DepoCyte) by intrathecal injectionGrowth factors:Patients must not have received growth factors for 7 days prior to CPX-351Patients must not have received pegfilgrastim for 14 days prior to CPX-351Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (males and females)Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (males and females)Age 6 to < 10 years: maximum serum creatinine 1.0 mg/dL (males and females)Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (males and females)Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (males) and 1.4 mg/dL (females)Age >= 16 years: maximum serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)Direct bilirubin < 1.5 x upper limit of normal (ULN) for age and institutionSerum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x upper limit of normal (ULN) for age and institution (unless it is related to leukemic involvement)Shortening fraction of >= 27% by echocardiogram, orEjection fraction of >= 50% by radionuclide angiogram or echocardiogramCorrected QT (using Bazett's formula [QTcB]) interval < 500 msecsPatients with seizure disorder may be enrolled if on anticonvulsants and if seizures are well controlledCentral nervous system (CNS) toxicity =< grade 2Patients with a known history of human immunodeficiency virus (HIV) are eligible, if they meet all of the following conditions:No history of HIV complications with the exception of cluster of differentiation (CD)4 count < 200 cells/mm^3No antiretroviral therapy with overlapping toxicity such as myelosuppressionHIV viral loads below the limit of detectionNo history of highly active antiretroviral therapy (HAART)-resistant HIVAll patients and/or their parents or legal guardians must sign a written informed consentAll institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be metExclusion Criteria:Patients who have received > 450 mg/m^2 daunorubicin equivalents; patients who relapse after receiving AAML0531/AAML1031 therapy will be eligible for this study, provided they have not received any additional anthracyclines; NOTE: for the purposes of determining eligibility for this protocol, the following cardiotoxicity multipliers will be used to determine daunorubicin equivalents:Doxorubicin (doxorubicin hydrochloride): 1Mitoxantrone: 3Idarubicin: 3Epirubicin: 0.5Patients who are currently receiving another investigational drugPatients receiving medications for treatment of left ventricular systolic dysfunctionPatients with any of the following diagnoses:Acute promyelocytic leukemia (APL)Down syndromeFanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndromeWilson's disease and any other disorder of copper metabolismJuvenile myelomonocytic leukemia (JMML)Patients with documented active, uncontrolled infection at the time of study entryPatients with known active hepatitis B virus (HBV) and hepatitis C virus (HCV) infectionsPatients with prior allergy to daunorubicin and/or cytarabineFemale patients who are pregnant are ineligibleLactating females are not eligibleFemale patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtainedSexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of chemotherapy
Study is for people with:
Acute Myeloid Leukemia
Phase:
Phase 1
Estimated Enrollment:
38
Study ID:
NCT02642965
Recruitment Status:
Active, not recruiting
Sponsor:
| https://www.survivornet.com/clinical-trials/acute-myeloid-leukemia/liposome-encapsulated-daunorubicin-cytarabine-fludarabine-phosphate-cytarabine-and-filgrastim-in-treating-younger-patients-with-relapsed-or-refractory-acute-myeloid-leukemia/ |
Isoform-Specific Modulation of Voltage-Gated Na+ Channels by Calmodulin | Circulation Research
Calmodulin (CaM) is a calcium-sensing protein that binds to Na+ channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of ex...
Isoform-Specific Modulation of Voltage-Gated Na +Channels by Calmodulin
Isabelle Deschênes
Nathalie Neyroud
,
Deborah DiSilvestre
,
Eduardo Marbán
,
David T. Yue
and
Gordon F. Tomaselli
Abstract
Calmodulin (CaM) is a calcium-sensing protein that binds to Na +channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (μ1) but not cardiac (hH1) Na +channels. Mutant CaM 1234did not alter the voltage dependence or the kinetics of gating of either μ1 or hH1. Mutation of the highly conserved IQ motif in the carboxyl terminus of both isoforms (IQ/AA) slowed the kinetics of current decay and abolished the effect of wild-type CaM on μ1, but did not alter hH1 currents. The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both μ1 and hH1 channels. Inhibition of Ca 2+/CaM kinase (CaM-K) slowed the current decay, the rate of entry into inactivation, and shifted the voltage dependence of hH1 in the depolarizing direction independent of CaM overexpression with no effect on μ1 Na +channels. CaM signaling modulates Na +currents in an isoform-specific manner, via direct interaction with skeletal muscle Na +channels and through CaM-K in the case of the cardiac isoform. The full text of this article is available at http://www.circresaha.org.
Voltage-gated Na +channels are essential for the generation of action potentials and cell excitability.1Na +channels are responsible for the upstroke of the action potential in excitable cells and are the target of local anesthetic drugs. Na +channels are composed of a pore-forming α-subunit and smaller β-subunits that have been implicated in assembly, trafficking, and posttranslational modulation of the α-subunit. 2
A number of interacting signaling pathways modulate the Na +channel. The function of neuronal and cardiac Na +channels is altered by cAMP-dependent protein kinase (PKA) phosphorylation of residues in the linker between domains I and II. PKA-dependent phosphorylation of the neuronal channel reduces current density, 3,4but directionally opposite effects are seen with cardiac Na +channels.5The α-subunit of the skeletal muscle channel is not affected by PKA despite the presence of consensus phosphorylation sites. 6,7In contrast to PKA, protein kinase C (PKC) alters the function of all mammalian sodium channel isoforms. 8–13PKC reduces channel conductance and alters gating in an isoform-specific manner; an effect largely attributed to phosphorylation of a highly conserved serine residue in the linker between domains III to IV of the channel. There is also evidence that neuronal sodium channel gating is modulated by a G-protein–coupled pathway acting through the carboxyl terminus. 14
Calmodulin (CaM) is a ubiquitous, small (16.7 kDa) calcium-binding protein that acts as a Ca 2+sensor translating changes in cytoplasmic Ca 2+into cellular responses by interacting with a diverse group of signaling molecules.15A group of kinases, Ca 2+/CaM-dependent kinases (CaM-K) are activated by CaM and phosphorylate a number of functionally diverse effectors from ion channels and receptors to transcriptional activators. Ion channels are prominent targets of CaM; for example, CaM is bound to L-type voltage–dependent Ca 2+channels and mediates Ca 2+-dependent inactivation. 16–19The possibility that CaM modulates the Na +current was suggested by yeast 2-hybrid experiments demonstrating the interaction of voltage-dependent sodium channels and CaM through an IQ-like motif in the carboxyl terminus of the α-subunit. 20
The functional consequences of CaM binding to Na +channels are unknown. We demonstrate that coexpression of CaM with Na +channels alters the function of the skeletal muscle (μ1) channels but not the cardiac (hH1) isoform. Further, mutation of the IQ motif in the carboxyl terminus of the μ1 skeletal muscle Na +channel alters inactivation gating and eliminates the effect of CaM on the expressed current. Inhibition of CaM-K by KN-93, but not the CaM-KII–specific inhibitor autocamtide-2 peptide (AIP), slowed cardiac Na +current decay, shifted the availability curve to more depolarized potentials, and slowed entry into inactivated states. Mutating the IQ motif eliminated CaM binding to carboxyl terminal peptides of both isoforms.
Materials and Methods
Transfections of HEK293 and C2C12 Cell Lines
Human embryonic kidney cells (HEK293; American Type Culture Collection, Manassas, Va) were used to express the cloned sodium channels μ1 and hH1 in presence of wild-type or mutant CaM 1234.17C2C12 cells (American Type Culture Collection) are a subclone derived from a mouse myoblast cell line expressing characteristic muscle proteins.21Cells were grown in DMEM high glucose supplemented with FBS 10%, l-glutamine (2 mmol/L), penicillin (100 U/mL), and streptomycin (10 mg/mL) in a humidified 5% CO 2atmosphere. Transfections of the cells were performed using lipofectamine according to the manufacturer’s instructions. Cells were patch-clamped or stained 1 to 2 days after transfection.
Patch-Clamp Methods
Macroscopic Na +currents from transfected cells were recorded using the whole-cell configuration of patch-clamp technique.22Cells with currents no larger than 6 nA were clamped with an Axopatch 200 patch-clamp amplifier using low-resistance electrodes and typical series resistance compensation of >80% that minimized voltage-clamp errors. Membrane currents were filtered at 5 kHz and digitized with 12-bit resolution. In all experiments, recording was begun 10 minutes after whole-cell access was attained with the exception of the CaM-K inhibitor experiments where recording was begun 15 minutes after patch rupture to ensure stabilization of the time-dependent shift in gating.
Solutions and Reagents
The patch pipette contained (in mmol/L) 35 NaCl, 105 CsCl, and 10 Cs-HEPES (pH 7.3) with no Ca 2+buffering. All of the experiments were initially performed using 105 mmol/L CsF in the pipette; however, due to possible confounding effects on phosphorylation reactions and Ca 2+buffering, the experiments were repeated with the CsCl-containing intracellular solution. No differences in the response to CaM overexpression were observed with the different pipette solutions. All of the data reported in the text and in the tables were obtained using CsCl with the exception of experiments in C2C12 cells, where CsF data are reported.
For the experiments with 504 nmol/L free Ca 2+, 5 mmol/L BAPTA and 3.7 mmol/L CaCl 2were added to the patch pipette. For the experiments with no free Ca 2+, 10 mmol/L BAPTA was added to the pipette solution and 0.1 mmol/L EGTA was added to the bath solution. The bath solution contained (in mmol/L) 150 NaCl, 2 KCl, 2 CaCl 2, 1 MgCl 2, 10 glucose, and 10 Na-HEPES (pH 7.4). The CaM-K inhibitor KN-93 (Calbiochem) and the inactive analog, KN-92, were added to the patch pipette at concentrations of 10 μmol/L. KN-92 and KN-93 were dissolved in DMSO (10 mmol/L stock solution); the final concentration of DMSO was 0.1%, which had no significant effect on the currents (data not shown). The CaM-KII–specific inhibitor, AIP (Calbiochem) was added to the pipette solution at 100 nmol/L. Experiments were performed at room temperature, 22°C to 23°C.
Pull-Down Assays
Fusion proteins of the μ1 and hH1 carboxyl termini containing the IQ motif and the mutated motif IQ/AA were constructed in pGEX using the glutathione S-transferase (GST) Gene Fusion System (Pharmacia). The Na
+
channel-specific sequences of the fusion peptides were μ1 (residues 1689 to 1742): ALKQTMEEKFMAANPSKVSYEPITTTLKRKQEEVCAIK
IQ
RAYRRHLLQRSVKQ and hH1 (residues 1870 to 1923): ALKIQMEEKFMAANPSKISYEPITTTLRRKHEEVSAMV
IQ
RAFRRHLLQRSLKH, where the underlined amino acids were changed to alanines in the IQ/AA mutants. Proteins were produced and purified according to the manufacturer’s instructions. Pull-down assays were performed by mixing 10 μg (1:1 molar ratio of NaIQ:CaM) or 30 μg (3:1 molar ratio of NaIQ:CaM) of each fusion protein with glutathione beads (70 μL). Binding of the beads to the GST-tagged fusion proteins was performed by incubating for 30 minutes at 4°C in solution A consisting of 25 mmol/L Tris, pH 7.6, and 1 mmol/L CaCl
2
. After a brief centrifugation, the supernatants were removed and the beads were mixed and incubated with solution A in the absence and presence of CaM for 2 hours at 4°C. The mixtures were washed and spun briefly. Then the proteins bound to the beads were eluted with SDS-Page 2X sample buffer (70 μL) and 30 μL of each sample was run on a 12.5% gel SDS-PAGE gel. After transfer to PVDF membranes CaM was detected by an anti-CaM monoclonal antibody (Upstate Biotechnology) and a horse radish peroxidase-linked secondary antibody.
Statistical Analysis
Data are expressed as mean±SEM. A 2-tailed Student’s ttest was used to assess statistical significance when appropriate. Differences were considered to be significant at a value of P<0.05.
Results
Effects of CaM Coexpression With μ1 Skeletal Muscle Na +Channels
To assess the effect of CaM binding on skeletal muscle sodium channels, we cotransfected HEK293 cells with μ1 and wild-type CaM or a mutant form of CaM with strongly impaired Ca 2+binding (CaM 1234).17In the absence of intracellular Ca 2+buffering, CaM overexpression did not significantly affect the whole-cell current (Figure 1A), current-voltage relationship (Figure 1B), voltage dependence of activation, time constants of inactivation (τ h), recovery from inactivation, or the rate of entry into inactivation (Table 1). However, the steady-state availability relation was significantly shifted in the hyperpolarizing direction (Figure 1C). In contrast to wild-type CaM, coexpression of mutant CaM 1234with the μ1 Na +channel produced no significant change in steady-state availability compared with the μ1 α-subunit expressed alone. The presence of the β 1-subunit did not significantly alter the steady-state availability curve of the μ1 channel compared with the α-subunit alone, nor did it alter the hyperpolarizing shift produced by CaM.Table 1summarizes the effects of wild-type and mutant CaM on the functional properties of the μ1 skeletal muscle Na +channel expressed in the presence and absence of the β-subunit with CaM.
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CaptionFigure 1.Biophysical properties of μ1 expressed in HEK293 cells in presence of CaM or mutant CaM 1234. A, Representative sodium currents through μ1 skeletal muscle channels in the absence (solid line) and presence of overexpression of CaM (dashed line) or a Ca 2+-binding deficient mutant CaM 1234(dotted line). Currents were elicited by 30-ms steps to −20 mV from a holding potential of −120 mV. B, The normalized current-voltage (IV) relationships elicited by voltage-clamp steps from −80 to +60 mV in 10-mV increments (mean±SEM) for μ1 (squares), μ1+CaM (circles), and μ1+mutant CaM 1234(triangles). C, Voltage dependence of steady-state inactivation measured by a 2-pulse protocol with 500-ms conditioning pulses from −140 to −30 mV followed by a test pulse to −30 mV. The data were fit to a Boltzmann distribution. D, Voltage dependence of steady-state inactivation, as described in C, but measured in the presence of 0.1 mmol/L EGTA in the bath solution and 10 mmol/L BAPTA in the intracellular solution.
<table> Table 1.Functional Effects of CaM and Mutant CaM 1234on μ1 Expressed in HEK293 Cells and on Skeletal Muscle Sodium Currents Recorded From C2C12 Cells<tr><th rowspan=1 colspan=1> Biophysical Parameters</th><th rowspan=1 colspan=1> Steady-State Inactivation (V ½in mV)</th><th rowspan=1 colspan=1> Decay Time Constant(τ hin ms at −20 mV)</th><th rowspan=1 colspan=1> Recovery From Inactivation(τ recin ms)</th><th rowspan=1 colspan=1> Entry Into Inactivation(Time Constant in ms)</th><th rowspan=1 colspan=1> Activation(V frac12;in mV)</th><th rowspan=1 colspan=1> n</th></tr><tr><td rowspan=1 colspan=7> n indicates number of cells.</td></tr><tr><td rowspan=1 colspan=7> *Significantly different from μ1 ( P<0.05);</td></tr><tr><td rowspan=1 colspan=7> †significantly different from μ1+β ( P<0.05);</td></tr><tr><td rowspan=1 colspan=7> ‡significantly different from C2C12 ( P<0.05);</td></tr><tr><td rowspan=1 colspan=7> §significantly different from μ1+KN-92 ( P<0.05);</td></tr><tr><td rowspan=1 colspan=7> ∥significantly different from μ1+KN-93 ( P<0.05); and</td></tr><tr><td rowspan=1 colspan=7> ¶significantly different from μ1+AIP ( P<0.05).</td></tr><tbody><tr><td rowspan=1 colspan=1> μ1</td><td rowspan=1 colspan=1> −68.0±0.9</td><td rowspan=1 colspan=1> τ h fast=0.72±0.09</td><td rowspan=1 colspan=1> 2.03±0.14</td><td rowspan=1 colspan=1> 931±59</td><td rowspan=1 colspan=1> −32.2±2.5</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM</td><td rowspan=1 colspan=1> −73.8±0.6 *</td><td rowspan=1 colspan=1> τ h fast=0.66±0.05</td><td rowspan=1 colspan=1> 1.89±0.20</td><td rowspan=1 colspan=1> 884±77</td><td rowspan=1 colspan=1> −31.1±2.7</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM1234</td><td rowspan=1 colspan=1> −68.3±0.7</td><td rowspan=1 colspan=1> τ h fast=0.71±0.04</td><td rowspan=1 colspan=1> 1.91±0.13</td><td rowspan=1 colspan=1> 879±65</td><td rowspan=1 colspan=1> −31.7±2.2</td><td rowspan=1 colspan=1> 7</td></tr><tr><td rowspan=1 colspan=1> μ1+β</td><td rowspan=1 colspan=1> −69.4±0.6</td><td rowspan=1 colspan=1> τ h fast=0.66±0.09</td><td rowspan=1 colspan=1> 1.95±0.15</td><td rowspan=1 colspan=1> 953±24</td><td rowspan=1 colspan=1> −33.1±3.0</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+β+CaM</td><td rowspan=1 colspan=1> −74.7±0.3 †</td><td rowspan=1 colspan=1> τ h fast=0.62±0.02</td><td rowspan=1 colspan=1> 2.02±0.26</td><td rowspan=1 colspan=1> 871±67</td><td rowspan=1 colspan=1> −32.9±2.6</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+β+CaM1234</td><td rowspan=1 colspan=1> −68.7±0.2</td><td rowspan=1 colspan=1> τ h fast=0.59±0.05</td><td rowspan=1 colspan=1> 1.89±0.23</td><td rowspan=1 colspan=1> 973±23</td><td rowspan=1 colspan=1> −33.3±3.1</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1> μ1 (0 Ca2+)</td><td rowspan=1 colspan=1> −73.2±0.2</td><td rowspan=1 colspan=1> τ h fast=0.66±0.06</td><td rowspan=1 colspan=1> 2.22±0.34</td><td rowspan=1 colspan=1> 901±35</td><td rowspan=1 colspan=1> −33.7±2.6</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM (0 Ca2+)</td><td rowspan=1 colspan=1> −75.0±0.4</td><td rowspan=1 colspan=1> τ h fast=0.61±0.05</td><td rowspan=1 colspan=1> 2.05±0.25</td><td rowspan=1 colspan=1> 890±29</td><td rowspan=1 colspan=1> −34.3±3.2</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM1234 (0 Ca2+)</td><td rowspan=1 colspan=1> −75.9±0.6</td><td rowspan=1 colspan=1> τ h fast=0.64±0.08</td><td rowspan=1 colspan=1> 1.99±0.46</td><td rowspan=1 colspan=1> 884±41</td><td rowspan=1 colspan=1> −34.1±3.6</td><td rowspan=1 colspan=1> 3</td></tr><tr><td rowspan=1 colspan=1> C2C12</td><td rowspan=1 colspan=1> −87.5±0.2</td><td rowspan=1 colspan=1> τ h fast=1.32±0.11</td><td rowspan=1 colspan=1> 5.93±0.82</td><td rowspan=1 colspan=1> 811±94</td><td rowspan=1 colspan=1> −30.7±3.0</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> C2C12+CaM</td><td rowspan=1 colspan=1> −94.2±0.7 ‡</td><td rowspan=1 colspan=1> τ h fast=1.30±0.09</td><td rowspan=1 colspan=1> 6.78±1.05</td><td rowspan=1 colspan=1> 760±67</td><td rowspan=1 colspan=1> −32.4±2.7</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> C2C12+CaM 1234</td><td rowspan=1 colspan=1> −85.8±0.7</td><td rowspan=1 colspan=1> τ h fast=1.24±0.13</td><td rowspan=1 colspan=1> 6.32±0.82</td><td rowspan=1 colspan=1> 779±74</td><td rowspan=1 colspan=1> −32.0±3.2</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1> μ1-IQ/AA</td><td rowspan=1 colspan=1> −78.6±1.0 *</td><td rowspan=1 colspan=1> τ h fast=0.68±0.03 *</td><td rowspan=1 colspan=1> 2.65±0.54 *</td><td rowspan=1 colspan=1> 901±44</td><td rowspan=1 colspan=1> −40.4±3.1</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.46±0.29</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> μ1-IQ/AA+CaM</td><td rowspan=1 colspan=1> −78.1±1.2 *</td><td rowspan=1 colspan=1> τ h fast=0.72±0.04 *</td><td rowspan=1 colspan=1> 3.19±0.69 *</td><td rowspan=1 colspan=1> 851±36</td><td rowspan=1 colspan=1> −42.1±3.7</td><td rowspan=1 colspan=1> 3</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.21±0.48</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> μ1+KN-92</td><td rowspan=1 colspan=1> −67.2±1.2</td><td rowspan=1 colspan=1> τ h fast=0.74±0.08</td><td rowspan=1 colspan=1> 1.92±0.21</td><td rowspan=1 colspan=1> 915±58</td><td rowspan=1 colspan=1> −34.1±2.8</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+KN-93</td><td rowspan=1 colspan=1> −66.0 ±0.9</td><td rowspan=1 colspan=1> τ h fast=0.79±0.09</td><td rowspan=1 colspan=1> 2.06 ±0.11</td><td rowspan=1 colspan=1> 907±49</td><td rowspan=1 colspan=1> −32.8±3.1</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM+KN-92</td><td rowspan=1 colspan=1> −73.4±1.0 §</td><td rowspan=1 colspan=1> τ h fast=0.69±0.07</td><td rowspan=1 colspan=1> 2.00±0.15</td><td rowspan=1 colspan=1> 889±61</td><td rowspan=1 colspan=1> −33.1±2.2</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM+KN-93</td><td rowspan=1 colspan=1> −73.8±0.7 ∥</td><td rowspan=1 colspan=1> τ h fast=0.70±0.08</td><td rowspan=1 colspan=1> 1.95±0.09</td><td rowspan=1 colspan=1> 874±38</td><td rowspan=1 colspan=1> −32.5±2.1</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1> μ1+AIP</td><td rowspan=1 colspan=1> −66.9 ±0.9</td><td rowspan=1 colspan=1> τ h fast=0.71±0.08</td><td rowspan=1 colspan=1> 2.01±0.44</td><td rowspan=1 colspan=1> 907±61</td><td rowspan=1 colspan=1> −32.8±2.4</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1> μ1+CaM+AIP</td><td rowspan=1 colspan=1> −73.8±1.3 ¶</td><td rowspan=1 colspan=1> τ h fast=0.69±0.12</td><td rowspan=1 colspan=1> 1.92±0.69</td><td rowspan=1 colspan=1> 887±101</td><td rowspan=1 colspan=1> −32.1±3.2</td><td rowspan=1 colspan=1> 3</td></tr></tbody></table>
The action of CaM on effector molecules often requires Ca 2+; therefore, we studied the effect of different free intracellular Ca 2+concentrations on the CaM modulation of μ1 sodium channels. Our standard recording conditions included no intracellular Ca 2+buffering and 2 mmol/L external Ca 2+. There was no significant difference in the effect of CaM on μ1 Na +current when [Ca 2+] iwas buffered to 504 nmol/L compared with control recording conditions (data not shown). However, when extracellular Ca 2+was buffered with 0.1 mmol/L EGTA and 10 mmol/L BAPTA was added to the intracellular solution to ensure the removal of free Ca 2+, the CaM-induced shift of the steady-state inactivation curve was no longer present (Figure 1D). Thus, the effect of CaM on gating of the skeletal muscle Na +current is Ca 2+-dependent (Table 1).
Effects of CaM Coexpression on the hH1 Cardiac Na +Current
The carboxyl terminal IQ-like binding motif is conserved across all isoforms of the mammalian Na +channel. Therefore, we examined the effect of CaM on the function of the human heart sodium channel, hH1. When coexpressed with hH1, neither wild-type CaM nor mutant CaM 1234significantly altered any whole-cell property of the current (Table 2). Expression of wild-type CaM and mutant CaM 1234proteins was confirmed by immunofluorescence staining (data not shown). CaM coexpression had no effect on the hH1 Na +current either in the absence or presence of the β 1-subunit at any intracellular Ca 2+concentration. A cell line stably expressing hH1 was used for the β 1-subunit coexpression experiments. An ≈−10 mV shift in the steady-state inactivation curve is observed in these cells compared with cells transiently transfected with hH1; however, CaM overexpression had no effect on the voltage dependence of inactivation. The rates of entry into and recovery from inactivation of the stably expressed channels was slower than transiently transfected hH1, but CaM overexpression had no significant effect on the kinetics of inactivation (Table 2).
<table> Table 2.Functional Effects of CaM and Mutant CaM 1234on hH1 Expressed in HEK293<tr><th rowspan=1 colspan=1> Biophysical Parameters</th><th rowspan=1 colspan=1> Steady-State Inactivation(V ½in mV)</th><th rowspan=1 colspan=1> Decay Time Constant(τ hin ms at −30 mV)</th><th rowspan=1 colspan=1> Recovery From Inactivation(τ recin ms)</th><th rowspan=1 colspan=1> Entry Into Inactivation(Time Constant in ms)</th><th rowspan=1 colspan=1> Activation(V ½in mV)</th><th rowspan=1 colspan=1> n</th></tr><tr><td rowspan=1 colspan=7> n indicates number of cells.</td></tr><tr><td rowspan=1 colspan=7> *Significantly different from hH1+KN-92 ( P<0.05);</td></tr><tr><td rowspan=1 colspan=7> †significantly different from hH1+CaM+KN-92 ( P<0.05).</td></tr><tbody><tr><td rowspan=1 colspan=1> hH1</td><td rowspan=1 colspan=1> −82.6±0.8</td><td rowspan=1 colspan=1> τ h fast=0.89±0.05</td><td rowspan=1 colspan=1> 4.25±0.51</td><td rowspan=1 colspan=1> 1265±138</td><td rowspan=1 colspan=1> −53.4±3.1</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.58±0.65</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+CaM</td><td rowspan=1 colspan=1> −80.6 ±0.4</td><td rowspan=1 colspan=1> τ h fast=0.81±0.10</td><td rowspan=1 colspan=1> 4.77±0.30</td><td rowspan=1 colspan=1> 1225±131</td><td rowspan=1 colspan=1> −52.1±2.5</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.02±0.84</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+CaM1234</td><td rowspan=1 colspan=1> −80.3 5 ±0.5</td><td rowspan=1 colspan=1> τ h fast=0.77±0.06</td><td rowspan=1 colspan=1> 4.29±0.36</td><td rowspan=1 colspan=1> 1201±121</td><td rowspan=1 colspan=1> −52.9±2.7</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.14±0.81</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+β</td><td rowspan=1 colspan=1> −90.1±0.6</td><td rowspan=1 colspan=1> τ h fast=0.84±0.06</td><td rowspan=1 colspan=1> 8.89±0.76</td><td rowspan=1 colspan=1> 1308±137</td><td rowspan=1 colspan=1> −57.5±3.5</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.43±0.52</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+β+CaM</td><td rowspan=1 colspan=1> −89.6±0.5</td><td rowspan=1 colspan=1> τ h fast=0.83±0.07</td><td rowspan=1 colspan=1> 8.22±0.64</td><td rowspan=1 colspan=1> 1303±111</td><td rowspan=1 colspan=1> −57.1±3.6</td><td rowspan=1 colspan=1> 4</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.69±0.32</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1-IQ/AA</td><td rowspan=1 colspan=1> −83.2±0.9</td><td rowspan=1 colspan=1> τ h fast=0.85±0.13</td><td rowspan=1 colspan=1> 4.89±0.29</td><td rowspan=1 colspan=1> 1198±135</td><td rowspan=1 colspan=1> −53.7±3.4</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.09±0.49</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1-IQ/AA+CaM</td><td rowspan=1 colspan=1> −81.6±1.1</td><td rowspan=1 colspan=1> τ h fast=0.90±0.11</td><td rowspan=1 colspan=1> 4.99±0.31</td><td rowspan=1 colspan=1> 1167±147</td><td rowspan=1 colspan=1> −54.6±3.2</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.94±0.26</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+KN-92</td><td rowspan=1 colspan=1> −87.1±0.9</td><td rowspan=1 colspan=1> τ h fast=0.91±0.11</td><td rowspan=1 colspan=1> 14.77±0.95</td><td rowspan=1 colspan=1> 1123±145</td><td rowspan=1 colspan=1> −54.3±4.0</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.88±0.61</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+KN-93</td><td rowspan=1 colspan=1> −72.4±0.7 *</td><td rowspan=1 colspan=1> τ h fast=1.90±0.11 *</td><td rowspan=1 colspan=1> 7.49±0.92 *</td><td rowspan=1 colspan=1> 3064±245 *</td><td rowspan=1 colspan=1> −51.5±4.5</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=6.54±0.43</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+CaM+KN-92</td><td rowspan=1 colspan=1> −86.4±1.1</td><td rowspan=1 colspan=1> τ h fast=0.98±0.07</td><td rowspan=1 colspan=1> 13.05±0.68</td><td rowspan=1 colspan=1> 1390±205</td><td rowspan=1 colspan=1> −54.6±3.2</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=5.04±0.33</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+Ca+KN-93</td><td rowspan=1 colspan=1> −70.7±1.2 †</td><td rowspan=1 colspan=1> τ h fast=1.95±0.09 †</td><td rowspan=1 colspan=1> 6.79±0.89 †</td><td rowspan=1 colspan=1> 3114±231 †</td><td rowspan=1 colspan=1> −52.1±3.2</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=6.89±0.62</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+AIP</td><td rowspan=1 colspan=1> −83.2±0.9</td><td rowspan=1 colspan=1> τ h fast=0.84±0.08</td><td rowspan=1 colspan=1> 4.46±0.78</td><td rowspan=1 colspan=1> 1214±105</td><td rowspan=1 colspan=1> −52.2±3.4</td><td rowspan=1 colspan=1> 6</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.87±0.61</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr><tr><td rowspan=1 colspan=1> hH1+CaM+AIP</td><td rowspan=1 colspan=1> −82.9±1.3</td><td rowspan=1 colspan=1> τ h fast=0.86±0.09</td><td rowspan=1 colspan=1> 4.34±0.71</td><td rowspan=1 colspan=1> 1270±111</td><td rowspan=1 colspan=1> −52.9±3.0</td><td rowspan=1 colspan=1> 5</td></tr><tr><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1> τ h slow=4.91±0.54</td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td><td rowspan=1 colspan=1></td></tr></tbody></table>
Effects of CaM Binding on Skeletal Muscle Na +Currents Recorded From C2C12 Cells
In order to study the effect of CaM on native skeletal muscle Na +channels, we transfected wild-type CaM and mutant CaM 1234into C2C12 cells, a mouse myoblast cell line. C2C12 cells showed typical skeletal muscle sodium currents (Figure 2andTable 1), as previously reported.21The time constants of decay (τ h) and recovery from inactivation are modestly but significantly slower in C2C12 cells compared with expressed μ1 currents recorded under identical conditions (Table 1). In the absence of exogenous CaM, the steady-state availability of C2C12 Na +currents is shifted ≈−20 mV compared with expressed μ1 currents. Expression of wild-type CaM in C2C12 cells significantly shifts the steady-state availability of the Na +currents in the hyperpolarizing direction (Figure 2C). However, coexpression of mutant CaM 1234did not shift the voltage dependence of the steady-state availability relationship (Figure 2C). Neither wild-type nor mutant CaM 1234altered the other whole-cell properties of C2C12 Na +current (Figure 2,Table 1).
<here is a image 44fd2276a507c2cb-126bba2b02194e7f>
CaptionFigure 2.Biophysical properties of sodium currents recorded from C2C12 cells in presence of CaM or mutant CaM 1234. A, Representative currents through C2C12 Na +channels in the absence (solid line) or presence of overexpression of CaM (dashed line) or mutant CaM 1234(dotted line) were recorded as shown inFigure 1. B, Normalized IV relationships, similar toFigure 1B, show no change in C2C12 cells overexpressing CaM (circles) or mutant CaM 1234(triangles) compared with C2C12 Na +currents alone (squares). C, Steady-state inactivation relationship is obtained as described in Figure 1 and exhibits a shift similar to that of expressed μ1 currents in the presence of wild-type CaM.
Mutation of CaM Binding Site
The isoleucine-glutamine (IQ) CaM binding domain is essential for CaM-mediated Ca 2+-dependent inactivation of the L-type Ca 2+current. 17,18Yeast 2-hybrid assays have established CaM binding to an IQ-like motif on the carboxyl terminal region of Na +channels.20In order to determine the role of the Na +channel IQ motif in CaM-induced shifts in availability, we mutated IQ to alanines in both μ1 (I1727A-Q1728A, μ1-IQ/AA) and hH1 (I1908A-Q1909A, hH1-IQ/AA) Na +channels and then coexpressed these mutant channels with wild-type CaM and mutant CaM 1234. The IQ/AA mutations in the μ1 background significantly altered the whole-cell current compared with the wild-type current. The current decay became more obviously biexponential with the addition of a slow component of decay that resulted in a pedestal of current of ≈5% of the peak at 30 ms after the voltage step (Figure 3A). The peak IV relationship (Figure 3B) was not altered but the steady-state availability curve of μ1-IQ/AA was shifted ≈−10 mV compared with μ1-WT (Figure 3C,Table 1). Interestingly, by mutating the IQ motif, we abolished the CaM-induced shift of the steady-state availability relationship seen with coexpression of wild-type CaM and wild-type μ1 (Figure 3C,Table 1).
<here is a image c0760c5f34085771-8712f047e60c7393>
CaptionFigure 3.Biophysical properties of μ1-IQ/AA mutant channels expressed in HEK293 cells in presence of CaM. A, Representative sodium currents through wild-type (solid line) and μ1-IQ/AA channels (−CaM dashed line, +CaM dotted line) recorded during steps to −20 mV; compared withFigure 1A, the currents exhibited a delayed decay and a pedestal of residual current independent of the presence of CaM 30 ms after the pulse. B, There is no significant shift in the normalized IV relationship elicited from a holding potential of −120 mV for μ1-IQ/AA in the presence (circles) or absence of CaM (squares). C, μ1-IQ/AA shifts the steady-state inactivation curve in the hyperpolarizing direction independent of the presence of CaM (−CaM filled squares, +CaM filled circles) compared with wild-type μ1 (−CaM open squares, +CaM open circles).
In contrast to μ1-IQ/AA, hH1-IQ/AA did not exhibit changes in whole-cell current decay compared with wild-type hH1. The wild-type hH1 current decay was best fitted with a biexponential function, and neither the time constants nor amplitudes of the components were altered by the IQ/AA mutations. Not surprisingly, coexpression of wild-type CaM with hH1-IQ/AA had no effect on any of the whole-cell properties of the current (Table 2).
CaM Binding to the IQ Motif
The colocalization of CaM and the Na +channel is further supported by protein binding experiments. GST-fusion proteins of carboxyl-terminal regions containing the wild-type IQ motifs and the IQ/AA mutants of the hH1 and μ1 Na +channels were made. The carboxyl terminal μ1 and hH1 fusion proteins with an intact IQ binding motif interact with CaM. In contrast, neither of the IQ/AA mutant proteins are able to pull-down CaM (Figure 4). Therefore, binding of CaM to the IQ motif appears to be necessary for the modulation of μ1 channel gating but is not sufficient in that binding to the hH1 carboxyl terminus does not alter gating of the cardiac isoform.
<here is a image d1799de563d33210-d52ed2c2ccfc01b9>
CaptionFigure 4.NaIQ/CaM interaction assays. μ1 and hH1 GST-fusion proteins of the C-terminal domain containing either the wild-type (IQ) or the mutated IQ motifs (IQ/AA) were incubated with glutathione-linked beads followed by incubation in the absence of CaM, or a 1:1 molar ratio of NaIQ:CaM or 3:1 molar ratio of NaIQ:CaM (3×). CaM (120 ng) was run as a control. The lanes labeled GST had no fusion proteins in the mixture and served as a control. CaM was detected using an anti-CaM monoclonal antibody. Increasing the molar ratio of NaIQ enhanced the CaM pull-down. Mutating the IQ-motif of both μ1 and hH1 eliminated CaM binding as shown by the absence of CaM pull-down.
Effect of CaM-K Inhibition on Na +Currents
The cellular effects of CaM often involve downstream signaling through CaM-K. The activity of Na +channels is known to be modulated through different phosphorylation pathways. Because CaM binds to an IQ-like motif located in the C-terminus of Na +channel, phosphorylation of the channel by CaM-K is possible. The isoform-specific differences in the response to CaM may result from differences in the channels as substrates for phosphorylation by CaM-K. To assess this possibility, we used a nonselective CaM-K inhibitor, KN-93, and its inactive analog, KN-92. We applied KN-93 and KN-92 intracellularly at a concentration of 10 μmol/L to μ1 Na +channels expressed alone and in the presence of CaM.
KN-93 and the inactive analog KN-92 had no effect on the voltage dependence or kinetics of μ1 gating either in the presence or absence of CaM overexpression. Specifically, neither compound altered the rate of current decay (Figure 5B), rates of recovery from or entry into inactivated states (Table 1). Further, neither compound altered the CaM-induced hyperpolarizing shift of the steady-state availability relationship of μ1 Na +channels (Figure 5A). The CaM-KII–specific inhibitor AIP (100 nmol/L) was applied to expressed μ1 currents with results similar to the KN compounds. AIP did not alter the voltage dependence or kinetics of gating of μ1 channels and did not diminish the hyperpolarizing shift of the steady-state inactivation relationship induced by CaM overexpression (Table 1).
<here is a image b25f7314b536a6ff-53b89c73c1c9b910>
CaptionFigure 5.Effect of CaM-K inhibition on μ1. A, Neither KN-93 (−CaM open squares, +CaM open circles) nor KN-92 (−CaM filled squares, +CaM filled circles) significantly shifts the steady-state inactivation curve of μ1 Na +currents. B, Representative Na +currents through μ1 channels in the presence of the CaM-K inhibitor KN-93 (−CaM solid line, +CaM dashed line).
In contrast, KN-93 had robust effects on hH1 current, independent of CaM coexpression. KN-93 slowed the current decay with the most prominent effect on the fast time constant (Figure 6A,Table 2), shifted the steady-state inactivation relationship in depolarizing direction (Figure 6B), and slowed entry into inactivated states (Figure 6D,Table 2).
<here is a image 256fc972618ec035-8d3d83649a8735bb>
CaptionFigure 6.Effect of CaM-K inhibition on hH1. A, Representative Na +currents through hH1 channels in the presence of the CaM-K inhibitor KN-93 (−CaM dashed line, +CaM dotted-dashed line) and its inactive analog KN-92 (−CaM solid line, +CaM dotted line). B, KN-93 (−CaM open squares, +CaM open circles) shifts the steady-state inactivation curve by ≈15 mV in the depolarizing direction compared with hH1 treated with KN-92 (−CaM filled squares, +CaM filled circles) and ≈10 mV compared with hH1 alone. C, Recovery from inactivation, elicited by a 30-ms prepulse to −30 mV with varying rest intervals at −120 mV followed by a 30-ms test pulse to −30 mV, is hastened by KN-93 but not KN-92. D, Entry of hH1 Na +currents into inactivated states assayed by varying the duration of a conditioning pulse to −30 mV followed by a return to −120 mV for 10 ms followed by a 30-ms test pulse to −30 mV is delayed by KN-93 but not KN-92.
KN-92 also had effects on hH1, but not μ1 currents: it shifted the steady-state inactivation curve in the hyperpolarizing direction and produced an apparent slowing of recovery at −120 mV. However, the currents are not fully reprimed at this voltage in the presence of KN-92. KN-92, and to a lesser extent KN-93, retards recovery from inactivation compared with hH1 alone; therefore, KN-induced slowed recovery from inactivation cannot be considered a specific effect of CaM-K inhibition. The slowing of recovery by these compounds was not observed in expressed μ1 channels.
In contrast, AIP, a selective CaM-KII inhibitor, had no effect on channel activity and did not block the depolarizing shift in the steady-state inactivation curve by the subsequent addition of KN-93 to the bath (data not shown). Thus, a CaM-K other than CaM-KII, possibly CaM-KIV, which is richly expressed in the heart, may modulate the shift in the voltage dependence of inactivation of cardiac Na +channels.
Discussion
CaM is the most ubiquitous Ca 2+-sensing protein in mammalian cells. The Ca 2+/CaM complex directly modulates the function of a number of proteins including a family of serine/threonine kinases (CaM-K), ion channels, and receptors. CaM that is constitutively tethered to L-type Ca 2+channels mediates Ca 2+-dependent inactivation and facilitation of the current. 16–18On Ca 2+binding, CaM associates with a conserved IQ motif23in the carboxyl terminus of the channel. The presence of a highly conserved IQ-like motif in the carboxyl terminus of the Na +channel suggested the possibility of CaM-mediated modulation of Na +currents. Supportive evidence for such a mechanism included the demonstration of Ca 2+-dependent and Ca 2+-independent binding of CaM to a carboxyl terminal fragment of the Na +channel containing the IQ motif.20The functional consequences, if any, of CaM binding to the Na +channel were previously unknown.
We demonstrate that CaM does indeed modify the function of the μ1 skeletal muscle isoform of the Na +channel, shifting the steady-state inactivation curve in the hyperpolarizing direction (Figure 1,Table 1). The CaM effect on gating requires intact Ca 2+binding because a mutant, CaM 1234, with impaired Ca 2+binding does not alter the gating of the μ1 Na +channel. In addition, buffering of Ca 2+eliminates the wild-type CaM-mediated shift in steady-state availability (Figure 1D,Table 1). As expected, buffering Ca 2+produced a hyperpolarizing shift in channel gating, and we cannot exclude the possibility that this shift masks the CaM effect. CaM modulation of the skeletal muscle Na +channel does not require the presence of the β 1-subunit, nor does β 1alter the effect of CaM on the expressed current (Table 1). The modulation of the expressed μ1 current was recapitulated in C2C12 cells, a bona fide skeletal muscle cell line. These data suggest that native skeletal muscle channels, regardless of subunit composition, are targets for CaM.
Analogous to the Ca 2+channel, an IQ-like motif is a crucial component of the functional effects of CaM on skeletal muscle Na +channels. Mutation of the IQ motif eliminates CaM binding to (Figure 4) and modulation (Figure 3) of μ1 skeletal muscle currents. Our data indicate that the IQ motif has important functional effects on skeletal muscle Na +currents independent of CaM binding. Indeed, the μ1-IQ/AA mutation itself slows the decay of the whole-cell current and shifts the steady-state inactivation curve to hyperpolarized potentials relative to wild-type μ1. In fact, the shift in the availability curve produced by mutating IQ to AA exceeds the shift produced by coexpression of CaM with wild-type μ1. It is unlikely that the effect of the IQ to AA mutation is simply the result of a loss of CaM binding because the direction of the shift is opposite to what would be predicted by the elimination of CaM binding (Figure 3C). Instead, this suggests that the IQ region of the skeletal muscle Na +channel is an important component of the channel’s inactivation machinery that is modulated by CaM-mediated signaling.
IQ-mediated binding of CaM to Na +channels is a necessary but not sufficient condition for modulation of channel function. hH1 and μ1 Na +channels have IQ motifs with similar CaM binding capacity (Figure 4), yet CaM coexpression does not alter the function of hH1 channels. The difference in the functional effects of CaM on the Na +channel isoforms may be the result of the conformation of CaM bound to the channel. It has been shown that CaM can bind to the IQ motif of the rat brain II Na +channel in its Ca 2+-bound and Ca 2+-free (apo-CaM) states.20Indeed, Ca 2+buffering eliminates CaM modulation of μ1 channel gating (Figure 1D). However, the functional roles of the IQ motifs in skeletal muscle and cardiac Na +channels appear to differ independent of CaM binding, as revealed by the IQ/AA mutant channels. Unlike the μ1 mutant channel, hH1-IQ/AA does not alter gating (Tables 1 and 2).
Alternatively, binding of CaM to the Na +channel may serve to facilitate phosphorylation of the channel complex by CaM-K. We do not have direct evidence for phosphorylation of either channel isoform; however, inhibition of CaM-K (possibly CaM-KIV) modifies cardiac Na +channel inactivation, shifting the steady-state inactivation curve in the depolarizing direction, slowing entry into inactivated states, and hastening recovery when compared with the inactive analog KN-92. KN-92 itself has effects on the cardiac Na +channel (shifting the inactivation curve in the hyperpolarizing direction and slowing recovery) that cannot be ascribed to CaM-K inhibition. The differential effects of CaM-K inhibition on skeletal muscle and cardiac channels suggest the possibility of distinct functionally significant phosphorylation sites on each of the channel isoforms. However, the existence and precise identity of such sites remain to be demonstrated.
CaM signaling appears to fine-tune the function of voltage-dependent Na +channels in isoform-specific ways. The physiological significance of such modulation is uncertain, but recruitment of CaM signaling tends to stabilize inactivation of skeletal muscle and cardiac channels, albeit by distinct molecular mechanisms.
Interestingly, the C-terminal region of the cardiac Na +channel is a hot spot for mutations that cause inherited cardiac arrhythmias, such as long-QT and Brugada syndromes. 24–30We have recently demonstrated that the C-terminus of the Na +channel plays a role in fast inactivation.31A common theme is that these disease-causing mutations alter gating and often disrupt inactivation of the Na +channel. The mutations may directly alter Na +channel function; however, it is possible that the effect of the mutation is through interruption of CaM/CaM-kinase signaling leading to destabilization of inactivation of the Na +channel.
In the heart under pathophysiological conditions associated with increased intracellular Ca 2+, CaM-KII appears to enhance the arrhythmogenic transient inward current.32Our data suggest that CaM may also regulate activation and repolarization of heart cells through effects on Na +channels altering the susceptibility to arrhythmias. Similarly, modulation of Na +channel availability may regulate the frequency of action potential firing in skeletal muscle, a possible mechanistic link to myotonias.
This manuscript was sent to Harry A. Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Footnotes
Correspondence to Gordon F. Tomaselli, MD, The Johns Hopkins University School of Medicine, 720 N Rutland Ave, 844 Ross Building, Baltimore, MD 21205. E-mail [email protected]
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(PDF) A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies from a Regional Innovation System in Western Switzerland
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies from a Regional Innovation System in Western Switzerland
November 2016
Technology Innovation Management Review 6(11):32-39
DOI: 10.22215/timreview/1033
Vincent Grèzes
HES-SO Valais-Wallis
University of Applied Sciences Western Switzerland / Valais-Wallis (HES-SO Valais-Wallis)
HES-SO Valais-Wallis
Download full-text PDF
Abstract and Figures
Despite the presence of a regional innovation system, the gross value added attributed to tourism in the Swiss region of Valais is declining. Innovation policies fostering private initiatives and collaboration between companies, researchers, and coaching services have been reinforced recently, and policy instruments are in place to support strategic industries. However, no incitement instrument is dedicated to supporting the co-creation and the creation of shared value through local actors. This article presents a co-creation process of shared value and the lessons learned while implementing a new mode of innovation and entrepreneurship in two case studies in the peripheral region of Valais, Switzerland. The aim of the process is the co-creation of shared value-based business models, with an emphasis on the use of crowdsourcing to find new ways to create shared value.
Co-created business model canvas for the Stars Park in the Val d'Anniviers …
Figures - uploaded by
Marc Schnyder
Content uploaded by Marc Schnyder
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
32
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A Process for Co-Creating Shared Value with the
Crowd: Tourism Case Studies from a Regional
Innovation System in Western Switzerland
Vincent Gr è zes, Béatrice Girod Lehmann,
Marc Schnyder, and Antoine Perruchoud
Introduction
Tourism generates almost 11% of the gross value added
of the canton of Valais, Switzerland, and almost 20% of
the workplaces of the region in 2014. However, the tour-
ism economy in the region of Valais faces a series of
challenges such as aging infrastructure, the emergence
of new competing tourism destinations, changes in cus-
tomer behaviour and in the legal framework, and the
high value of the Swiss franc. In 2014, the region wel-
comed almost 22 million visitors, who spent around 3.4
million Swiss francs; but this represents a decline of 4
million visitors from the level seen in 2000 (OVT, 2016).
Hence, the tourism economy must now assert itself in a
highly competitive international market. The small and
medium-sized enterprises (SMEs) from Valais must
therefore find innovative development approaches and
new ideas that will be useful to not only tourism busi-
nesses and clients, but the local population as well.
Despite the presence of universities of applied sciences,
a SWOT analysis of the French speaking part of Switzer-
land (Western Switzerland) realized by the Conference
of the Heads of Department of Public Economy in the
field of innovation policies for the period 2012–2015, re-
vealed gaps in SMEs’ cooperation with schools and re-
search institutes, as well as in the innovation process of
the region's firms. The analysis concluded that, despite
the improvement of coaching services and technology
accessibility through the regional innovation system,
the innovation intensity declined in the region (CDEP-
SO, 2015). Hence, the current interregional program
aims to improve and to foster synergies and the conver-
gence of actual innovation services. This program, pro-
moting a regional innovation system that is able to
reinforce the relations between firms, scientists, and in-
stitutions, aims to finance and to initiate accompany-
ing innovative projects using sectorial (e.g., ICT,
cleantech) and thematic approaches with the Innotour
Despite the presence of a regional innovation system, the gross value added attributed to
tourism in the Swiss region of Valais is declining. Innovation policies fostering private initi-
atives and collaboration between companies, researchers, and coaching services have
been reinforced recently, and policy instruments are in place to support strategic indus-
tries. However, no incitement instrument is dedicated to supporting the co-creation and
the creation of shared value through local actors. This article presents a co-creation pro-
cess of shared value and the lessons learned while implementing a new mode of innova-
tion and entrepreneurship in two case studies in the peripheral region of Valais,
Switzerland. The aim of the process is the co-creation of shared value-based business mod-
els, with an emphasis on the use of crowdsourcing to find new ways to create shared value.
Life can be much broader, once you discover one
simple fact, and that is that everything around you
that you call life was made up by people that were
no smarter than you. And you can change it, you
can influence it, you can build your own things that
other people can use.
Steve Jobs (1955–2011)
Entrepreneur, inventor, and industrial designer
“ ”
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
policy, which is dedicated to tourism. According to the
broader New Regional Policy, the Swiss regional innova-
tion systems refer to functional economic spaces, bene-
fiting from the triple helix essential to the innovation
process (firms, universities, and institutions) (CDEP-
SO, 2015). But, except for the Innotour policy support-
ing cooperation actions such as bundling products, no
incitement instrument is dedicated to fostering tourist-
ic activities using a tourism clustering approach, such
as fostering the interconnections between companies
and institutions involved in tourism activities, includ-
ing suppliers, services, governments, higher-education
institutions, and competitors (Capone, 2004).
This approach relies, however, on a new paradigm de-
scribed by Porter and Kramer (2011) through the
concept of creating shared value, which expresses that
“societal needs, not just conventional economic needs,
define markets, and social harms can create internal
costs for firms”. As formulated by Alia (2011), the argu-
ment of Milton Friedman expressing that “What is good
for business is good for society” can be now reworded
according to Porter’s theory of creating shared value to
“What is good for society is good for business”. Indeed
Porter and Kramer (2011) present three different levels
of action enabling companies to create shared value: i)
at the enterprise level, in the design of products and
markets; ii) in terms of economic sectors, in defining
(and redefining) productivity in the value chain; and iii)
at the level of the interaction of companies with their
environment (including research institutes), allowing
the formation of clusters at local level. Moreover,
Kramer and Pfitzer (2016) assert that “companies must
sometimes team up with governments, NGOs, and even
rivals to capture the economic benefits of social pro-
gress”. Indeed, clusters constitute strategic regional re-
sources in order to support innovation and to
transform it into regional development and competit-
iveness by facilitating relations and canalizing know-
ledge (Alberti & Giusti, 2012).
Developing a competitive advantage requires consider-
ation of the business environment, both in terms of re-
source management and adaptation of business value
proposals to the market. These considerations are part
of the concept of customer development proposed by
Blank (2011) based on customer discovery, customer
validation, customer creation, and company building.
Cadman and Bildfell (2012) report that important
shared value initiatives have been implemented by
more and more companies. However, until now, only
about 10% of companies have integrated customer ex-
perience in their core strategy. According to Köpcke
(2008), external collaboration such as through open in-
novation or crowdsourcing allows organizations to pro-
mote better public adoption of innovations in a context
where the average rate of the innovation failure is
between 30% and 70%. Some experimentation has been
done in order to involve the public in the innovation
process among tourism practitioners using open innov-
ation or crowdsourcing approaches (Doctor et al., 2016)
or with a living lab approach (Lapointe et al., 2015).
However, according to our research, few studies have
been undertaken focusing on the question of fostering
innovation and growth in a touristic region through the
creation of shared value or on improving local touristic
clusters with the crowd (i.e., professionals, residents,
and tourists).
Hence, this article presents lessons learned through the
implementation of new modes of innovation through
improved cooperation between local companies in the
region of Valais, Switzerland. The aim is to use a crowd-
sourcing approach to co-create shared value-based
business models and thereby find new way to create
shared value.
Methodology
We chose the multiple case study method for its capa-
city, in a qualitative approach, to identify the effects of
a phenomenon where the researchers have little con-
trol over the studied events; moreover, the multiple
case study approach allows us to consider the phe-
nomenon in recurrent situations (Collerette, 1997;
Stake, 1994; Yin, 1984). Two regions were selected as
cases, according to the need identified by our political
and professional partners (i.e., local development agen-
cies and the regional company association). The mul-
tiple case study approach enables us to test two distinct
situations. The first case was realized with a group of
beneficiaries belonging to the same enterprise, which is
an entire resort of 100 chalets developed 35 years ago
under the umbrella of one single enterprise (Fedo
Tschuggen AG), and which was in financial difficulties.
The second case was dedicated to a group of un-
bundled beneficiaries but based on a united territory:
the Val d’Anniviers, which is facing a strong decline in
visits by tourists.
In order to elicit new paths of innovation, we used
crowdsourcing that, in opposition to outsourcing,
refers to the crowd (Howe, 2006) for its ability to gener-
ate ideas without distinguishing between contributors
and allowing professionals, the residents, and tourists
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
to participate. Crowdsourcing is a quick and easy way
to involve a large community to gather ideas in order to
solve a problem (Mendoca & Sutton, 2008). Gassmann
(2013) describes the crowdsourcing process as "inter-
active new knowledge transfer and problem solving to
external stakeholders through public and semi-public
call to a large group. Creative topics are typically at the
center, but repetitive tasks are also possible. Typically,
this call is made through Internet”. In summary, Gass-
mann defines crowdsourcing as “an interactive innova-
tion strategy based on the community.” Operationally,
this research relies on phases adapted from the five
steps of crowdsourcing identified by Muhdi and col-
leagues (2011) (Figure 1).
Finally, in order to facilitate cooperation and co-cre-
ation among the local professionals, we used Oster-
walder and Pigneur's (2011) business model canvas
because of its ease of use and effectiveness as a brain-
storming tool. Indeed, its nine building blocks enable
participants to brainstorm about a business project,
which then allows multiple stakeholders to co-create a
new and common business model.
Although co-creation is commonly understood as joint
value creation by a company and its customers, where
value creation comes from outside of the firm and the
traditional value chain model (Prahalad & Ramaswamy,
2004; Porter, 1980), we used a different position of fos-
tering co-creation through local professionals using the
inputs of the crowd in the idea-generation process.
With this approach, we tend to reinforce the coopera-
tion between local enterprises, according to the expect-
ations of the public.
Project Details
In order to meet the expectations and needs of the pop-
ulation and the hosts, who are the end consumers of
the tourism products and services, we chose to imple-
ment the steps of customer discovery and customer val-
idation through a crowdsourcing process.
Crowdsourcing enabled us to generate a "4P" process
involving a partnership of people (population), private
companies, and the public institutions and researchers.
Indeed, the applied research at the basis of the innova-
tion policy described in this article is based on a partner-
ship between the Entrepreneurship & Management
Institute and the Tourism Institute of the University of
Applied Sciences of Western Switzerland (HES-SO Valais
Wallis;
hevs.ch/en/
) and the local economic development
agencies: the Valais Excellence company association
(
valais-excellence.ch/fr/amvs/
), the regional brand Valais
Wallis (
valais.ch/en/
), the Valais Tourism Observatory
(
tourobs.ch
), and the Regions- und Wirtschaftszentrum
Oberwallis (
rw-oberwallis.ch/allgemein/home
).
According to Muhdi and colleagues (2011), the five key
phases of crowdsourcing (Figure 1) contain specific sub-
tasks that we operationalized to foster the creation of
shared value through crowd innovation, as shown in
Table 1. The crowdsourcing process was realized with
the iBrain (
ibrain.atizo.com
) online innovation platform,
which is a branded version of the Swiss crowdsourcing
platform developed by Atizo AG for the University of Ap-
plied Sciences of the Valais.
Results
By the end of the crowdsourcing process, the first case
(the chalet resort) had attracted 88 ideas from 35 differ-
ent people. However, despite the many novel ideas
arising out of the crowdsourcing process, a lack of effect-
ive communication between the key stakeholders (i.e.,
the shareholders and chalet owners) – apparently
related to the financial difficulties affecting the resort –
meant that they could not agree on a new convergent
business model. Hence, this case failed to reach its ob-
jective of improving the situation of a single enterprise
because of the unwillingness of long-term partners to
cooperate in a new project. It appears that, before any
concrete work can begin, a fundamental discussion of
objectives must be undertaken by the shareholders, who
currently are unable to agree on a common goal.
The crowdsourcing process of the second case (Val
d’Anniviers) collected 64 ideas from 34 different people.
The stakeholders of this case are local professionals
from this newly merged municipality, which is a re-
grouping of six ancient municipalities. The new muni-
Figure 1. The five phases of the crowdsourcing process
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
Table 1. Alignment of this study's project phases with important crowdsourcing tasks of crowdsourcing identified by
Muhdi et al. (2011)
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
cipality has already established a tourism commission
to cooperate between political and professional per-
sons in order to improve the attractiveness of the re-
gion to tourists. The participants represented local
politicians and local touristic professionals such as ho-
tels, cable car companies, real estate agencies, trans-
portation organizations, and specialized shops. The
participants selected a niche idea: the creation of a
"stars park" for stargazing. For the professionals, this
could be an opportunity to reinforce the attractiveness
of the local area. For visitors, the project aims to offer a
new experience by creating a pool of darkness that be-
comes an ideal location to view the night sky. For the
municipality, the project aims to strengthen local skills
and resources while incorporating best practices in en-
ergy savings at the municipal level. Figure 2 shows the
corresponding business model co-created following
the crowdsourcing process. This business model is
based on existing local key resources: dark places (due
to the location in a narrow valley) and the local sky ob-
servatory, as well as reinforced communication, spe-
cialized human resources (e.g., astronomers), and
dedicated labels. Building on those resources, this mod-
el will propose values such as knowledge from the sky
and the stars, discovery experiences (e.g., astronomy,
local products, new activities, silence, or concerts in
the mountains) to a varied public (e.g., local tourists,
families, seniors, and workers). The relationship with
customers should enhance experience with weekly sky
maps, and channels should be improved by partner-
ships, such as with scientific camps, public transport
partners, and craftsmen and economic associations.
During this designing phase, the blocks of the model
relating to revenue streams and cost structures were
not addressed because of the time available for the
brainstorming and the difficulties in building such fin-
ancial plans in this co-creation phase and the visionary
character of the discussions.
The next steps of the project will be led by a team of
students specialized in tourism products and services
design supervised by two professors specialized in
business model innovation and in service design meth-
ods from the School of Business and Tourism of the
University of Applied Sciences of Western Switzerland
(HES-SO Valais-Wallis). The measurement of energy
savings and public awareness will be achieved by a
multidisciplinary team of researchers capable of meas-
uring the energy savings and reductions in light pollu-
tion.
Figure 2. Co-created business model canvas for the Stars Park in the Val d’Anniviers
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
Conclusion
The results of the case studies show different outcomes
emerging from different situations. On one hand, when
the shareholders were initially brought together, they
had not been able to overcome their existing postures
to benefit from the crowdsourcing approach to reveal-
ing opportunities. Indeed, the previous relationship
and the challenge it represented was the main cause of
the failure of the process. This case teaches us that a
lack of existing conflicts between stakeholders can be
seen as a necessary starting condition for success of the
co-creation process. On the other hand, when a group
of professionals was unbundled, the elaboration of a
new idea to cope with a societal challenge reached the
best results. The proposed “stars park” constitutes a
new product and service relying on existing resources.
Our results also show that the participation of the popu-
lation, with all the creativity it can demonstrate, is not
useful without a healthy collaboration between the
stakeholders. Finally, this project includes all three
levels of action enabling the creation of shared value ac-
cording to Porter and Kramer (2011): designing new
products and markets, redefining productivity in the
value chain, and allowing the formation of clusters at
local level.
We also realized a distinction between the creation of
shared value, as argued by Porter and Kramer (2011),
and the co-creation of shared value. The co-creation of
shared value is based on crowdsourcing the original
business idea and then co-creating business solutions
with several actors. Furthermore, the distinction with
the sharing economy concept is based on the aim of the
project, seeking to create value for the society and the
environment in addition to businesses. The sharing
economy constitutes “a principle of maximizing the
utility of assets and shareable resources by means of
renting, lending, swapping, bartering and giving them
away in order to avoid their idle existence, and is cur-
rently being facilitated by emerging collaborative busi-
ness ICT infrastructures in the marketplace and soci-
ety" (Romero et al., 2015).
The major limitations of this research are based on the
provenance of the original needs that we intentionally
sourced from the local professionals in order to facilit-
ate our sectorial approach to tourism activities. This
point will be addressed in a further research where the
expression of the needs is based on a citizen dialogue at
a municipal scale, aiming at eliciting societal and local
challenges and looking for social innovation.
Regarding the improvement of the regional innovation
system and the enhancement of the local cluster, the
Valais Excellence enterprises’ association recognized
the utility of the process and will integrate and repro-
duce it in order to further fostering innovation through
the co-creation of shared value in the region. They
already plan to elaborate an indicator model able to
measure the creation and the co-creation of shared
value by future participants.
Acknowledgments
The results of the first case in this study were presented
at the 5th NORSA Conference held in in Grimstad, Nor-
way, on January 15–16, 2015, and the results of the
second case were discussed at the 10th International
Regional Innovation Policies Conference held at the
Karlsruhe Institute of Technology (KIT) on October
14–16, 2015, which were organized together with the
Fraunhofer Institute for Systems and Innovation Re-
search ISI, Karlsruhe, and the Bureau d'Economie
Théorique et Appliquée (BETA) at the Université de
Strasbourg. We thank our colleagues, the conference
participants, and the reviewers and editors of the TIM
Review for their precious feedback and recommenda-
tions.
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
38
ics and Social Sciences from the University of Fri-
bourg, Switzerland, and holds a master's degree
from Western Washington University in the United
States.
Technology Innovation Management Review November 2016 (Volume 6, Issue 11)
39
www.timreview.ca
Citation: Gr è zes, V., Girod Lehmann, B., Schnyder, M., & Perruchoud, A. 2016. A Process for Co-Creating Shared Value with the Crowd:
Tourism Case Studies from a Regional Innovation System in Western Switzerland. Technology Innovation Management Review , 6(11): 32–39.
http://timreview.ca/article/1033
Keywords: innovation, tourism, tourism cluster, co-creation, shared value, regional innovation system, crowdsourcing, business models
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http://dx.doi.org/10.1007/978-3-319-24141-8_40
Stake, R. E. 1994. Case Studies. In N. K. Denzin & Y. S. Linco (Eds.),
Handbook of Qualitative Research: 236–247. London: Sage.
Yin, R. K. 1984. Case Study Research, Design and Methods. London:
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A Process for Co-Creating Shared Value with the Crowd: Tourism Case Studies
Vincent Gr è zes, Béatrice Girod Lehmann, Marc Schnyder, and Antoine Perruchoud
... In the first category, there was a variety of data collection and techniques of analysis. Articles on case studies performed data triangulation (e.g.,
Grezes et al., 2016;
Wiltshier & Clarke, 2017), content analysis of in-depth interviews (e.g., Reichenberger, 2017), analysis of short interview content (e.g., Kelly et al., 2017), narrative analysis (Wood & Kinnunen, 2020), and analysis of documents (e.g., Davey et al., 2017). Moreover, the contexts were wide-ranging including agritourism, festivals, sharing economy, etc., as were the units of analysis (tourists, guests, researchers, employees, and companies, among others). ...
Value co-creation in tourism and hospitality: A systematic literature review
Article
Thiago de Luca Sant'ana Ribeiro
B. K. Costa
Manuel Aníbal Silva Portugal Vasconcelos Ferreira
Otávio Bandeira De Lamônica Freire
... Despite the burgeoning literature on digital entrepreneurship and business models in the sharing economy, there are only a few case studies shedding light on their regional dimension: Paulauskaite et al. (2017) demonstrate the importance of the sharing economy for the regional economies, for instance, Airbnb connected to regional tourism.
Grèzes et al. (2016)
, and Gyimóthy and Meged (2018) highlight the specific business models for tourism-based sharing-economy initiatives in a specific case region. Other examples presented for the sharing economy in its regional context illustrate urban phenomena such as fashion libraries in Nordic capital cities (Pedersen and Netter 2015). ...
Regional Sharing-Economy Entrepreneurs and the Diversity of Their Business Models
Chapter
May 2021
Birgit Leick
Mehtap Aldogan Eklund
Susanne Gretzinger
Anna Marie Dyhr Ulrich
... The available case studies show that tourism is an industry that offers such opportunities.
Grèzes et al. (2016)
illustrate how crowdsourcing technologies were used in a Swiss tourism cluster to develop new ideas and attract new business opportunities for the regional tourism industry. Gyimóthy and Meged (2018) report about a Danish municipality that established a sharingeconomy based communitarian tourism initiative to make the destination more attractive to visitors. ...
Digital entrepreneurs in the sharing economy
Chapter
Jan 2020
Birgit Leick
Mehtap Aldogan Eklund
Co-creation in tourism: a systematic mapping study
Article
Full-text available
Tourism Rev
hamid reza Yazdani
Purpose
The purpose of this study is to organize and analyze the existing literature on co-creation in tourism to identify the state-of-the-art studies and the research gap in this field.
Design/methodology/approach
As the research questions seek to provide an overview of the studies in the available literature, the systematic mapping study (SMS) has been selected as the research method. A suitable mapping study method for analyzing and structuring a broad research field concerning methods, designs and research focuses on the existing publications. In total, 137 articles published during 2006–2019 in reliable academic databases such as Science Direct, Emerald, Scopus, Wiley, ProQuest, Sage, Web of Science and Taylor and Francis were selected and analyzed.
Findings
The results show a rising trend of published articles in tourism, with the maximum number published in 2019 and the minimum number in 2006. Also, analysis of input articles revealed that most of the studies focused on the antecedents and prerequisites for co-creation and paid less attention to the co-creation context. Other findings show that in the field of tourism, the hospitality sector, especially hotels have paid special attention to co-creation. The majority of papers were the empirical type with quantitative design. Furthermore, most studies used the survey method, while the case study and other methods were the next choices.
Originality/value
This study addresses a major research gap by summarizing the literature related to value co-creation with a specific focus on tourism using the SMS method that provides an overview of the studies in this field. Categorizing papers through SMS helps researchers to review the status of studies in a visual summary to identify gaps and directions for future research.
Regional Innovation Ecosystems and Smart Specialization: Opportunities and Challenges for Regions
Article
Global competition is today a reality and making smart regions smarter through smart specialization is currently on the political and economic agenda of territories. This study aims to contribute to clarifying the framework for the regional innovation ecosystems as well as identifying new research paths. Through extensive research using the Web of Science database with resource to a bibliometric analysis on smart specialization, six clusters were identified: cluster 1-innovation networks and triple helix; cluster 2-regional innovation systems; cluster 3-regional innovation network; cluster 4-smart innovation policies; cluster 5-smart specialization; and cluster 6-Asian innovation systems. Several future lines of research recently published in literature distributed by the six clusters were identified. This study also contributes to open new research horizons in these areas of knowledge, allowing the emergence of new streams of thought on the part of scholars, policymakers, economic agents and society in general.
MODELE BIZNESOWE GOSPODARKI CYFROWEJ JAKO CZYNNIK ZMIAN STRUKTURALNYCH RYNKU TURYSTYCZNEGO - STAN BADAŃ
Cel. Identyfikacja luki badawczej w obszarze modeli biznesowych (MB) w turystyce i sformułowanie programu badań w tym zakresie w celu analizy zmian strukturalnych rynku. Metoda. Przegląd i synteza publikacji z baz EBSCO, Emerald Insight, ProQuest, Science Direct i Web of Science, poświęconych MB w turystyce w latach 2000-2018. Identyfikacja wspólnych tematów i wskazanie luk badawczych. Wyniki. Wyodrębniono najczęściej podejmowane tematy badawcze: 1) konfiguracje MB w obszarach: turystyki i hotelarstwa, transportu, usług pośrednictwa i e-commerce; 2) analiza typów wartości; 3) trwałość modelu biznesowego; 4) podatność na wpływ technologii; 5) rola otoczenia formalno-prawnego. Ograniczenia badań i wnioskowania. Zakres analizy ograniczono do wymienionych baz danych i przeglądu artykułów naukowych w języku angielskim. Pominięto raporty branżowe, jako niespełniające wymogów metodologicznych prac naukowych, mimo że ilustrują one zjawisko pojawiania się nowych podmiotów w turystyce oraz zanikania granic rynków, branż i pod-miotów. Implikacje praktyczne. Operacjonalizacja koncepcji MB i odpowiedź na pytanie, jakie jest rzeczywiste źródło kryzysu branż i podmiotów rynku turystycznego, pozwoli uniknąć niewłaściwych rozwiązań. Pomimo zmian ustawowych, ukierunkowanych na zapewnienie jednakowych warunków prawnych funkcjonowania podmiotów gospodarki turystycznej, utrzymują się różnice wynikające z różnej efektywności MB oraz niedostrzegania zmian strukturalnych, ograniczających szanse rozwoju i elastycznego reagowania na warunki otoczenia. Oryginalność pracy. Artykuł wskazuje, w jaki sposób naukowcy poddają operacjonalizacji koncepcję MB i postrzegają warunki jego modyfikacji. Wraz z ustalonymi kierunkami dalszych badań, pozwoli to ustanowić wspólną podstawę koncepcyjną i usystematyzować zasoby wiedzy przydatne w badaniach MB rynku turystycznego. Rodzaj pracy. Artykuł o charakterze przeglądowym.
Digital Economy Business Models as Factors of Structural Change in the Tourist Market – State of Research
Article
Full-text available
Purpose. Identifying the research gap in the area of tourism business models (MB) and formulating a research programme to analyse structural changes within the tourism market. Method. Review and synthesis of publications from the EBSCO, Emerald Insight, ProQuest, Science Direct and Web of Science databases, devoted to tourism MB in the years 2000-2018. Identification of common topics and identification of research gaps. Findings. The research topics most frequently undertaken were: 1) MB configurations in the areas of tourism and hotel industry, transport, brokerage services and e-commerce; 2) analysis of value types; 3) sustainability of the business model; 4) susceptibility to the impact of technology; (5) role of formal and legal environment. Research and conclusion limitations. The scope of analysis was limited to the mentioned databases and a review of scientific articles in English. Industry reports were omitted as not meeting the methodological requirements of scientific works, despite the fact that they illustrate the phenomenon of the emergence of new entities in tourism and the disappearance of the borders of markets, industries and entities. Practical implications. Operationalisation of the MB concept and the answer to the question, what is the real source of the crisis of the industries and entities of the tourist market, will lead to avoiding improper solutions. Despite statutory changes aimed at ensuring equal legal conditions for the functioning of tourism economy entities, differences resulting from different MB effectiveness and failure to recognise structural changes limiting the chances for development and flexible response to environmental conditions persist. Originality. In the article, it is indicated how scientists operationalise the MB concept and perceive the conditions for its modification. Together with the established directions of further research, this will allow to create a common conceptual basis and systematise knowledge resources useful in research on MB tourism market. Type of paper. Research paper.
The Impact of the Sharing Economy on Business and Society: Digital Transformation and the Rise of Platform Businesses
Book
Digital platforms at work
Based on a large-scale randomised survey in Denmark, this article examines the scope of digital platforms and the potential linkages between distinct platforms (labour and capital platforms) and individuals’ exposure to precariousness. Our analysis demonstrates that the scope and size of income generated via digital platforms remains limited and online income is typically a supplement rather than the main income source. Secondly, the characteristics of individuals accruing income from capital as opposed to labour platforms differ. Labour platforms like Uber often attract low-skilled workers, migrants, unemployed and young people, whilst highly educated workers often with a high-income and strong ties to the labour market, are active on capital platforms like Airbnb. We argue that these differences influence individuals’ exposure to precariousness, as they indicate the ability by each individual to compensate for the less or non-regulated online setting.
Co-création de valeurs partagées pour redynamiser une région de montagne à travers le tourisme nocturne : étude de cas en Suisse romande
Une vallée relativement périphérique des Alpes valaisannes, le Val d’Anniviers, a été au cœur d’un projet de recherche appliquée censé redynamiser son tourisme. En effet, la Haute École de Gestion et Tourisme, à Sierre, Valais (Suisse), via ses instituts de recherche en entrepreneuriat, management et tourisme, a développé une démarche de co-création réunissant un large spectre d’acteurs institutionnels, économiques, touristiques et de la société civile et permis de concevoir une offre touristique inédite pouvant intéresser une partie de la clientèle potentielle. Ce produit, à savoir la création d’un « Parc aux étoiles », prétend à un succès certain non seulement de par la localisation et la topographie favorables des lieux pour l’observation du ciel étoilé, mais aussi étant donné la présence, à St-Luc, village situé dans la vallée en question, d’un observatoire et d’un Sentier des planètes, qui reproduit le système solaire à l’échelle humaine. Par ailleurs, l’on constate une demande en hausse pour des offres originales impliquant la décélération, la réduction du stress et un certain retour à la nature. Ce sont des tendances que l’on retrouve dans l’offre de tourisme de ciel étoilé proposée, laquelle vise à faciliter l’observation des astres par le biais de la réduction de la pollution lumineuse. Cet article présente la méthodologie employée dans ce processus de co-création en l’insérant dans les contextes historique, économique, social et environnemental afin qu’elle puisse être reproduite ailleurs, en tenant compte des conditions locales.
Green Virtual Enterprise Breeding Environments Bag of Assets Management: A Contribution to the Sharing Economy
David Romero
Ovidiu Noran
Hamideh Afsarmanesh
Green Virtual Enterprise Breeding Environments (GVBEs) are long-term strategic alliances of green enterprises and their related support institutions aimed at offering the necessary conditions to efficiently promote and establish common working and sharing principles with the intention of creating sustainable (shared) value in a collaborative way. The Sharing Economy (SE) is founded on the principle of maximising the utility of assets and other shareable resources by means of renting, lending, swapping, bartering and giving them away in order to avoid their idle existence, and is currently being facilitated by emerging collaborative business ICT infrastructures in the marketplace and society. The SE provides the ability to GVBE members to unlock the untapped social, economic and environmental value of their underutilised assets and other shareable resources towards higher resource efficiency. This paper explores the enabling role of the GVBE bag of assets as a virtual and physical warehouse, including collaborative procurement and shareable assets management strategies, in order to facilitate the sharing of tangible and intangible resources between GVBE members. The GVBE bag of assets is put forward as a novel internal sustainable business model, based on a conceptual framework, taking advantage of idle assets and other shareable resources within the breeding environment in order to save costs and generate new revenue streams (economic), make efficient use of resources (environment) and create deeper social connections – trust – among member enterprises (social).
The crowdsourcing process: an intermediary mediated idea generation approach in the early phase of innovation
Louise Muhdi
Michael Daiber
Sascha Friesike
Roman Boutellier
Intermediary mediated crowdsourcing (CS) has become a widely adopted open innovation approach for idea generation in various companies of different industries. Despite many success stories and a large body of literature in the fields of idea generation, online competition and open innovation, little is known about the intermediary mediated CS process in the early stage of the innovation process. An explorative, qualitative and quantitative multi-case study research design was applied to extract the longitudinal data that were analysed in this research. Based on 12 CS projects executed by nine Swiss companies from four industries on the Swiss intermediary CS platform atizo.com, five important phases of the intermediary mediated CS process were identified and described. Additionally, important tasks within each phase which ought to be considered by companies when engaging in an intermediary mediated CS project for idea generation were elaborated.
In Crowdsourcing - Innovationsmanagement mit Schwarmintelligenz
| https://www.researchgate.net/publication/326309770_A_Process_for_Co-Creating_Shared_Value_with_the_Crowd_Tourism_Case_Studies_from_a_Regional_Innovation_System_in_Western_Switzerland |
Vaccination Response in Individual Monozygotic Twins - Full Text View - ClinicalTrials.gov
Vaccination Response in Individual Monozygotic Twins
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02296359 Recruitment Status :
Terminated (Insufficient enrollment) First Posted : November 20, 2014 Last Update Posted : August 14, 2015
Sponsor:
Michigan State University
Information provided by (Responsible Party):
George Mias, Michigan State University
Study Details
Study Description
Brief Summary:
Respiratory viruses are known to be risk factors for asthma (e.g respiratory syncytial viruses, RSVs, and Human Rhinoviruses, HRVs, may induce bronchiolitis, and wheezing illnesses respectively). The common flu is also known to be a risk factor and the Centers for Disease Control and Prevention (CDC) recommends that asthmatics receive the annual flu vaccine, as a high-risk group for related asthma exacerbations. The investigators will be evaluating the variation in individual responses over time after controlled immune activation following influenza vaccination of monozygotic twins, both discordant for asthma, and concordant non-asthmatic. The transition from initial healthy to immune-system activated physiological states post vaccination will provide unprecedented molecular (omics) data on the molecular dynamics of immune response to vaccination, and novel insight into the flu response. The investigators will infer novel networks and pathways and as well as the dynamics of genes and mechanisms involved in asthma, flu vaccination, and individual responses, and correlate them to evaluated personalized genetic risks in the same study. The investigators will be able to also contrast the vaccination response in asthmatic and non-asthmatic individuals, in a longitudinal approach which has never been performed before using multiple-omics that included an immunization response.
Condition or disease Intervention/treatment Individuality Asthma Immune System and Related Disorders Biological: Influenza Vaccination
Detailed Description:
Asthma pathogenesis and exacerbations have been associated to multiple risk factors, particularly respiratory viruses. In children respiratory syncytial viruses (RSVs) may induce bronchiolitis, and Human Rhinoviruses (HRVs) also may induce wheezing illnesses. RSVs and HRVs are age dependent risk factors for asthma, with the influenza virus also considered a prominent risk factor in adults. The Center for Disease Control recommends influenza vaccination in asthmatics annually. Both HRV and RSV infections were detected in a pilot integrative personal omics investigation, and provided a unique temporal expression signature in the non-asthmatic subject, with the involvement of a common set of antigen and defense response genes, as well as immune related pathways. These observed patterns in addition to the results of the vaccination study will be used as a guide, to find differences in healthy versus asthmatic patients' pathway activations which will provide insights into the genes and mechanisms involved in asthma pathogenesis and immune response to influenza vaccination. The twin paradigm will allow us to control for multiple confounding factors and focus on the individual genetic and possible epigenetic variation. The investigators will be able to infer novel networks and pathways and get into the genes and mechanisms involved in asthma, flu vaccination, and individual responses, while evaluating personalized genetic risks compared to medical history in the same study.
Our primary investigation involves integrative multi-omics monitoring of individual monozygotic twins, healthy or discordant for asthma, following their flu vaccination, over a period of two annual vaccination cycles. The investigators will be collecting blood samples from monozygotic twin volunteers, for multiple time-points post influenza vaccination. The measurements will be repeated the following year after a second vaccination. Genomic sequencing will be used to evaluate the volunteer's genomic risks based on variants with known disease association. Full transcriptome (via RNA-Sequencing), proteome and metabolome profiling (via mass spectrometry) will be performed per time-point, as well as cytokine profiling. This will allow the dynamic monitoring of thousands of molecular components and their responses to vaccination, capturing both the initial innate response reaction in addition to the adaptive response and return to baseline. The study involves following responses in blood and saliva components after influenza vaccination. Two annual vaccinations will be considered, one per year for 2 years, and at 8 time points samples will be collected.
This study involves a simple blood draw, saliva collection, standard FDA-approved influenza vaccine administration and Spirometry.
Study Design
Layout table for study information Study Type : Observational Actual Enrollment : 1 participants Observational Model: Case-Control Time Perspective: Prospective Official Title: Vaccination Response in Individual Monozygotic Twins Study Start Date : October 2014 Actual Primary Completion Date : August 2015 Actual Study Completion Date : August 2015
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Asthma Flu Flu Shot Vaccines
Drug Information available for: Influenza Vaccines
U.S. FDA Resources
Groups and Cohorts
Group/Cohort Intervention/treatment Asthma Discordant Monozygotic Twins This is a group where one of the monozygotic twins has asthma and the other is non-asthmatic. Influenza Vaccination will be performed for both cohorts. Biological: Influenza Vaccination The individuals will be followed to observe their immune system activation, following their vaccination with the standard influenza vaccine approved for the year by the FDA. Non-Asthma Concordant Monozygotic Twins This is a group where both of the monozygotic twins are non-asthmatic. Influenza Vaccination will be performed for both cohorts. Biological: Influenza Vaccination The individuals will be followed to observe their immune system activation, following their vaccination with the standard influenza vaccine approved for the year by the FDA.
Outcome Measures
Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Integrated Omics profile [ Time Frame: all time points (8 per year for 2 years per subject) ]
The study will construct RNA-expression, protein profiles and small molecule profiles on immune cells as these change over time prior to and following immune activation by the vaccine. The collective temporal patterns will be used to classify immune response
Biospecimen Retention: Samples With DNA
If the volunteers agree,tissue is stored for usage in future research without identifiers. This includes cells from blood and saliva and extracted DNA, RNA and protein. The cells may be used to grow a new cell line that may be maintained in the laboratory.
Eligibility Criteria
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes Sampling Method: Non-Probability Sample
Study Population
Monozygotic Twins over 18 years of age with and without asthma, without gender or ethnicity restrictions.
Criteria
Inclusion Criteria:
Volunteers are eligible to participate in this study if both they and their twin sibling have agreed to participate. If after their enrollment in the study, one of the twin siblings decides to withdraw, then:
If one sibling withdraws during Year 1, the other sibling will be allowed to continue their participation in the study and to complete the current study Year. However they will not be included in the randomly selected applicants that will continue participation in Year 2 of the study.
If one sibling withdraws duringYear2, the other sibling will be able to conclude Year2 study activities. -
Exclusion Criteria:
Volunteer is under18.
Presence of any medical conditions that the study investigators believe will affect participation in the study or its results.
Presence of a mental incapacity and/or cognitive impairment that would prevent a subject from adequately understanding, or cooperating with, the study protocol.
Volunteers with any severe allergies (life-threatening) or that have ever had a life-threatening allergic reaction after a dose of flu vaccine, or have a known severe allergy to any part of this vaccine, will be advised not to participate.
If a potential subject has ever had Guillain-Barré Syndrome (a severe paralyzing illness, also called GBS), they will be advised not to get the influenza vaccine and be excluded from this study.
For female participants If they are already enrolled and become pregnant during this study, the investigators will temporarily withdraw them from the study from the day they become pregnant. If they would like to stay in the study, the investigators may continue their participation after their delivery.
If participants are not feeling well on the scheduled day of vaccination the investigators will suggest that they postpone the vaccination until they feel better. If they agree, the vaccination will be re-scheduled for a later date.
Information from the National Library of Medicine
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02296359
Locations
Layout table for location information United States, Michigan Clinical and Translational Science Institute East Lansing, Michigan, United States, 48824
Sponsors and Collaborators
Michigan State University
Investigators
Layout table for investigator information Principal Investigator: George Mias, PhD Michigan State University
Layout table for additonal information Responsible Party: George Mias, Assistant Professor, Michigan State University ClinicalTrials.gov Identifier: NCT02296359 History of Changes Other Study ID Numbers: 14-848FM First Posted: November 20, 2014 Key Record Dates Last Update Posted: August 14, 2015 Last Verified: August 2015
| https://clinicaltrials.gov/ct2/show/NCT02296359 |
Huxley Lectures: Stephen Shennan & Stephen Levinson
The website for the Royal Anthropological Institute.
Huxley Lectures: Stephen Shennan & Stephen Levinson
Tuesday 14 December 2021, 01:30pm - 05:30pm
THE HUXLEY MEMORIAL LECTURES FOR 2020 & 2021
Tuesday 14 December in the BP Lecture Theatre, Clore Education Centre, the British Museum, Great Russell Street, London WC1B 3DG.
1.30pm - the 2020 Huxley Lecture from Prof Stephen Levinson, Max Planck Institute for Psycholinguistics
3.00pm - the 2021 Huxley Lecture from Prof Stephen Shennan, University College London
Prof Stephen Levinson
The ‘interaction engine’: the evolution of the infrastructure for language
Thomas Henry Huxley, ‘Darwin’s bulldog’, believed in the underlying unity of the human species but on the voyage of HMS Rattlesnake was struck by the cultural and linguistic diversity of Melanesia. Indeed, the deep structural diversity of languages suggests that our language capacities are not based on any single template but rather on an underlying ability and motivation for infants to acquire a culturally transmitted system (Darwin’s ‘instinctive tendency to acquire an art’). The hypothesis presented here is that this ability has an interactional base that has discernable precursors in other primates – a behavioural parallel to the anatomical similarities that Huxley was the first to point out in detail. This interactional base is more or less invariant across cultures, constitutes the context for language use and learning, and acts like a machine tool for producing languages. In this lecture I explore two specific evolutionary routes that may have allowed humans to develop this interactional foundation for an elite communication system.
Prof Stephen Shennan
Population and the dynamics of culture change
In a paper published in Current Anthropology in 2000, I argued that we should see the changes documented in the archaeological record as the result of processes of cultural ‘descent with modification’, by analogy with Darwin’s term for biological evolution. I proposed that understanding these changes required archaeologists to return to many of the issues raised by the culture-history agenda rejected 30-40 years previously and largely despised ever since. I suggested that the single most important factor in understanding culture change was population dynamics. First, because past populations had been much more dynamic, in terms of processes of expansion and contraction, than had been appreciated. Second, this mattered because many of the skills involved in artefact production were acquired by children from their parents or other close relatives of the older generation, so, if a particular local population expanded, then so would the artefact forms associated with it; correspondingly, the opposite would be the case if the population declined or disappeared. The importance of this link between cultural and demographic patterns, had almost certainly been underestimated.
In the intervening 20 years there has been an explosion of theoretical and empirical work addressing the relationship between cultural and demographic patterns, using new lines of evidence and novel perspectives. In this lecture, I will review some of that work, with a focus on areas where I have been involved, in particular the spread of farming into Europe and its aftermath, where I will show the way in which new methods and sources of evidence have changed ideas and in doing so borne out some of my suggestions and modified others.
The event is free, but places must be booked. Please book your placehere
Enquiries to: RAI, 50 Fitzroy St, London W1T 5 BT; tel 020 7387 0455;email
Location:BP Lecture Theatre, Clore CentreBritish MuseumGreat Russell StreetLondonWC1B 3DGUnited Kingdom
| https://therai.org.uk/events-calendar/past-events/eventdetail/753/-/huxley-lectures-stephen-shennan-stephen-levinson |
AAC Publications - Cerro Kishtwar, West Face and South Ridge, Yoniverse; White Sapphire (6,040m), West Face, La Virée des Contemporains
At the end of September Denis Burdet (Swiss), David Lama (Austrian), Stefan Siegrist (Swiss), and American photographer Robert Frost made the secon...
Cerro Kishtwar, West Face and South Ridge, Yoniverse; White Sapphire (6,040m), West Face, La Virée des Contemporains
India, Kishtwar Himalaya
Climb Year: N/A. Publication Year: 2012.
At the end of September Denis Burdet (Swiss), David Lama (Austrian), Stefan Siegrist (Swiss), and American photographer Robert Frost made the second ascent of Cerro Kishtwar (6,155m). This area of the eastern Kishtwar Himalaya, untouched by the mountaineering community for almost two decades, holds many unnamed, unclimbed summits.Limited information and outdated maps made planning difficult, and after approaching up the Haptal Valley the team faced initial problems when they realized that to make an alpine-style attempt they would need to move base camp closer. They established an advanced base at 5,000m.
Their first idea was to link the west and northwest faces, and on September 25th all four climbed north-facing slopes of loose rock covered with snow and ice to reach a glacier terrace at 5,400m, where they placed a camp. The day was long, as 40cm of fresh snow from two weeks previous had not consolidated. Next day they saw a logical line that had not been visible from below: a thin diagonal ice ramp/couloir on the west face that curved up for 200m toward the south ridge. However, they were unable to reach the couloir that day and rappelled back to camp, to have a rest day and then set out early for the summit.
On the 28th the alarm went off at 3 a.m., and they left with light sacks. The first six pitches in the couloir were ice and styrofoam, good for climbing but less than ideal for placing pro. They were mostly reliant on rare rock belays. The couloir steepened to 85° before giving way to vertical rock, which gave climbing up to 6a. The temperature was -25°C but on reaching the south ridge they were able to warm their feet in the sun. The crest above, difficult at first, then with easier sections on rock and snow, led to the southeast summit, which they reached at 1:15 p.m. The GPS gave an altitude of 6,155m, rather than previously quoted heights of 6,200m and 6,220m. All except Frost traversed for 15 minutes to the northwest summit (one rappel, then an easy snow ridge), which they measured as five meters lower. Twenty-six rappels brought them back to camp just after dark, and on the 29th they all descended to advanced base. They named the route Yoniverse (1,200m, WI5 6a).
Several days later Burdet and Siegrist left for an unclimbed peak south of Cerro Kishtwar, on the ridge leading to Sentinel Peak (5,950m). On October 4 after a long day in heavy snow, they camped at 5,200m below the western side of the mountain, the alarm set for 3:30 a.m. on the 5th. They opted for a narrow, deep gully on the west face, slanting left toward the summit. Being acclimatized, they climbed fast, and after an avalanche-prone traverse, found themselves in a chimney system similar to Exocet on Patagonia’s Cerro Standhardt. There was dry-tooling, 90° ice, a difficult roof, and tricky protection. They topped out at a col to find the peak has a double summit. Leaving one sack, they traversed northwest, at first over horribly loose rock on the north flank of the crest, until after two pitches they discovered a hole leading onto the south flank, where the rock was much better. A couple more pitches led to the top, which they recorded as 6,040m GPS. Reversing their steps they continued over the southeast summit (5,980m) and down the south ridge (Eagle Ridge). Toward the end of the descent, they made four rappels down the southwest flank and reached camp at 7 p.m. They named the peak White Sapphire (33°20.532' N, 76°34.430' E) and the route La Virée des Contemporains (850m, WI5 with two crux pitches of WI6, M6, and A2).
– Hans Ambuhl, Visual Impact GMBH, andStephan Siegrist , Switzerland
Editor's note: In October 1991 Brendan Murphy and Andy Perkins made a capsule-style attempt on the rounded rock pillar in the center of the northwest face. They had approached the region from Leh to the north over the Umasi La. After 17 days and 28 pitches, up to A3 and Scottish 6, they reached the north ridge, crossed to the northeast flank, and were 100m below the summit when their food ran out. Faced with more hard climbing, they bailed. In September 1993, Mick Fowler and Stephen Sustad (Fowler returning after a previous attempt with Mike Morrison in 1989) spent four days following a diagonal ice ramp left of the Murphy-Perkins line to a notch on the north ridge, where they crossed to the northeast flank and continued up mixed ground, passing the 1991 high point, to the northwest summit (1,300m, ED+). They traversed to the higher southeast summit before descending their route. The climbing was mainly ice and mixd, 25 pitches up to Scottish 6 and A3. The expedition was only allowed to approach this troubled area from the south via Manali, Udaipur, and along the Chenab River to Atholi/Gulabgarh—the route followed by the 2011 team. The mountain was named for its similar appearance to Cerro Torre.
| http://publications.americanalpineclub.org/articles/12201228700 |
HUMANGGP:037216 - FACTA Search
Query: HUMANGGP:037216 (
aquaporin 3
)
130
A wealth of studies performed with a spectrum of methods spanning simple clearance studies to the molecular identification of ion transporters has increased our understanding of how approximately 1.7 kg of NaCl and 180 L of H2O are absorbed by renal tubules in man and how the urinary excretion is fine-tuned to meet homeostatic requirements. This review will summarize our current understanding. In the proximal nephron, approximately 60 to 70% of the filtered Na+ and H2O is absorbed together with approximately 90% of the filtered HCO3-. The exact quantities are determined by many regulatory factors, such as glomerulotubular balance, angiotensin II, endothelin, sympathetic innervation, parathyroid hormone, dopamine, acid base status and others. The essential components of absorption are luminal membrane Na+ /H+ exchange and the basolateral ( Na+ + K+)-ATPase. In the thick ascending limb of the loop of Henle, 20 to 30% of the filtered NaCl is absorbed via Na+2Cl-K+ cotransport driven by the basolateral ( Na+ + K+)-ATPase. No H2O is absorbed at this nephron site. The transport rate is determined by the Na+ load and by several hormones and neurotransmitters, including prostaglandins, parathyroid hormone, glucagon, calcitonin, arginine vasopressin (AVP), and adrenaline. In the distal tubule, some 5 to 10% of the filtered load is absorbed via Na+Cl- cotransport in the luminal membrane driven by the basolateral ( Na+ + K+)-ATPase. The rate of transport is again determined by the delivered load and by several hormones and neurotransmitters. One of the tasks of the collecting duct is to control the absorption of approximately 10 to 15% of the filtered H2O, regulated by AVP, and just a few percent of the filtered Na+ , controlled by aldosterone and natriuretic hormone. The water absorption proceeds through the luminal membrane via aquaporin 2 and through the basolateral membrane via aquaporin 3 channels and is driven by the osmotic gradient built up by the counter current concentrating system. The Na+ absorption occurs via Na+ channels present in the luminal membrane driven by the basolateral ( Na+ + K+)-ATPase. With no pharmacological interference, urinary excretion of Na+ can vary between less than 0.1% and no more than 3% of the filtered load, and that of H2O can vary between 0.3 and 15%.
...
PMID:Physiology of renal sodium transport. 1065 44
The urea transporters UT-A1 and UT-A3 mediate rapid transepithelial urea transport across the inner medullary collecting duct (IMCD). In a previous study, using a new mouse model in which both UT-A1 and UT-A3 were genetically deleted from the IMCD (UT-A1/3(-/-) mice), we investigated the role of these transporters in the function of the renal inner medulla. Here the authors report a new series of studies investigating more generally the renal phenotype of UT-A1/3(-/-) mice. Pathologic screening of 33 tissues revealed abnormalities in both the testis (increased size) and kidney (decreased size and vascular congestion) of UT-A1/3(-/-) mice. Total urinary nitrate and nitrite (NOx) excretion rates in UT-A1/3(-/-) mice were more than double those in wild-type mice. Total renal blood flow was not different between UT-A1/3(-/-) and wild-type mice but underwent a greater percentage decrease in response to NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) infusion. Whole kidney GFR (FITC-inulin clearance) was not different in UT-A1/3(-/-) mice compared with controls and underwent a similar increase in response to a greater dietary protein intake. Fractional urea excretion was markedly elevated in UT-A1/3(-/-) mice on a 40% protein diet, reaching 102.4 +/- 8.8% of the filtered load, suggesting that there may be active urea secretion somewhere along the renal tubule. Although there was a marked urinary concentrating defect in UT-A1/3(-/-) mice, there was no decrease in aquaporin 2 or aquaporin 3 expression. Furthermore, although urea accumulation in the inner medulla was markedly attenuated, there was no decrease in sodium ion concentration in tissue from outer medulla or two levels of the inner medulla. These results support our conclusion that the urinary concentrating defect in UT-A1/3(-/-) mice is caused by a failure of urea transport from the IMCD lumen to the inner medullary interstitium, resulting in osmotic diuresis.
...
PMID:Renal phenotype of UT-A urea transporter knockout mice. 1582 9
The trophectoderm (TE) is the first epithelium to be generated during mammalian early development. The TE works as a barrier that isolates the inner cell mass from the uterine environment and provides the turgidity of the blastocyst through elevated hydrostatic pressure. In this study, we investigated the role of tight junctions (TJs) in the barrier function of the TE during mouse blastocyst formation. RT-PCR and immunostaining revealed that the mouse TE expressed at least claudin 4, 6, and 7 among the 24 members of the claudin gene family, which encode structural and functional constituents of TJs. When embryos were cultured in the presence of a GST-fused C-terminal half of Clostridium perfringens enterotoxin (GST-C-CPE), a polypeptide with inhibitory activity to claudin 4 and 6, normal blastocyst formation was remarkably inhibited; the embryos had no or an immature blastocoel cavity without expansion, and blastomeres showed a rounded shape. In these embryos, claudin 4 and 6 proteins were absent from TJs and the barrier function of the TE was disrupted; however the basolateral localization of the Na+ /K+-ATPase alpha1 subunit and aquaporin 3 , which are thought to be involved in blastocyst formation, appeared normal. These results clearly demonstrate that the barrier function of TJs in the TE is required for normal blastocyst formation.
...
PMID:Tight junctions containing claudin 4 and 6 are essential for blastocyst formation in preimplantation mouse embryos. 1798 Mar 58
Ultrastructural and immunohistochemical studies were conducted on the gill epithelium of the Mediterranean rainbow wrasse (Coris julis). We analysed the immunolocalisation of aquaporin 3 ( AQP3 ) and aquaporin 1 (AQP1) in the gills using confocal microscopy. The ultrastructural features of the gill were investigated using transmission and scanning electron microscopy. The C. julis gill apparatus showed structural characteristics typical for Teleostei. Immunolocalization revealed differential localization of AQP1 and AQP3 in the gill epithelium. Double immunolabelling for Na+ /K+ ATPase with AQP1or AQP3 revealed that AQP1 is localised in chloride cells, whereas AQP3 is localized in both the chloride cells and the accessory cells. This result suggests an active role of these cells in water/glycerol transport in saltwater fish.
...
PMID:Localization of aquaporin 1 and 3 in the gills of the rainbow wrasse Coris julis. 1942 55
The European eel, Anguilla anguilla, is considered an endangered species that is under pressure for many reasons. Among others, the introduced parasite Anguillicola crassus is thought to play an important role in the decline of eel populations. These nematodes have been shown to negatively affect many fitness-related traits in eels, e.g., growth, osmoregulation, and stress tolerance. Nevertheless, there has been little work on the way in which the host-parasite interaction influences the molecular regulation of these key physiological processes. We experimentally analyzed the effect of this nematode on the expression of genes involved in the physiology of European eels during their continental life. Included are genes that are implicated in the eel's somatic growth (insulin-like growth factor 1 and thyroid hormone receptor beta), osmoregulation ( Na+ /K+-ATPase beta1 and aquaporin 3 ), and hematopoiesis (hemoglobin alpha-chain). Our results showed the absence of an effect on genes involved in fish growth; the parasite may, however, have an effect on osmoregulation and hematopoiesis. We also noted a differential impact of male and female parasites on the expression of some genes, perhaps owing to the sexual dimorphism in body size of the parasite.
...
PMID:Changes in gene expression in European eels (Anguilla anguilla) induced by infection with swim bladder nematodes (Anguillicola crassus). 2004 87
Recent studies show that ion channels/transporters play important roles in fundamental cellular functions that would be involved in the cancer process. We review the evidence for their expression and functioning in human gastric cancer (GC), and evaluate the potential of cellular physiological approach in clinical management. Various types of ion channels, such as voltage-gated K(+) channels, intracellular Cl(-) channels and transient receptor potential channels have been found to express in GC cells and tissues, and to control cell cycles. With regard to water channels, aquaporin 3 and 5 play an important role in the progression of GC. Regulators of intracellular pH, such as anion exchanger, sodium -hydrogen exchanger, vacuolar H(+)-ATPases and carbonic anhydrases are also involved in tumorigenesis of GC. Their pharmacological manipulation and gene silencing affect cellular behaviours, suggesting their potential as therapeutic targets for GC. Our studies indicate the intracellular Cl(-) concentration could act as a mediator of cellular signaling and control cell cycle progression in GC cells. Further, we demonstrate the cytocidal effects of hypotonic shock on GC cells, and indicate that the blockade of Cl(-) channels/transporters enhances these effects by inhibiting regulatory volume decrease. A deeper understanding of molecular mechanisms may lead to the discovery of these cellular physiological approaches as a novel therapeutic strategy for GC.
...
Blastocoel expansion during embryo development is known to be reliant on the Na+ /K+-ATPase pump, but little is known about the relative contribution of active ( Na+ /K+-ATPase pump) and facilitated diffusion (aquaporins) water transport during blastocoel re-expansion after vitrification. The aims of this study were to examine potential effects of artificial blastocoel collapse (ABC) on markers of embryo stress and the contribution of active and facilitated diffusion water transport mechanisms to blastocoel re-expansion. Day 5 mouse embryos were vitrified using either a standard protocol, laser pulse ABC, a hyperosmotic sucrose ABC protocol or both laser pulse and sucrose. Using real-time polymerase chain reaction, no differences were found in the gene expression of the endoplasmic reticulum (ER) stress markers activating transcription factor 4 (Atf4) or heat shock protein 90-alpha (Hsp90α) 2h after warming. Similarly, expression of the Na+ /K+-ATPase pump gene, ATPase, Na+/K+ transporting, beta 1 polypeptide (Atp1b1) and protein did not differ between groups. Aquaporin 8 (Aqp8) gene expression was significantly lower in the laser+sucrose ABC group than in fresh controls, and aquaporin 3 (Aqp3) expression significantly higher in standard vitrified embryos compared with all other groups. Ouabain, a potent and specific Na+ /K+-ATPase pump inhibitor, inhibited blastocoel re-expansion in both standard protocol- and laser ABC-vitrified embryos, reducing both groups to the same rate of re-expansion 3h after warming. These results demonstrate that ABC before vitrification does not alter mRNA or protein expression of Na+ /K+-ATPase, or mRNA levels of ER stress genes Atf4 and Hsp90α. Activity of the pump may be increased in ABC embryos, with potential compensation by AQP3 when it is compromised.
...
PMID:Artificial blastocyst collapse prior to vitrification significantly improves Na
+
/K
+
-ATPase-dependent post-warming blastocoel re-expansion kinetics without inducing endoplasmic reticulum stress gene expression in the mouse. 3009 82
Background Arginine vasopressin dependent antidiuresis plays a key role in water- sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.
...
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=HUMANGGP%3A037216%7C111111%7C0%7C0%7C346930%7C0%7C10 |
Matter of: Computervision Corporation File: B-257141 Date: August 12, 1994 | U.S. GAO
DIGEST Protest challenging agency's negative responsibility determination is denied where protester fails to show that agency acted in bad faith or...
Matter of: Computervision Corporation File: B-257141 Date: August 12, 1994
B-257141 Aug 12, 1994
Highlights
DIGEST Protest challenging agency's negative responsibility determination is denied where protester fails to show that agency acted in bad faith or that determination was unreasonable in light of firm's overall financial posture. The RFP provided that the contract would be awarded to the "responsive and qualified [offeror] who submits a proposal that will result in the lowest overall cost. . . .". It stated further that "[a]ll proposals will be evaluated to determine if the [offeror] is qualified . . . before an evaluation of . . . prices is performed.". Each offeror was to submit its "most recent financial statement. Included with Computervision's offer was its latest Form 10-K (for the fiscal year ending December 31.
View Decision
Matter of: Computervision Corporation File: B-257141 Date: August 12, 1994
DIGEST
Attorneys
DECISION
We deny the protest.
The RFP sought proposals to provide "unlimited on-site remedial maintenance for all Sun Microsystems products," and defined remedial maintenance as "service to correct equipment malfunction . . . as required on an unscheduled basis, and installation of engineering change orders." The RFP provided that the contract would be awarded to the "responsive and qualified [offeror] who submits a proposal that will result in the lowest overall cost. . . ." It stated further that "[a]ll proposals will be evaluated to determine if the [offeror] is qualified . . . before an evaluation of . . . prices is performed." The RFP included a series of qualification requirements including financial resources. Under that requirement, each offeror was to submit its "most recent financial statement," and the RFP stated that the offeror "must be solvent and in sound financial condition."
The University received nine offers in response to the RFP. Included with Computervision's offer was its latest Form 10-K (for the fiscal year ending December 31, 1992), as filed with the U.S. Securities and Exchange Commission. The 10-K contained Computervision's recent financial statements and other detailed information about the firm.
The University states that the evaluation of offers was conducted in two stages. The "qualification" evaluation, which the University reports "took the form of a responsibility determination," was performed first, followed by a price evaluation of the proposals submitted by the responsible offerors. Computervision was found to be nonresponsible for failing to meet the financial resources qualification criterion of the RFP.
The determination was based on three factors. First, using a Defense Contract Audit Agency (DCAA) Contract Audit Manual "Z score prediction model," the University assessed Computervision's financial statements as indicating a trend for "probable future financial distress." Second, the evaluators understood Computervision's 10-K form to indicate that the firm is "currently under Chapter 11 Bankruptcy." Third, the University obtained a Dun & Bradstreet (D&B) report which indicated a less than satisfactory or unbalanced financial condition and a downward business trend. The University concluded that Computervision did not comply with the requirement that the offeror be "solvent and in sound financial condition" and disqualified the firm from further consideration for the award. The contract was awarded to Grumman Corporation.
In its challenge to the University's conclusion concerning its financial condition, Computervision points out that, in fact, it has never filed for bankruptcy but that a major (formerly 100-percent) shareholder had. The protester complains that this mistake "permeated and tainted" the entire evaluation of Computervision's financial capability.
Generally, a finding of responsibility requires, among other things, that the potential contractor affirmatively demonstrate that it has sufficient financial resources to perform the contract or the ability to obtain them. Federal Acquisition Regulation (FAR) Sec. 9.104-1. Absent such an affirmative showing, the FAR requires the contracting officer to make a nonresponsibility determination. FAR Secs. 9.103(b)-(c). In making this determination, the contracting officer is vested with a wide degree of discretion and business judgment. Construcciones Electromecanicas, S.A., B-242656 et al., May 8, 1991, 91-1 CPD Para. 448. We therefore will not question a nonresponsibility determination unless it is the result of bad faith or lacks any reasonable basis. Id.
In response to the protest, the agency has included in its report a declaration from the University cost/price analyst who was responsible for evaluating the financial status of Computervision. The analyst concedes that he mistakenly interpreted the 10-K form to state that Computervision was in bankruptcy. He states that while he noted the bankruptcy, it was not sufficient in and of itself to show financial instability. He states further that "[i]n any case, I would have proceeded with a financial analysis of Computervision and the bankruptcy issue had no effect on this decision." The financial analysis included ascertaining a Z score rating, obtaining a D&B report, and independently reviewing the financial material submitted by the protester.
When he conducted his original analysis, the cost/price analyst prepared a memorandum explaining the results of his analysis. Attached to the memorandum were calculations showing how the Z scores for Computervision were determined and how the scores should be interpreted, as well as the unfavorable D&B report. While the memorandum contained a sentence stating that Computervision is currently under Chapter 11 bankruptcy, the administrator who reviewed the memorandum and ultimately determined Computervision to be nonresponsible states that "I knew that bankruptcy alone is not grounds for determining a firm to be not responsible" and that his determination that Computervision was not responsible was based on the analysis of the cost/price analyst, the Z score rating, and the D&B report. The agency and the University concluded, therefore, that the misunderstanding concerning the bankruptcy did not materially contribute to the nonresponsibility determination and that the determination was reasonably based and supported by substantial independent information. We agree.
While the protester contends that the error concerning the alleged bankruptcy tainted the evaluation, it is clear from the record that University officials viewed the information, at most, as a starting point for their financial review, which was required by the RFP in any event. They recognized that without detailed information, their understanding that the firm had filed for bankruptcy was of little use in their determination. Consequently, they sought independent indicators of the firm's financial condition. In light of the detailed financial information analyzed by the University indicating probable financial distress, financial instability, and a downward trend, we find that the University had a reasonable basis for its determination and that the determination did not materially result from the mistaken belief that Computervision had filed for bankruptcy.
Computervision also alleges that the University made errors in the computation of the Z scores which resulted in assigning the protester misleadingly low scores. The protester concedes, however, that even using the scores which it believes to be correct, the DCAA manual, which explains the use of the Z scores, would assign a rating of "[p]robable future financial distress," to Computervision. Nevertheless, it argues that since the University relied heavily on the Z scores, different numerical scores may have affected the University's conclusion.
The DCAA Contract Audit Manual states that the "Z score is useful in assessing financial capability risk and helping to identify contractors that may have financial problems" and in predicting "bankruptcy potential." The manual cautions that "[a]lthough the model should not be relied upon to support a financial condition assessment by itself, it does provide an initial alert to the auditor that further analysis is needed."
The Z score model uses the following five financial ratios, which are adjusted in accordance with a specified formula:
X1 = Working capital/total assets X2 = Retained earnings/total assets X3 = Earnings before interest and taxes/total assets X4 = Market value of equity/total liabilities X5 = Sales/total assets
The Z score is the sum of these ratios, as adjusted by the formula. The manual states that the Z score is interpreted as follows:
Score Indication
Less than 1.81 Probable future financial distress 1.81 to 2.99 Possible future financial distress Greater than 2.99 No or little chance of financial distress
The Z scores which the University calculated for Computervision were negative numbers. Those scores were as follows:
1991 -.009 1992 -.718 1993 -.393
During the course of the protest, the University conceded that these scores were based on the use of incorrect "earnings before interest and taxes" figures. Using the correct figures, the University states that the protester's scores would be as follows:
1991 .328 1992 -.319 (No score for 1993 was computed.)
The University argues that the original computational error was a minor, technical error which had no material bearing on the ultimate outcome of its nonresponsibility determination. Since both the original and recomputed scores fall below 1.81, the University asserts that the conclusion that the financial statements indicate probable future financial distress is unchanged.
Computervision contends that the University and agency position "fails to place the Z score in its proper context and ignores other fatal mistakes in [the University's analysis]." The protester also contends that its Z scores for the last 3 years range from 1.29 to 1.45--higher than even the corrected scores assigned by the University during the course of this protest.
We need not resolve the fundamental dispute between the parties concerning the proper method of calculating Z scores. In this regard, given that the DCAA manual assigns the same indication of financial distress to the scores as calculated by the protester and the University, we do not see, nor has the protester explained, why the numerical difference is significant. As Computervision asserts, the Z scores should not be used by themselves. The protester's argument concerning the alleged errors in the Z score computation, in our view, places undue importance on the mechanics of the formula and fails to address the financial difficulties which the formula is intended to signal. In this regard, based on the indicated probable financial distress, the University reasonably obtained the most recent D&B report that independently concluded that the financial condition of the protester was unbalanced and its trend downward. This conclusion was based on an analysis of the same financial data as that which formed the basis of the poor Z score rating. Thus, contrary to the protester's position, the University, in fact, inquired further when faced with the results of the Z score analysis indicating probable financial distress and did not "blindly" adopt that conclusion.[2] In sum, the University reasonably concluded that the protester was not a responsible offeror based on the poor Z scores and the D&B report, which provided an independent assessment of the firm's financial condition.
Finally, we reject the protester's argument that the University should have requested additional information from the firm before finding it nonresponsible. A contracting officer may base such a determination upon evidence in the record without affording offerors the opportunity to explain or otherwise defend against the evidence. Oertzen & Co. GmbH, B-228537, Feb. 17, 1988, 88-1 CPD Para. 158. Moreover, there is no requirement that an offeror be advised of the determination in advance of the award. Id.
The protest is denied.
1. The University is subject to our bid protest jurisdiction as an M&O contractor that effectively awards subcontracts "by or for" the government. DOE's regulations provide for our Office to consider protests involving acquisitions by M&O contractors such as the University. Department of Energy Acquisition Regulation, 48 C.F.R. Sec. 970.7107 (1993); AT&T, B-250516.3, Mar. 30, 1993, 93-1 CPD Para. 276. We review subcontract awards by prime M&O contractors under a "federal norm" standard, i.e., to determine whether the procurements and subsequent awards are consistent with the policy objectives set forth in statutes and regulations which apply directly to federal agency procurements. Elma Eng'g, 70 Comp.Gen. 81 (1990), 90-2 CPD Para. 390.
2. Computervision alleges that the University did not appreciate that the company is in a period of transition and that it was steadily gaining financial strength. While agencies are not required, and are generally not in a position, to predict future financial developments of an offeror, we note that the most recent D&B report continues to show a downward trend and unbalanced financial condition for Computervision. There is also no basis in the record to conclude, as the protester does, that the University "ignored" the "important financial data contained in the D&B report" such as worldwide revenues--this information was readily available from both the 10-K and the D&B report.
| https://www.gao.gov/products/b-257141 |
Miller v. Bd. of Probation and Parole - Pennsylvania - Case Law - VLEX 888049822
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Pennsylvania
Miller v. Bd. of Probation and Parole
Court Commonwealth Court of Pennsylvania Writing for the Court FRIEDMAN, , and COHN. and McCLOSKEY, Senior. Citation 837 A.2d 618 Parties Joseph P. MILLER, Jr., Petitioner,
v.
PENNSYLVANIA BOARD OF PROBATION AND PAROLE, Respondent. Decision Date 04 December 2003
837 A.2d 618
Joseph P. MILLER, Jr., Petitioner,
v.
PENNSYLVANIA BOARD OF PROBATION AND PAROLE, Respondent
Commonwealth Court of Pennsylvania.
Submitted on Briefs October 24, 2003.
837 A.2d 619
David Crowley, Bellefonte, for petitioner
Chad L. Allensworth, Harrisburg, for respondent.
BEFORE: FRIEDMAN, Judge, and COHN, Judge. and McCLOSKEY, Senior Judge.
OPINION BY Judge COHN.
Joseph P. Miller, Jr., appeals from an order of the Pennsylvania Board of Probation and Parole (Board) that denied his request for administrative relief and upheld penalties for technical parole violations. The Board concluded that there was substantial evidence to support the findings that Miller had violated three parole conditions by failing to maintain contact with his parole agent (# 3A), violating curfew (# 7 CT1), and failing to submit to urinalysis testing (# 7 CT2). On appeal we must decide two issues: 1) whether Miller intentionally violated the failure to report and curfew conditions and 2) whether the Board lacked "jurisdiction" to recommit him for failure to submit to urinalysis testing where he was, at the time, incarcerated on the other parole violation charges and, hence, allegedly not "on parole."
Miller was originally sentenced to imprisonment for 10-30 years for third degree murder and aggravated assault. He was paroled on December 1, 1997 to a community corrections center, at which time his maximum date was August 1, 2016, and he was required to report regularly to his parole officer as instructed. After having failed to report and using cocaine, he received a Level I Conference on January 15, 2003, and became subject to the following: 1) weekly reporting to Agent Jones at a designated location on Spring Garden Street in Philadelphia; 2) a special condition of curfew, requiring him to be in his approved residence between 8:00 p.m. and 6:00 a.m.; and 3) submitting a urine sample for testing each time he
837 A.2d 620
met with his parole officer or upon request
On January 21, 2003 Jones stopped at Miller's residence at 8:00 p.m. and discovered that he was not there.(N.T. 13-14). In addition, Miller failed to report the following day to the Spring Garden location, although he should have done so. On February 6, 2003, the Board issued a warrant to commit and detain and Miller was arrested later that same day by Board agents Jones and Nunez. After Miller was placed in the holding cell, Jones departed and, later that same day, Nunez' supervisor asked him to get a urine sample from Miller. Jones stated that Miller had assured him that he would provide a urine sample, but Nunez stated that, when he sought to obtain one, Miller claimed he could not comply because he had a urinary tract infection.(N.T. 18). This incident formed the basis for the charge of failing to submit to urine testing.
The Board held a technical parole violation hearing and recommitted Miller to serve nine months back-time as a technical parole violator, finding that he had committed all three violations. His request for administrative relief was denied and this appeal ensued. 1
First, we begin our analysis by observing that Miller admits that he was not present at his approved residence on January 21, 2003 at 8:00 p.m., and that he did not report to the parole office the following day. Thus, the Board has met its burden to show, by a preponderance of the evidence, that the curfew and failure to report violations did occur. 2 However, Miller asserts that these violations were unintentional because he was, at that time, hospitalized in a mental ward, and was not released until February 6, 2003, when he signed himself out. He relies on Hudak v. Pennsylvania Board of Probation and Parole, 757 A.2d 439 (Pa.Cmwlth.2000), petition for allowance of appeal denied, 565 Pa. 657, 771 A.2d 1291 (2001). In that case, we held that where the parolee had been hospitalized with a ruptured colon and, consequently, could not report for his curfew, he should not be recommitted because the parole violation required "some kind of fault" on the parolee's part. The critical distinction between that case and this one, however, is that in Hudak it was undisputed that the parolee was actually in the hospital at the relevant time. In this case, however, the parole agent disputed this fact. He testified that he had called the hospital repeatedly and that "he [Miller] was not there."(N.T. 12.) The public defender argues that the hospital was precluded from releasing this information under various confidentiality laws. While this may be true, he was still obligated to put on evidence to establish Miller's hospital stay. Miller claims he was never given any release papers and, so, could provide nothing more than his bare assertion that he had been there.In such
837 A.2d 621
circumstances, we conclude that the Board, acting within its province as the judge of credibility matters,
Sigafoos,
had substantial evidence to conclude that Miller had committed these two violations and had not shown a justifiable excuse...
12 practice notes
Com. v. Davis United States Superior Court of Pennsylvania June 14, 2004 ...of parole established by the Board. Wile, Pennsylvania Law of Probation and Parole § 1.6 (1993). Miller v. Bd. of Probation and Parole, 837 A.2d 618 , 622 (Pa.Cmwlth.2003). Since commitment to a halfway house necessarily requires removal from a prison and allows the prisoner "to serve a peri......
Santiago v. Bd. of Probation and Parole, 85 C.D. 2007. United States Commonwealth Court of Pennsylvania December 3, 2007 ...protection of the publics safety and the adequate supervision of the offender ...." Miller v. Pennsylvania Board of Probation and Parole, 837 A.2d 618 , 622 (Pa.Cmwlth.2003) (citing Section 1 of the Parole Act, 61 P.S. § 331.1.) If the punishment for the new crimes committed while on parole ......
Fehnel v. Pa. Bd. of Prob. & Parole, 446 C.D. 2013 United States Commonwealth Court of Pennsylvania December 5, 2013 ...of his or her parole. See Price v. Pa. Bd. of Prob. & Parole, 863 A.2d 618 (Pa. Cmwlth. 2004); Miller v. Pa. Bd. of Prob. & Parole, 837 A.2d 618 (Pa. Cmwlth. 2003); Smalls v. Pa. Bd. of Prob. & Parole, 823 A.2d 274 (Pa. Cmwlth. 2003); Sigafoos v. Pa. Bd. of Prob. & Parole, 503 A.2d 1076 (Pa......
Commonwealth v. Davis, 2004 PA Super 219 (PA 6/14/2004), 1410 MDA 2003. United States United States State Supreme Court of Pennsylvania June 14, 2004 ...of parole established by the Board. Wile, Pennsylvania Law of Probation and Parole § 1.6 (1993). Miller v. Bd. of Probation and Parole, 837 A.2d 618 , 622 (Pa. Cmwlth. 2003). Since commitment to a halfway house necessarily requires removal from a prison and allows the prisoner "to serve a pe......
12 cases
Com. v. Davis United States Superior Court of Pennsylvania June 14, 2004 ...of parole established by the Board. Wile, Pennsylvania Law of Probation and Parole § 1.6 (1993). Miller v. Bd. of Probation and Parole, 837 A.2d 618 , 622 (Pa.Cmwlth.2003). Since commitment to a halfway house necessarily requires removal from a prison and allows the prisoner "to serve a peri......
Santiago v. Bd. of Probation and Parole, 85 C.D. 2007. United States Commonwealth Court of Pennsylvania December 3, 2007 ...protection of the publics safety and the adequate supervision of the offender ...." Miller v. Pennsylvania Board of Probation and Parole, 837 A.2d 618 , 622 (Pa.Cmwlth.2003) (citing Section 1 of the Parole Act, 61 P.S. § 331.1.) If the punishment for the new crimes committed while on parole ......
Fehnel v. Pa. Bd. of Prob. & Parole, 446 C.D. 2013 United States Commonwealth Court of Pennsylvania December 5, 2013 ...of his or her parole. See Price v. Pa. Bd. of Prob. & Parole, 863 A.2d 618 (Pa. Cmwlth. 2004); Miller v. Pa. Bd. of Prob. & Parole, 837 A.2d 618 (Pa. Cmwlth. 2003); Smalls v. Pa. Bd. of Prob. & Parole, 823 A.2d 274 (Pa. Cmwlth. 2003); Sigafoos v. Pa. Bd. of Prob. & Parole, 503 A.2d 1076 (Pa......
Commonwealth v. Davis, 2004 PA Super 219 (PA 6/14/2004), 1410 MDA 2003. United States United States State Supreme Court of Pennsylvania June 14, 2004 ...of parole established by the Board. Wile, Pennsylvania Law of Probation and Parole § 1.6 (1993). Miller v. Bd. of Probation and Parole, 837 A.2d 618 , 622 (Pa. Cmwlth. 2003). Since commitment to a halfway house necessarily requires removal from a prison and allows the prisoner "to serve a pe......
| https://case-law.vlex.com/vid/miller-v-bd-of-888049822 |
(PDF) Distribution and relative abundance of striped dolphins, and distribution of sperm whales in the Ligurian Sea cetacean sanctuary
PDF | On Jan 1, 2000, J.C.D. Gordon and others published Distribution and relative abundance of striped dolphins, and distribution of sperm whales in the Ligurian Sea cetacean sanctuary | Find, read and cite all the research you need on ResearchGate
Distribution and relative abundance of striped dolphins, and distribution of sperm whales in the Ligurian Sea cetacean sanctuary
January 2000
Journal of Cetacean Research and Management2(1):27-36
Authors:
<here is a image 1568dcee4cc4451f-f82fdf3e6d296bb2>
Jonathan Gordon
University of St Andrews
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
J.N. Matthews
J.N. Matthews
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
S. Panigada
S. Panigada
<here is a image 42d3af35698e5d16-2076c58c1ff3f0fb>
Alexandre Gannier
Groupe de Recherche sur les Cétacés
Content uploaded by Giuseppe Notarbartolo di Sciara
... This approach makes it possible to test whether the probability of occurrence of an event can be predicted from a set of quantitative and qualitative predictor variables (Hosmer & Lemeshow, 2000). Binary logistic regression has already been used to investigate cetacean distribution
(Gordon et al., 2000;
Azzellino et al., 2012;Torreblanca et al., 2019). However, OS provide information about occurrences. ...
... see Gannier, 2005). Moreover, this species has the broadest and most ubiquitous distribution, which has led several authors to suggest that striped dolphins have weak habitat preferences
(Gordon et al., 2000;
Panigada et al., 2008;Cotté et al., 2010;Azzellino et al., 2012). Our results also suggest that this species has the broadest distribution, given that the largest fuzzy set of differentially favourable locations was obtained for striped dolphins (Table 2). ...
... The differential response of striped dolphins to bathymetry underlines its pelagic habitat preference, as reported in other studies conducted in different areas of the Western Mediterranean Sea, such as the Northwestern Mediterranean sea
(Gordon et al., 2000;
Panigada et al., 2008;Azzelino et al., 2012), the Alboran Sea (Cañadas et al., 2002;Giménez et al., 2017a), the Northern Ionian Sea (Carlucci et al., 2016), the Spanish Levantine coast (Gómez de Segura et al., 2008), and in other areas in the Mediterranean basins such as the Gulf of Corinth (Bearzi et al., 2016). According to the dataset analysed, this species was sighted in waters with an average depth of 1450.44 ± 805.82 m. ...
Spatial and temporal partitioning of the Western Mediterranean Sea by resident dolphin species.
Full-text available
<here is a image 9e97ef9013c27edb-46736c207e36e751> Estefanía Torreblanca
<here is a image 60c7fa1617500d46-a3db1fb0dda5d5e7> Raimundo Real
<here is a image 1cf6a9ac51d2c63c-9e58d875b068964b> Juan Antonio Camiñas
<here is a image 019a9497e62fda32-d53011024177ea6b> Jose Carlos Báez
A classic issue in ecology is to understand how similar species coexist in a given area (i.e., sympatry). The situation of dolphins in the Western Mediterranean Sea may represent a special case of sympatry in that three similar species (the short-beaked common dolphin [Delphinus delphis], the striped dolphin [Stenella coeruleoalba], and the bottlenose dolphin [Tursiops truncatus) are under strong human impacts in the same area. From the viewpoint of ecology and conservation biology, it is challenging to determine how these three dolphin species live together and avoid competitive exclusion in the setting of such impacts. The Spanish Institute of Oceanography has a dataset of dolphin species opportunistic sightings. Using these data, we constructed three binary variables, comprising the sighting of one species versus the sighting of either of the other two species. We obtained three significant probability models after performing logistic regression of these binary variables on a set of spatio-temporal explanatory variables. We analysed these models from the perspective of fuzzy set theory by applying the favourability function to the probability models, fuzzy operations overlap, and entropy. The results show that common dolphins are differentially favoured in the eastern part of the study area and far away from main shipping routes. The striped dolphin was differentially favoured in the western part of the study area, above deep waters, near main shipping routes, and in summer and spring. Finally, bottlenose dolphins were differentially favoured in the mid-western part of the study area, in winter, and over shallow waters.
... This constraint in species identification is even more relevant during multispecies monitoring programs (Redfern et al. 2006). Vocalization rates are also behavioral-context-dependent
(Gordon et al. 2000)
. Silent animals may not be detected, and even some highly vocal species such as sperm whales have been observed to remain silent for hours whilst resting on the surface (Jaquet et al. 2001, Barlow & Taylor 2005. ...
... In order to increase detection rates, visual and acoustic methods have been applied in combination in some surveys of single cetacean species
(Gordon et al. 2000
, Akamatsu et al. 2001, Barlow & Taylor 2005, Pikesley et al. 2012, Richman et al. 2014, Burham et al. 2016 or of multiple species within a particular family, such as Delphinidae (Simard et al. 2015, Thompson et al. 2015. However, simultaneous application of visual and acoustic methods in multispecies surveys is still relatively uncommon or has only recently been adopted in some places (Fossati et al. 2017, Verfuss et al. 2018. ...
Better together: Analysis of integrated acoustic and visual methods when surveying a cetacean community
<here is a image d461409a479c48a0-d9ddd7969f562ab3> Larissa Dalpaz
Alexandre Douglas Paro
FG Daura-Jorge
<here is a image 3a12db5d21d57161-0ee98b3e1648c098> Leonardo Wedekin
Understanding the relative performance of data collection methods is critical for the production of robust results in any biological field study. This is particularly relevant for monitoring studies of rare and inconspicuous species, such as some cetaceans. Here, we compared how passive acoustic and visual survey methods performed when surveying a multispecies cetacean community in a large-scale survey area and whether the simultaneous application of these methods leads to complementary results. For both methods we compared (1) frequency of unscheduled survey stoppages, (2) detection ranges, (3) success in identifying species, (4) precedence of either method in synchronous detections, (5) detection rates, and (6) influence of sea state on detection rates. Data were collected during 4 surveys conducted between 2015 and 2017, using simultaneous visual and acoustic methods in the Santos Basin, Brazil. A total of 1492 h of simultaneous sampling yielded 617 detections, of which 46.5% (n = 287) were exclusively acoustic, 18.5% (n = 114) were exclusively visual, and 35% (n = 216) were corresponding detections of the same group made by each method, resulting in 108 paired detections. The simultaneous application of visual and acoustic methods was complementary. Acoustics were more efficient in detecting cetaceans—detecting first and further from the vessel and with a greater detection rate—whereas visual observation was more accurate for species identification. When used together, detection rates per species increased, reducing potential biases. By improving acoustic classification through visually confirmed sightings, this integrated approach has the potential to provide a reliable sound library for cetaceans in the Southwest Atlantic Ocean.
... Due to its small size, cryptic coloration, erratic behavior, and small group size, they are difficult to observe in the wild (Bastida & Rodríguez 2009;Barcellos & Santos 2021). Therefore, passive acoustic monitoring has the potential to better recognize the dolphin presence (Simon et al. 2010;Caruso et al. 2019;Gregorietti et al. 2021), density
(Gordon et al. 2000)
, and habitat use (Lammers et al. 2008;Carusso et al. 2017;Papale et al. 2020). Moreover, this monitoring has the potential to know the dolphins' behavior in close proximity to the fishing operation where there are potentially entangled (Paitach et al. 2021;2022). ...
Acoustic detection of Franciscana dolphin (Pontoporia blainvillei) in Southern Buenos Aires Province, Argentina Report to the International Whaling Commission
<here is a image f6eed94bb8367390-be390bff5d8b4fc6> Gisela Giardino
Giuseppa Buscaino
<here is a image e9bab7ca54a2c91f-3cde9d938df044a8> Ricardo Bastida
<here is a image 5a60fce640f87f2d-5083669806fe3986> Diego Rodriguez
Our main interest is to detect the acoustic presence of franciscana dolphins in an area free of fishing pressure and then compare it with the detections made in areas with active bycatch. To meet that objective, two acoustic detectors (FPODS) were first placed in Chapadmalal (Free fishing zone) and then in two artisanal fishing gillnets in Claromecó (Buenos Aires Province, Argentina). We found high frequency and narrow band (HFNB) click positive detection in both sites. These preliminary results confirm that passive acoustic is a good tool to assess' franciscana presences in both scenarios. Moreover, understanding the echolocation behavior around the gillnets would lead to better mitigation tools designed in order to reduce bycatch.
... The stereophony of the sonobuoy allowed us to compute TDoAs tracks, enabling an efficient browse of long-term data for annotation of presence/ absence as well as for estimating the number of simultaneous individuals. The Mediterranean sperm whale subpopulation had already been studied at very large geographical scales [41][42][43] , while other populations were monitored over long time period such as Gordon et al.
44
www.nature.com/scientificreports/ To our knowledge, this is the first time that a Mediterranean sperm whale study involving passive acoustic monitoring has been carried out covering such a long time period, across different seasons/years and in stereophony. ...
Passive acoustic monitoring of sperm whales and anthropogenic noise using stereophonic recordings in the Mediterranean Sea, North West Pelagos Sanctuary
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Marion Poupard
Maxence Ferrari
<here is a image cb5b7a52977abc6f-75d3ecd24ebed4b0> Paul Best
<here is a image 664d57a624df5f25-6c09994fca3b1a74> Hervé Glotin
A total of 147 days spread over 4 years were recorded by a stereophonic sonobuoy set up in the Mediterranean sea, near the coast of Toulon, south of France. These recordings were analyzed in the scope of studying sperm whales (Physeter macrocephalus) and the impact anthropic noises may have on this species. With the use of a novel approach, which combines the use of a stereophonic antenna with a neural network, 226 sperm whales’ passages have been automatically detected in an effective range of 32 km. This dataset was then used to analyze the sperm whales’ abundance, the background noise, the influence of the background noise on the acoustic presence, and the animals’ size. The results show that sperm whales are present all year round in groups of 1–9 individuals, especially during the daytime. The estimated density is 1.69 whales/1000 km2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^2$$\end{document}. Animals were also less frequent during periods with an increased background noise due to ferries. The animal size distribution revealed the recorded sperm whales were distributed in length from about 7 to 15.5 m, and lonely whales are larger, while groups of two are composed of juvenile and mid-sized animals.
... On constate, depuis deux décennies, une évolution de la fréquence d'observation du Cachalot, dont la population serait actuellement comprise entre 200 et 1000 individus en Méditerranée occidentale (Rendell et al., 2014). Ainsi, seulement 4 % des écoutes acoustiques signalaient le Cachalot au cours de prospections conduites conjointement dans le bassin liguro-provençal en 1994 par l'International Fund for Animal Welfare, le Groupe de Recherche sur les Cétacés et l'Institut Tethys
(Gordon et al., 2000)
, tandis que de 2003 à 2010, cette proportion s'élevait à 20 %, pour une zone d'étude favorisant le talus (données personnelles, rapport non publié https://www.cetaces.org/publications/). Une forte remontée du nombre de Cachalots dans notre zone d'étude pourrait entraîner une évolution de l'écologie des trois autres teuthophages à l'échelle du bassin, même si cette hypothèse est difficile à étayer. ...
Comparaison de l’habitat estival de quatre cétacés teuthophages préférentiels en Méditerranée nord-occidentale
REV ECOL-TERRE VIE
<here is a image 42d3af35698e5d16-2076c58c1ff3f0fb> Alexandre Gannier
Comparison of the summer habitat of four preferential teuthophagous cetaceans in north-western Mediterranean Sea.
More than 50 squid species inhabit the Mediterranean Sea and four of the common cetacean species are preferential squid eaters. This suggests that teuthophagous cetaceans might be in competition for food and suitable habitats. Descriptive and multivariate analyses were carried out from long term dedicated survey data (1988-2012) in the north-western Mediterranean, including the northern Tyrrhenian Sea. A total of 298 on-effort sightings were obtained between 1988 and 2012, including 202 on effective effort : 157 observations of Sperm whale, 39 of Cuvier's beaked whale, 49 of Long-finned pilot whale and 53 of Risso's dolphin. Five environmental variables (depth, slope, distance-to-200m-isobath (D200), monthly chlorophyll concentration and SST) were defined for every 3x3 km cell in the western basin, as well as summer sighting rates using Pennington estimators for each individual species. Based on Kruskal-Wallis test, the observed habitats were not homogeneous for all species, excepted for SST : preferred depth was significantly distinct for each species. D200 was also distinct, with the exception of the pair Cuvier's beaked whale/ pilot whale. Based on a discriminant analysis (stepwise ascending mode), four variables contributed significantly (Wilk''s lambda = 0.49) to habitat description of the four species, the most important of them being the depth. Discriminant function was highly efficient to classify Cuvier's beaked whale and pilot whale habitats (respectively 84.6 % and 83.7 % success rate), but sperm whale was poorly discriminated from other species (29.6 % correct prediction). Cuvier's beaked whale and pilot whale habitats were well separated, when those of sperm whale and Risso''s dolphin largely overlapped. From available results from different regions worldwide, it seems that Risso's dolphins and pilot whales are rarely abundant together in a given area, which raises the question of a possible competition between these teuthophagous delphinids. Based on published literature, these findings are correlated with known diet preferences, even if sperm whale preys are still poorly documented in the Mediterranean.
... Specifically, bathymetric features were extremely significant in predicting species persistent areas with preference for the deepest portion of the basin Panigada et al., 2008;Aïssi et al., 2015;Morgado et al., 2017). Despite the lower power of the sperm whale model, our results still catch the known bimodal distribution for the species, highlighting the importance of both deeper areas as well as the areas of the steep slope closer to the continental shelf
(Gordon et al., 2000;
Gannier et al., 2002a;Tepsich et al., 2014). For the fin whale, the model is also capable of identifying an area outside coverage of our surveys, specifically the area eastern of northern Sardinia. ...
Locating ship strike risk hotspots for fin whale (Balaenoptera physalus) and sperm whale (Physeter macrocephalus) along main shipping lanes in the North-Western Mediterranean Sea
OCEAN COAST MANAGE
<here is a image dc3bfd1907117379-e3ea80252f568e66> Francesca Grossi
Elise Lahaye
<here is a image e4ecb0e2eeafe973-7c0f2cde229e350c> Aurelie Moulins
<here is a image e9bdea12f27b6037-5af26141e7edd7c9> Paola Tepsich
The Pelagos Sanctuary is the only pelagic marine protected area in the Mediterranean Sea, instituted for the conservation of cetaceans. Considering the number and size of commercial and touristic ports located along its coasts, this protected area is highly impacted by human activities, and especially marine traffic. Fin whales and sperm whales are regularly sighted in the Pelagos Sanctuary, and ship strikes with large vessels are one of the main threats affecting these two species. Mapping hotspots of distribution along main shipping lanes could be an effective conservation tool, as they directly allow locating high risk areas. In this work, we used data collected during summer from 2009 to 2019, along main marine traffic corridors in the central region of Pelagos Sanctuary. Ship strike hotspots have been identified, considering the persistence of distribution hotspots over the 11 years period. Hotspots occurrence has then been predicted over the entire Pelagos Sanctuary area applying Generalized Additive Models, allowing for ship strike risk assessment over the marine protected area. Our results highlighted the recurrence of important areas for both species along shipping lanes characterized by high vessel traffic, identifying regions where to address conservation measures.
... Even then, human error remains a prevalent source of variability. However, the use of passive acoustic monitoring (PAM) can overcome many of these limitations (di Sciara and Gordon, 1997;
Gordon et al., 2000)
. PAM devices can be deployed for several months at a time and collect data without human error whilst being minimally affected by environmental conditions (Nuuttila et al., 2013b). ...
Static passive acoustic monitoring of odontocetes in a wind farm development off Blyth, Northumberland, UK.
Oct 2017
<here is a image 1a012767c30a5e1f-cf7ca2d67e336696> Kelsey Potlock
Sarah Kenney
<here is a image def64176588daac6-875ce7ff48748b9d> Andrew J Temple
<here is a image 0d1ca605e268eb06-3ee187a8d8ebeaa9> Per Berggren
Offshore wind energy is rapidly expanding across Europe in response to increasing power demands. Blyth, off the northeast coast of England, is a relatively shallow, coastal area where a 15 turbine (3 array) windfarm is in development. In this study, passive acoustic monitoring (PAM) is used to investigate potential impacts on regularly occurring odontocete species (Phocoena phocoena, Lagenorhynchus albirostris, and Tursiops truncatus) between the pre-, during, and post-construction phases. 11 Cetacean Click Detectors (C-PODs) are anchored throughout the development site to monitor spatial and temporal variation in odontocete occurrence and foraging activity. 6,800,000 minutes of recordings were collected during the pre-construction phase between March 2015 and March 2017. Preliminary examinations of the data show that both delphinids and porpoises occur year round, with relative porpoise occurrence 20x higher than dolphins. The apparent difference in species occurrence likely relates to echolocation behaviour and this will be investigated in further detail. Temporally, porpoise relative occurrence was greater in December to February across all C-POD sites while dolphins occurred more frequently in the summer months, coinciding with increased salmon abundance in the area. This apparent mismatch in occurrence peaks could also indicate a level of area exclusion, with aggressive interactions between the two being noted anecdotally. Spatially, there was a higher occurrence of Buzz Positive Minutes (BPM), indicative of foraging activity, at the northernmost locations of the development site for dolphins. The BPM for porpoises showed greater variability across all sites within the study area, indicating no preference for location. The total proportion of BPMs per DPM for porpoises (29.8%) suggest higher use of the area for foraging compared to delphinids (15.0%). The data gathered 2015-2017 comprises the pre-construction data to be used as a baseline and comparison with the during-construction 2017 and post-construction 2018 phases of the windfarm development.
... Seasonal and/or peculiar events, such as gales of northwesterly wind (so-called Mistral), can also influence the phytoplankton community structure, and then the biological activity (Thyssen et al., 2014). The seasonal increase in Chl a, from fall to early spring, in this region benefits the entire marine food web including zooplankton, macrozooplankton, and cetaceans (Forcada et al., 1995;
Gordon et al., 2000)
. Due to its biological importance, the Ligurian Sea became, in The regional circulation and frontal system that regulate the physical and biological dynamics of the Ligurian Sea are nowadays well understood. ...
Vertical Motions and Their Effects on a Biogeochemical Tracer in a Cyclonic Structure Finely Observed in the Ligurian Sea
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Louise Rousselet
<here is a image a0ad79f2ebbe6830-912f7d3ea8212f9c> Andrea M. Doglioli
Alain de Verneil
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> A. Petrenko
Vertical velocities can be estimated indirectly from in situ observations by theoretical frameworks like the ω‐equation. Direct measures of vertical exchanges are challenging due to their typically ephemeral spatiotemporal scales. In this study we address this problem with an adaptive sampling strategy coupling various biophysical instruments. We analyze the 3‐D organization of a cyclonic mesoscale structure finely sampled during the Observing Submesoscale Coupling At High Resolution cruise in the Ligurian Sea during fall 2015. The observations, acquired with a moving vessel profiler, highlight a subsurface low‐salinity layer (≃50 m), as well as rising isopycnals, generated by geostrophic cyclonic circulation, in the structure's center. Reconstructed 3‐D fields of density and horizontal velocities are used to estimate the vertical velocity field down to 250 m by applying the adiabatic QG ω‐equation, for the first time in this region. The vertical motions are characterized by multipolar patterns of downward and upward velocities on the edges of the structure and significantly smaller vertical velocities in its center. Both the 3‐D distribution of particles (size ≥100 μm), measured with a laser optical plankton counter, and the Synechococcus and Prochlorococcus abundances (cell per cubic meter) measured by flow cytometry are consistent with the 3‐D velocity field. In particular, a secondary vertical recirculation is identified that upwells particles (from 250 to 100 m) along isohalines to the structure's center. Besides demonstrating the effect of vertical patterns on biogeochemical distributions, this case study suggests to use particle matter as a tracer to assess physical dynamics.
... One wide-ranging study (Gannier et al., 2002) found sperm whales distributed along the Hellenic Trench and the west coast of Greece, around the Balearic Islands of Spain, and along the northwestern Mediterranean from the Gulf of Lyons to the Ligurian Sea. Examples of more localised studies include those of
Gordon et al. (2000)
who determined the distribution of sperm whales using acoustic point surveys in the Ligurian Sea, and Frantzis et al. (2014) who carried out extensive acoustic research in the waters of southwestern Greece showing concentrations of sperm whales along the Hellenic Trench and its continuation to the northwest and east. ...
Abundance estimates for sperm whales in the Mediterranean Sea from acoustic line-transect surveys
<here is a image 7f215cb679ed3013-b68d5d75add9ea8d> Tim Lewis
<here is a image 1c922fbbfa9930b9-90166532b2eccdbd> Oliver Boisseau
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Magnus Danbolt
<here is a image fbc9a7b51aea78bf-d619abb9e4acd516> Anna Moscrop
The Mediterranean sub-population of sperm whales is believed to be isolated and is classified as Endangered on the IUCN Red List. Although there is evidence to suggest the population is declining, there is a lack of abundance data. A series of acoustic line-transect surveys were undertaken between 2004 and 2013. In 2004, 3,946km of acoustic effort was conducted in the southern Western Mediterranean basin, resulting in the detection of 159 sperm whales. While in 2007 and 2013, 10,276km of acoustic effort was conducted in the Eastern Mediterranean basin, resulting in the detection of 24 sperm whales. A pooled detection function gave an effective strip half-width of 9.8km. A correction for availability bias was made for each block based on published simulations using data on sperm whale acoustic behaviour: estimates of g(0) were 0.95-0.96. Estimated abundances were: Southern Western Mediterranean Block 634 animals [374-1,077] (95% log-normal confidence interval); Hellenic Trench Block 41 [17-100]; Central Aegean Sea Block 33 [5-203]; Herodotus Rise Block 5 [1-28] and Southern Adriatic Sea Block 2 [0-12]. Estimates for all other blocks were zero. The density of sperm whales in the surveyed Southern Western Mediterranean Block was over 17 times higher than for the surveyed Eastern Mediterranean (2.12 and 0.12 whales per 1,000km² respectively). These results, combined with an acoustic survey of the northern Ionian Sea in 2003 and aerial surveys in the northern Western Mediterranean basin in 2010-11, covered approximately 57% of the likely sperm whale habitat in the Western Mediterranean and 75% in the Eastern Mediterranean. Approximate total estimates of sperm whale abundance in the Western and Eastern Mediterranean basins based on extrapolation to the unsurveyed areas are 1,678 and 164 whales respectively. This gives an estimate for the whole Mediterranean Sea of 1,842 animals.
Short communication: New records of sperm whale social units in the Pelagos Sanctuary, Mediterranean Sea
In the Ligurian Sea, the northern part of the Western Mediterranean Sea, sperm whales (Physeter macrocephalus Linnaeus, 1758) are historically sighted as solitary individuals or loose aggregations of males, while social units are extremely occasional. On 21 August 2020, two different social units were recorded in this area with an estimate of 21 individuals in total (12 in the first and nine in the second). The Mediterranean sperm whale subpopulation is considered Endangered under the IUCN Red List and an understanding of its movements and social structure is lacking. These observations increase our knowledge on its conservation biology and possible threats.
| https://www.researchgate.net/publication/281339378_Distribution_and_relative_abundance_of_striped_dolphins_and_distribution_of_sperm_whales_in_the_Ligurian_Sea_cetacean_sanctuary |
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Batley and District Mencap;Northorpe Hall Child & Family Trust;Care Opinion;Sacmha Carers Group (Sheffield African Caribbean Mental Health Association);Weston Park Cancer Information And Support Centre;West Yorkshire Adhd Support Group;Cloverleaf Advocacy Services;St Anne'S Community Services;Ants (A Nice Time On Saturdays);Hallamshire Hearties Cardiac Support Group
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Batley and District Mencap
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S3 9EH11.4 miles away
Information supplied by Provides a service for African and Caribbean carers and carers of African and Caribbean people, both as individuals and through groups.
Target group n/aData not available
Weston Park Cancer Information And Support Centre
Address & contact detailsTel: 0114 553 333023 Northumberland Road
Sheffield
South Yorkshire
S10 2TX11.5 miles away
Information supplied by n/aData not available
Target group Anyone affected by cancer: patient, carer, relative, friend, work colleague etc.
West Yorkshire Adhd Support Group
Address & contact details11.5 miles away
Information supplied by We offer peer support to adults with ADHD and parents of children with suspected or diagnosed ADHD. We have an active Facebook page and hold regular face-to-face and Zoom meetings. We also run weekend and holdiay activities for children with ADHD and their siblings.
Target group Anyone affected by ADHD in the West Yorkshire area.
Cloverleaf Advocacy Services
Address & contact detailsTel: 01924 438438Kirklees Office
26 Bond Street
Dewsbury
West Yorkshire
WF13 1AU11.5 miles away
Information supplied by We provide free and confidential person centred advocacy services for people with mental health needs, people with learning disabilities, people with physical or sensory impairments, acquired brain injury, older people and carers. This includes self-advocacy and service user involvement initiativ... Continue reading overview
Target group Advocacy services for people with mental health needs, people with learning disabilities, people with physical or sensory impairments, acquired brain injury, older people and carers
St Anne'S Community Services
Address & contact detailsTel: 01484 428955Area Office
Edgerton Villa
22 - 24 Edgerton Road
Huddersfield
West Yorkshire
HD3 3AD11.5 miles away
Information supplied by Providing services for people with learning disabilities, mental health problems, homeless people and people with drug or alcohol problems.
St Anne's offers housing and accommodation based support in partnership with other housing providers and a range of community based services, in addition t... Continue reading overview
Target group Service available to carers and those they care for with a mental health need.
Ants (A Nice Time On Saturdays)
Address & contact detailsTel: 0114 222 8547Sheffield Volunteering
The Union
Western Bank
Sheffield
South Yorkshire
S10 2TG11.6 miles away
Information supplied by This project is for children aged 8 - 11 who have been affected by a bereavement in their family.
The group meets once a month on a Saturday and run craft/team building activities in the morning and then go out and do activities such as bowling, climbing, canoeing etc in the afternoon.
Target group Any children aged 8 - 11 in the Sheffield area affected by a bereavement.
Hallamshire Hearties Cardiac Support Group
Address & contact detailsTel: 0114 281 6614St Mark's Church Hall
Beech Hill Road
Sheffield
South Yorkshire
S10 2SE11.6 miles away
Information supplied by Hallamshire Hearties Cardiac Support Group offers support and social activities for angina sufferers and people who have had heart attacks or cardiac surgery and their relatives and/or carers. Organises speakers at meetings. Retains contact with professional people and current after care practice... Continue reading overview
Target group Angina sufferers and people who have had heart attacks or cardiac surgery and their relatives and/or carers.
| https://www.nhs.uk/service-search/other-services/Carer-centres-and-services/Penistone/Results/139/-1.626/53.526/371/16707?ResultsOnPageValue=10¤tPage=5&distance=25&isNational=0&totalItems=388 |
Silent Cal | Fact | FactRepublic.com
Interesting Facts with Sources & Pics. Random & Cool Facts. Alternative Facts, Facts of the Day, Weird Tidbits, Crazy Facts, Celebrity Trivia, Comic Facts
Silent Cal
American president Calvin Coolidge was a man of few words, and got the nickname "Silent Cal." He once remarked, "I think the American people want a solemn a*s as a President." When satirist Dorothy Parker heard he had died, she responded, "How can you tell?"
Summary from Source
His grandfather Calvin Galusha Coolidge served in the Vermont House of Representatives. His eldest John said it "Hurt [Coolidge] terribly." John became a railroad executive, helped to start the Coolidge Foundation, and was instrumental in creating the President Calvin Coolidge State Historic Site. Coolidge forged another key strategic alliance with Guy Currier, who had served in both state houses and had the social distinction, wealth, personal charm and broad circle of friends which Coolidge lacked, and which would have a lasting impact on his political career. In 1911, the State Senator for the Hampshire County area retired and successfully encouraged Coolidge to run for his seat for the 1912 session; Coolidge defeated his Democratic opponent by a large margin. Coolidge intended to retire after his second term as was the custom, but when the president of the state senate, Levi H. Greenwood, considered running for lieutenant governor, Coolidge decided to run again for the Senate in the hopes of being elected as its presiding officer. A delegate from Oregon, Wallace McCamant, having read Have Faith in Massachusetts, proposed Coolidge for vice president instead. The suggestion caught on quickly with the masses starving for an act of independence from the absent bosses, and Coolidge was unexpectedly nominated. Harding ran a "Front-porch" campaign from his home in Marion, Ohio, but Coolidge took to the campaign trail in the Upper South, New York, and New England - his audiences carefully limited to those familiar with Coolidge and those placing a premium upon concise and short speeches.
After the conventions and the death of his younger son Calvin, Coolidge became withdrawn; he later said that "When he [the son] died, the power and glory of the Presidency went with him." Even as he mourned, Coolidge ran his standard campaign, not mentioning his opponents by name or maligning them, and delivering speeches on his theory of government, including several that were broadcast over the radio. In 1925, Coolidge ordered the withdrawal of Marines stationed in Nicaragua following perceived stability after the 1924 Nicaraguan general election, but redeployed them there in January 1927 following failed attempts to peacefully resolve the rapid deterioration of political stability and avert the ensuing Constitutionalist War; Henry L. Stimson was later sent by Coolidge to mediate a peace deal that would end the civil war and extend American military presence in Nicaragua beyond Coolidge's term in office. To extend an olive branch to Latin American leaders embittered over America's interventionist policies in Central America and the Caribbean, Coolidge led the U.S. delegation to the Sixth International Conference of American States, January 15-17, 1928, in Havana, Cuba, the only international trip Coolidge made during his presidency. Coolidge did not have a vice president during his first term, but Charles Dawes became vice president during Coolidge's second term, and Dawes and Coolidge clashed over farm policy and other issues. Coolidge had been reluctant to endorse Hoover as his successor; on one occasion he remarked that "For six years that man has given me unsolicited advice-all of it bad." Even so, Coolidge had no desire to split the party by publicly opposing the nomination of the popular commerce secretary. Coolidge published his autobiography in 1929 and wrote a syndicated newspaper column, "Calvin Coolidge Says," from 1930 to 1931. Shortly before his death, Coolidge confided to an old friend: "I feel I no longer fit in with these times." Coolidge is buried in Plymouth Notch Cemetery, Plymouth Notch, Vermont. Newspaper clippings about Calvin Coolidge in the 20th Century Press Archives of the ZBW..
| https://factrepublic.com/facts/37872 |
Cont. | Download Table
Download Table | Cont. from publication: The Spectrum of Small Intestinal Lesions in Patients with Unexplained Iron Deficiency Anemia Detected by Video Capsule Endoscopy | Background and objectives: Video-capsule endoscopy (VCE) has shown a large range (38–83%) of diagnostic yield in unexplained iron deficiency anemia (IDA) and obscure-occult bleeding. Therefore, we retrospectively investigated the VCE-detected spectrum and the prevalence of... | Capsule Endoscopy, Iron Deficiency Anemia and Bleeding | ResearchGate, the professional network for scientists.
Table 3
- available via license: CC BY
Cont.
Source publication
The Spectrum of Small Intestinal Lesions in Patients with Unexplained Iron Deficiency Anemia Detected by Video Capsule Endoscopy
Article
Full-text available
Feb 2019
Antonella Contaldo
Giuseppe Losurdo
Francesca Albano
[...]
Mariabeatrice Principi
Background and objectives: Video-capsule endoscopy (VCE) has shown a large range (38–83%) of diagnostic yield in unexplained iron deficiency anemia (IDA) and obscure-occult bleeding. Therefore, we retrospectively investigated the VCE-detected spectrum and the prevalence of small bowel injuries and associated risk factors in inpatients with both of...
Citations
... VCE is a non-invasive device, which allows investigating small bowel lesions, especially in patients with unexplained iron deficiency anemia and obscure/occult bleeding
[1]
. Among potential sources of intestinal hemorrhage, cutaneous melanoma metastasis deserves a special mention. ...
Small Bowel Metastatic Melanoma: An Emblematic “Coal-Black” Appearance at Videocapsule Endoscopy
Article
Full-text available
Nov 2021
MED LITH
Alessia Todeschini
Ilaria Loconte
Antonella Contaldo
Enzo Ierardi
Mariabeatrice Principi
A 80-year-old woman underwent vulvar melanoma resection and segmental lung resection for pulmonary metastasis. Immunotherapy with Nivolumab was performed. One year later, the patient was admitted for gastrointestinal (GI) recurrent bleeding and severe anemia. Esophagoastroduodenoscopy and colonoscopy did not show any abnormality, while videocapsule endoscopy (VCE) revealed an irregular and exophytic whitish area with a “coal-black” central depression. Small bowel resection was performed and histological examination revealed S100 protein strongly positive melanoma metastasis. The patient died six months later from disease progression. A “coal-black” appearance of intestinal metastatic melanoma has been described only twice before this report. In one case the patient had been treated by immunotherapy with interferon A and dendritic cell-based vaccination. In our patient, it is presumable that the picture we observed was a consequence of Nivolumab treatment inducing the disappearance of melanocytes in the area surrounding the metastasis with the onset of the central coal-black lesion encircled by whitish tissue. This picture should be emblematic of intestinal metastatic melanoma in subjects treated with immunotherapy showing occult/obscure bleeding.
... In order of frequency, the distribution of positive nding reported in this study were angiodysplasia 10,17,
20,
21]. In comparison to published data, the number of signi cant ndings outside the small bowel is high in our study. ...
Video Capsule endoscopy in patients with Iron Deficiency Anaemia: Experience at a Regional Australian Service
Preprint
Full-text available
Sep 2021
Maddison Furner
Robyn Nagel
Janani Pinidiyapathirage
Background
Few studies have examined the diagnostic yield of video capsule endoscopy (VCE) in patients with iron deficiency anaemia (IDA). This retrospective study aims to identify the yield of VCE, distribution of VCE findings in IDA and factors predictive of positive findings among patients presenting to a gasteroendoscopy practice in regional Australia.
Methods
Findings of consecutive VCE studies between March 2017 and April 2020 performed in patients with unexplained IDA and negative conventional endoscopy were included in this retrospective analysis. All endoscopies were performed and reported by a single specialist physician. Relevant clinical data including demographics, medication use, haemoglobin and ferritin levels were extracted into a standardised spreadsheet with procedural findings. A positive diagnostic yield was considered when VCE diagnosed one or more lesions that could explain the IDA. Statistical analysis was used to determine variables correlated with definite VCE findings.
Results
In total 123 procedures were included. Mean age of the patients was 67.9 years. Mean haemoglobin and ferritin levels were 93.3 g/L and 11.9ug/L, respectively. Positive findings were present in 54.5% of patients with the most frequent finding being angiodysplasia (52.2%). Haemoglobin level was the only variable associated with a positive finding. A significant number of studies had significant findings outside the small bowel (41.8%), overwhelmingly within reach of conventional upper endoscopy (89.3%).
Conclusions
VCE is a valuable diagnostic modality in patients with IDA. Low haemoglobin was associated with a positive finding on VCE in this group of patients.
... For occult bleeding, two systematic reviews, three prospective studies, and 12 retrospective studies have demonstrated a high yield for VCE in patients with iron deficiency anemia [105,
106]
, with a pooled diagnostic yield of 47 %. The yield is increased in older patients [107,108] and those with a low hemoglobin [109], although significant pathology can also be found in young patients [110]. ...
Revising the European Society of Gastrointestinal Endoscopy (ESGE) research priorities: A research progress update
Article
Apr 2021
ENDOSCOPY
Pradeep Bhandari
Gaius Longcroft-Wheaton
Diogo Libanio
Pedro Pimentel-Nunes
Mario Dinis-Ribeiro
Background One of the aims of the European Society of Gastrointestinal Endoscopy (ESGE) is to encourage high quality endoscopic research at a European level. In 2016, the ESGE research committee published a set of research priorities. As endoscopic research is flourishing, we aimed to review the literature and determine whether endoscopic research over the last 4 years had managed to address any of our previously published priorities.
Methods As the previously published priorities were grouped under seven different domains, a working party with at least two European experts was created for each domain to review all the priorities under that domain. A structured review form was developed to standardize the review process. The group conducted an extensive literature search relevant to each of the priorities and then graded the priorities into three categories: (1) no longer a priority (well-designed trial, incorporated in national/international guidelines or adopted in routine clinical practice); (2) remains a priority (i. e. the above criterion was not met); (3) redefine the existing priority (i. e. the priority was too vague with the research question not clearly defined).
Results The previous ESGE research priorities document published in 2016 had 26 research priorities under seven domains. Our review of these priorities has resulted in seven priorities being removed from the list, one priority being partially removed, another seven being redefined to make them more precise, with eleven priorities remaining unchanged. This is a reflection of a rapid surge in endoscopic research, resulting in 27 % of research questions having already been answered and another 27 % requiring redefinition.
Conclusions Our extensive review process has led to the removal of seven research priorities from the previous (2016) list, leaving 19 research priorities that have been redefined to make them more precise and relevant for researchers and funding bodies to target.
... P = 0.009), and mass/tumor (7.95 vs. 2.25%, P = 0.0001) lesions were detected with SBCE (22). Contaldo et al.
(23)
showed that VCE could reveal the source of obscure-occult bleeding in a high percentage of unexplained iron-deficiency anemia. However, our result did not find the validity of SBCE in the investigation of patients with IDA and negative findings on a previous diagnostic workup. ...
Effectiveness of Improved Use of Chewing Gum During Capsule Endoscopy in Decreasing Gastric Transit Time: A Prospective Randomized Controlled Study
Article
Full-text available
Feb 2021
Liang Huang
Yue Hu
Fang Chen
Shan Liu
Bin Lu
Background/Aim: Chewing gum throughout small bowel capsule endoscopy (SBCE) increases completion rates (CRs) but decreases small bowel transit time (SBTT) and diagnostic yield (DY). We determined the effects of chewing gum early during SBCE on gastric transit time (GTT), SBTT, CR, DY, and gastroscopy intervention.
Methods: We prospectively enrolled patients (ages 16–80 years) undergoing SBCE between January and June 2019. Patients were randomized to a chewing gum group (103 patients) and a control group (102 patients). Patients in the former group chewed one piece of gum for ~15 min every 30 min during the first hour of SBCE. Two gastroenterologists blinded to the study group examined the data.
Results: GTT was shorter in the chewing gum group (19.0 min, interquartile range: 17.0–52.0 min) than in the control group [42.5 min (23.25–60 min); P = 0.01]. SBTT was similar in the two groups [318.5 min (239.5–421.3 min) vs. 287.0 min (216.0–386.0 min); P = 0.08]. Gastroscopy rate was lower in the chewing gum group (15.53 vs. 32.35%, P = 0.005). CR (95.15 vs. 89.22%, P = 0.114) and DY (66.02 vs. 59.80%, P = 0.359) did not differ between the groups. The number of abnormal-lesion types detected per patient was higher in the chewing gum group [1.0 (0.0–2.0) vs. 2.0 (0.0–2.0); P = 0.049].
Conclusions: Chewing gum early during SBCE significantly reduced GTT and gastroscopy intervention, with no influence on SBTT (Trial number: NCT03815136).
... Anemia may be defined as a hemoglobin concentration in body and it vary from person to person and gender to gender. The concentrations of hemoglobin in men that have anemia is below 13g/dl and in young girls of more than 15 have below 12g/dl
[2]
. And it may be for long duration and its condition may be vary from mild to severe in different people. ...
Anemia Symptoms, Causes, Prevention, Diagnosis and Treatmen
Article
Full-text available
Aug 2020
Nasrullah
Rana Khalid Iqbal
Natasha Khalid
Anemia is a disease in which we do not have enough and healthy red blood cells that contain iron containing protein hemoglobin (protein which carry out oxygen from lungs and transport it to all parts of body), anemia have many types everyone with its own cause, it can either be long term or temporary. Anemia occurs when blood loss due to physical injury or due to menstruationin female. It has symptoms like the r sickle shape hemoglobin and lack of normal shape of it. It can be prevented by eating balance diet and also using iron supplements. Anemia symptoms are fatigue and yellowish skin and eyes and feeling fever all the time.
... This gastrointestinal bleeding risk is higher especially in the presence of preexisting lesions like angiodysplasias and erosions [47][48][49][50]. This study highlights the usefulness of videocapsule endoscopy in providing clear information in patients with unexplained iron deficiency anaemia
[51]
. ...
Non-Vitamin K Antagonist Oral Anticoagulants and the Gastrointestinal Bleeding Risk in Real-World Studies
Article
Full-text available
May 2020
Larisa Anghel
Radu Sascău
Anca Trifan
Ioana Mădălina Zota
Cristian Stătescu
In the present study, we aimed to provide evidence from high-quality real world studies for a comprehensive and rigorous analysis on the gastrointestinal bleeding (GIB) risk for non-vitamin K antagonist oral anticoagulants (NOACs). We performed a systematic search of MEDLINE, EMBASE and PUBMED, and of 286 records screened, we included data from 11 high-quality real-world studies, coordinated by independent research groups over the last 3 years, that reported major GIB events in patients given NOACs or vitamin K antagonists for patients with nonvalvular atrial fibrillation. The lowest risk of gastrointestinal bleeding was with apixaban compared with warfarin (hazard ratio (HR) for GIB for apixaban ranging between 0.45 (95% confidence interval (CI) 0.34 to 0.59) and 1.13 (95% CI 0.79 to 1.63)). Apixaban was associated with a lower risk of GI bleeding than dabigatran ((HR ranging between 0.39 (95% CI 0.27 to 0.58) and 0.95 (95% CI 0.65 to 1.18)) or rivaroxaban ((HR ranging between 0.33 (95% CI 0.22 to 0.49) and 0.82 (95% CI 0.62 to 1.08)). The results of our study confirm a low or a similar risk for major GIB between patients receiving apixaban or dabigatran compared with warfarin, and apixaban appears to be associated with the lowest risk of GIB.
... Эксперты считают основной причиной железодефицитной анемии при приеме НПВС энтеропатию [11], что было подтверждено в исследовании с помощью видео-капсульной эндоскопии
[12]
. ...
Chronic heart failure and the frequency of taking nonsteroidal anti-inflammatory drugs: a register-based study on the possible risks
Article
Full-text available
Feb 2020
E. I. Tarlovskaya
Yu. V. Mikhailova
Aim. To study the frequency of taking nonsteroidal anti-inflammatory drugs (NSAIDs) and possible adverse events in patients with cardiovascular diseases and heart failure (HF) hospitalized in the Heart Failure Therapy Center (Nizhny Novgorod).
Material and methods. According to the local register, the study included 336 patients (men — 156 and women — 180, average age — 71 (63; 80)), hospitalized in Heart Failure Therapy Center in Nizhny Novgorod from February 1 to November 1, 2019. Examination and treatment of patients was performed based on current clinical practice guidelines and standards. According to the results of echocardiography, HF with preserved ejection fraction was diagnosed in 70% of patients, HF with mid-range ejection fraction — in 20%, and HF with reduced ejection fraction — in 10%. Based on data on the outpatient NSAIDs taking, all participants were divided into 2 groups: NSAID+ (n=63) and NSAID(n=273).
Results. Among hospitalized patients, 18,7% of patients took NSAIDs on an outpatient basis, without a doctor’s prescription, more often non-selective, mainly by mouth, for stopping arthralgia. The frequency of emergency hospitalizations due to acute HF decompensation depending on the NSAIDs taking did not significantly differ. In the NSAID+ group, acute kidney injury was diagnosed 3 times more often and 10 times more often when NSAIDs were taken ≥1 times a week. Anemia was diagnosed more often in the NSAID+ group, when taking NSAIDs ≥1 times a week. In the NSAID+ group, grade 2-4 anemia was significantly more often diagnosed.
Conclusion. None of the patients took the recommended NSAIDs with a low cardiovascular risk. Patients taking NSAIDs were more likely to have a history of atrial fibrillation and acute cerebrovascular accident. Patients from the NSAID+ group had the higher incidence of acute kidney injury and anemia.
... Rarely, if bleeding is excessive or the lesions extensive, the patient may need resection of the affected bowel [17]. Other causes are Meckel's Diverticulum, particularly in children, Crohn's disease, vascular occlusions, intussusceptions and volvulus [19,
20]
. Intestinal ischaemia including ischaemic colitis, results in intraluminal blood loss and may present with dark blood passed per rectum. ...
Citation: Weledji EP.Anaemia in Alimentary Tract Disease
Article
Full-text available
May 2019
Elroy Patrick Weledji
Blood loss from the alimentary tract may be chronic and occult resulting in anaemia, or, acute requiring emergency resuscitation, investigation and management. Anaemia in alimentary tract disease usually results from deficiency of iron, vitamin B12 or folic acid. In this review, the common causes of chronic anaemia manifesting in the alimentary tract are discussed. The importance of clinically diagnosing and treating the underlying disease is emphasized.
The Effect of ethanol extract of Jatropha tanjoresis on haematological and histopathological properties of phenyl hydrazine induced anaemic rats
Article
Full-text available
Dec 2022
Adedoyin Dayo
Bikomo Ewenodere Ojigho
Sikiru Abiola Ojokuku
lawal ridwan abiodun
Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Update 2022
Article
Nov 2022
ENDOSCOPY
Marco Pennazio
Emanuele Rondonotti
Edward J. Despott
Xavier Dray
Konstantinos Triantafyllou
Main Recommendations
MR1 ESGE recommends small-bowel capsule endoscopy as the first-line examination, before consideration of other endoscopic and radiological diagnostic tests for suspected small-bowel bleeding, given the excellent safety profile of capsule endoscopy, its patient tolerability, and its potential to visualize the entire small-bowel mucosa.Strong recommendation, moderate quality evidence.
MR2 ESGE recommends small-bowel capsule endoscopy in patients with overt suspected small-bowel bleeding as soon as possible after the bleeding episode, ideally within 48 hours, to maximize the diagnostic and subsequent therapeutic yield.Strong recommendation, high quality evidence.
MR3 ESGE does not recommend routine second-look endoscopy prior to small-bowel capsule endoscopy in patients with suspected small-bowel bleeding or iron-deficiency anemia.Strong recommendation, low quality evidence.
MR4 ESGE recommends conservative management in those patients with suspected small-bowel bleeding and high quality negative small-bowel capsule endoscopy.Strong recommendation, moderate quality evidence.
MR5 ESGE recommends device-assisted enteroscopy to confirm and possibly treat lesions identified by small-bowel capsule endoscopy.Strong recommendation, high quality evidence.
MR6 ESGE recommends the performance of small-bowel capsule endoscopy as a first-line examination in patients with iron-deficiency anemia when small bowel evaluation is indicated.Strong recommendation, high quality evidence.
MR7 ESGE recommends small-bowel capsule endoscopy in patients with suspected Crohn’s disease and negative ileocolonoscopy findings as the initial diagnostic modality for investigating the small bowel, in the absence of obstructive symptoms or known bowel stenosis.Strong recommendation, high quality evidence.
MR8 ESGE recommends, in patients with unremarkable or nondiagnostic findings from dedicated small-bowel cross-sectional imaging, small-bowel capsule endoscopy as a subsequent investigation if deemed likely to influence patient management.Strong recommendation, low quality evidence.
MR9 ESGE recommends, in patients with established Crohn’s disease, the use of a patency capsule before small-bowel capsule endoscopy to decrease the capsule retention rate.Strong recommendation, moderate quality evidence.
MR10 ESGE recommends device-assisted enteroscopy (DAE) as an alternative to surgery for foreign bodies retained in the small bowel requiring retrieval in patients without acute intestinal obstruction.Strong recommendation, moderate quality evidence.
MR11 ESGE recommends DAE-endoscopic retrograde cholangiopancreatography (DAE-ERCP) as a first-line endoscopic approach to treat pancreaticobiliary diseases in patients with surgically altered anatomy (except for Billroth II patients).Strong recommendation, moderate quality evidence.
2.3+ billion citations
| https://www.researchgate.net/figure/Cont_tbl2_331389326 |
The Case for Anonymity | Proceedings - March 2000 Vol. 126/3/1,165
This is the proper time and
The Case for Anonymity
Proceedings
This is the proper time and the appropriate forum in which to publish concerns about the mandatory anthrax vaccination policy, and it is a terrible shame that they must be expressed under a cloak of anonymity. But the facts speak for themselves: as widely reported, military personnel refusing the anthrax immunization have been branded as malcontents, hypochondriacs, and renegades (despite, in many cases, exemplary records to the contrary)—and as a result, have been sentenced to jail, received bad-conduct discharges, issued punitive administrative letters, or administratively separated.
The Department of Defense's retribution against vocal critics and those refusing the vaccine has ended many promising careers and stifled even the most-adamant voices. Consequently, the concerns of military personnel about the mandatory anthrax vaccine program have never been fully aired. Some members are voting with their feet by leaving the services, rather than have substances of questionable value that could jeopardize their short- and long-term health injected into their bodies-where they and their families will bear the full risk. Among those who stay, the undercurrent of worry and fear about the vaccine intensifies, as authorities continue to compound the error rather than fix the problems. I have been a serving officer for more than 17 years. I am a graduate of a war college, hold a post-graduate degree, and have received numerous personal awards, including a national award by a professional military organization. The government will soon force me to choose between my health and my career. At present, there is not one document that definitively establishes the vaccine's efficacy against inhaled anthrax spores. Further, there is no greater testimony to the risk of the vaccine and the flawed nature of this policy than the health sacrifice of military men and women (such as those at Dover AFB) who now suffer from its results. Given what I know about the vaccine, I cannot currently endorse it to my troops. As a result, the morale of my family and myself has sunk to an all-time low. If I could retire today, I would.
As a military leader, I have always been taught to "take care of my people." I am deeply saddened and distressed by the DoD's lack of concern for its most important asset—its people. For some time, I have been tempted to remain silent (as DoD wishes), and hope that policy makers would do the right thing. Unfortunately, the hard reality is that decision makers have cloaked the mandatory vaccination policy under the guise of a "moral obligation" to protect forces from attack, despite unverified efficacy against the airborne anthrax threat. Further, despite apparent negative health impacts of the vaccine, policy makers have shown little inclination to act for the welfare and in the best interests of service members without severe pressure. It would be an unconscionable disservice to my troops and to all my fellow service members and their families to turn aside and allow this policy, which has the potential to gravely impact so many, to continue without challenge. I pray that my comments, despite their anonymity, will serve as a catalyst to promote a policy that respects the health and well-being of all men and women in our armed forces.
| https://www.usni.org/magazines/proceedings/2000/march/case-anonymity |
Workflow | Download Scientific Diagram
Download scientific diagram | Workflow from publication: Estimating OpenStreetMap Missing Built-up Areas using Pre-trained Deep Neural Networks | Although built-up areas cover only a small proportion of the earth's surface, these areas are closely tied to most of the world's population and the economic output, which makes the mapping of built-up areas a vital challenge. Thanks to the generous contribution of... | Neural Networks, Estimation and Accuracy | ResearchGate, the professional network for scientists.
Figure 3
Workflow
Source publication
Estimating OpenStreetMap Missing Built-up Areas using Pre-trained Deep Neural Networks
Conference Paper
Full-text available
Hao Li
Benjamin Herfort
Alexander Zipf
Although built-up areas cover only a small proportion of the earth's surface, these areas are closely tied to most of the world's population and the economic output, which makes the mapping of built-up areas a vital challenge. Thanks to the generous contribution of volunteers, OpenStreetMap shows great capability in addressing this challenge, while...
Context in source publication
Context 1
... this study, we propose a built-up areas mapping method based on pre-trained object detection DNNs (
Figure 3
). Our method intends to learn a robust building detection model from available OSM building features, which should be able to yield reliable prediction results even on independent test areas. ...
Citations
... Chen et al. (2018) first proposed a machine-assisted mapping method based on active learning from multiple crowds, which was then validated in humanitarian mapping projects in Malawi. More recently,
Li et al. (2019)
designed a pre-trained DNN, which was fine-tuned on existing OSM building features, to detect human settlements (from satellite image tiles) and estimate OSM missing built-up areas in Tanzania. A follow-up study confirmed the capability of ML-based building detection models for this application domain, which facilitated three different scenarios of humanitarian mapping in Mozambique after the landfalls of Cyclone Idai and Kenneth in 2019. ...
... Previous works confirmed the HRSL as a competitive map product of human settlements in sub-Saharan Africa. The HRSL was suggested as one of the most accurate settlement layer when considering a 150m spatial resolution in
Li et al. (2019)
. For comparison with the prediction of our model the HRSL were downsampled from the original 30m resolution to a 10m grid. ...
... Moreover, our findings suggested a preference of FSTL with only one shot to achieve the fastest performance boosting, which significantly relax the labeling efforts needed in humanitarian mapping activities. Regarding the RQ2, besides the competitive detection accuracy and performance boosting of the FSTL method, we produced the OSM missing building maps (DeepVGI) with over 96% ACC, which not only outperformed the state-of-the-art open building layers (e.g., HRSL, GOB) but also improved the spatial resolution from 150m
, Li et al. 2019
) to 10m. More importantly, we discussed the limitations of this work and shared suggestions of future work directions in Section 6, aiming at supporting better and faster humanitarian mapping from both a machine-assisted mapping perspective and an OSM data quality assessment perspectives. ...
Improving OpenStreetMap missing building detection using few-shot transfer learning in sub-Saharan Africa
Article
Full-text available
Mar 2022
Hao Li
Benjamin Herfort
Sven Lautenbach
Jiaoyan Chen
Alexander Zipf
OpenStreetMap (OSM) has been intensively used to support humanitarian aid activities , especially in the Global South. Its data availability in the Global South has been greatly improved via recent humanitarian mapping campaigns. However, large rural areas are still incompletely mapped. The timely provision of map data is often essential for the work of humanitarian actors in the case of disaster preparation or disaster response. Therefore, it has become a vital challenge to boost the speed and efficiency of existing humanitarian mapping workflows. We address this challenge by proposing a novel few-shot transfer learning (FSTL) method to improve the accuracy of OSM missing building detection. We trained two popular object detection models (i.e., Faster R-CNN and SSD) in a training area in Tanza-nia and transferred the model to target areas in Cameroon and Mozambique. The FSTL method significantly improved the base model performance even with only one training shot. Moreover, we successfully produced a grid-based OSM missing building map (DeepVGI) of 10m spatial resolution with over 96% Overall Accuracy (ACC) and 0.85 Matthhews Correlation Coefficient (MCC) in both Cameroon and Mozambique. Such maps show great potential to assess and estimate the overall completeness of OSM buildings to support humanitarian mapping activities, especially in places where other (e.g., buildings, roads) datasets are not available.
... Nevertheless, the lack of abundant training samples as well as accurate semantic information has been long identified as a modelling bottleneck of such data-hungry machine learning applications. Correspondingly, OpenStreetMap (OSM) shows great potential in tackling this bottleneck challenge by providing massive and freely accessible geospatial training samples
[4,
5]. More importantly, OSM has exclusive access to its full historical data [6], which could be further analyzed and employed to provide intrinsic data quality measurements of the training samples. ...
From Historical OpenStreetMap data to customized training samples for geospatial machine learning
Conference Paper
Full-text available
Jul 2020
Zhaoyan Wu
Hao Li
Alexander Zipf
... In Jean et al. (2016) [25] a convolutional neural network is used to distinguish urban areas, non-urban area, roads, and water in optical satellite imagery for predicting poverty in Nigeria, Tanzania, Uganda, Malawi, and Rwanda. In
Li et al. (2019)
[26], a pre-trained neural network is employed to estimate large scale OSM missing built-up areas in Tanzania. Regarding land cover mapping, several authors propose workflows based on deep neural networks with a focus on urban areas [27,28]. ...
... In Jean et al. (2016) [25] a convolutional neural network is used to distinguish urban areas, non-urban area, roads, and water in optical satellite imagery for predicting poverty in Nigeria, Tanzania, Uganda, Malawi, and Rwanda. In Li et al. (2019)
[26]
, a pre-trained neural network is employed to estimate large scale OSM missing built-up areas in Tanzania. Regarding land cover mapping, several authors propose workflows based on deep neural networks with a focus on urban areas [27,28]. ...
Mapping Human Settlements with Higher Accuracy and Less Volunteer Efforts by Combining Crowdsourcing and Deep Learning
Article
Full-text available
Jul 2019
Benjamin Herfort
Hao Li
Sascha Fendrich
Sven Lautenbach
Alexander Zipf
Reliable techniques to generate accurate data sets of human built-up areas at national, regional, and global scales are a key factor to monitor the implementation progress of the Sustainable Development Goals as defined by the United Nations. However, the scarce availability of accurate and up-to-date human settlement data remains a major challenge, e.g., for humanitarian organizations. In this paper, we investigated the complementary value of crowdsourcing and deep learning to fill the data gaps of existing earth observation-based (EO) products. To this end, we propose a novel workflow to combine deep learning (DeepVGI) and crowdsourcing (MapSwipe). Our strategy for allocating classification tasks to deep learning or crowdsourcing is based on confidence of the derived binary classification. We conducted case studies in three different sites located in Guatemala, Laos, and Malawi to evaluate the proposed workflow. Our study reveals that crowdsourcing and deep learning outperform existing EO-based approaches and products such as the Global Urban Footprint. Compared to a crowdsourcing-only approach, the combination increased the quality (measured by Matthew’s correlation coefficient) of the generated human settlement maps by 3 to 5 percentage points. At the same time, it reduced the volunteer efforts needed by at least 80 percentage points for all study sites. The study suggests that for the efficient creation of human settlement maps, we should rely on human skills when needed and rely on automated approaches when possible.
A CONCEPTUAL MODEL FOR CONVERTING OPENSTREETMAP CONTRIBUTION TO GEOSPATIAL MACHINE LEARNING TRAINING DATA
Article
Full-text available
Jun 2022
H. Li
A. Zipf
In the recent decade, Volunteered Geographical Information (VGI), in particular the OpenStreetMap (OSM), has helped to fill substantial data gaps in base maps, especially in Global South, thus has become a promising source of massive, free training data together with rich and detailed semantic information for geospatial artificial intelligence (GeoAI) applications. Although intensive works have explored the potential of generating training data from OSM, a systematic approach of harvesting OSM contribution as quality-aware training data for different GeoAI tasks is still missing. To fill this research gap, we proposed a conceptual model consisting of three major components: historical OSM and external datasets, quality indicators, and GeoAI models. As a proof of concept, we validated our conceptual model with an example task of detecting OSM missing buildings in Mozambique, where the impact of different error sources (e.g., completeness, alignment, rotation) in training data were compared and investigated in a quantitative manner. The lessons learned in this paper shed important lights on cooperating OSM data quality aspects with the development of more explainable GeoAI models.
A CONCEPTUAL MODEL FOR CONVERTING OPENSTREETMAP CONTRIBUTION TO GEOSPATIAL MACHINE LEARNING TRAINING DATA
Conference Paper
In the recent decade, Volunteered Geographical Information (VGI), in particular the OpenStreetMap (OSM), has helped to fill substantial data gaps in base maps, especially in Global South, thus has become a promising source of massive, free training data together with rich and detailed semantic information for geospatial artificial intelligence (GeoAI) applications. Although intensive works have explored the potential of generating training data from OSM, a systematic approach of harvesting OSM contribution as quality-aware training data for different GeoAI tasks is still missing. To fill this research gap, we proposed a conceptual model consisting of three major components: historical OSM and external datasets, quality indicators, and GeoAI models. As a proof of concept, we validated our conceptual model with an example task of detecting OSM missing buildings in Mozambique, where the impact of different error sources (e.g., completeness, alignment, rotation) in training data were compared and investigated in a quantitative manner. The lessons learned in this paper shed important lights on cooperating OSM data quality aspects with the development of more explainable GeoAI models.
Detecting OpenStreetMap missing buildings by transferring pre-trained deep neural networks
Accurate and complete geographic data of human settlements is crucial for effective emergency response, humanitarian aid and sustainable development. Open- StreetMap (OSM) can serve as a valuable source of this data. As there are still many areas missing in OSM, deep neural networks have been trained to detect such areas from satellite imagery. However, in regions where little or no training data is available, training networks is problematic. In this study, we proposed a method of transferring a building detection model, which was previously trained in an area wellmapped in OSM, to remote data-scarce areas. The transferring was achieved via fine-tuning the model on limited training samples from the original training area and the target area. We validated the method by transferring deep neural networks trained in Tanzania to a site in Cameroon with straight distance of over 2600 km, and tested multiple variants of the proposed method. Finally, we applied the fine-tuned model to detect 1192 buildings missing OSM in a selected area in Cameroon. The results showed that the proposed method led to a significant improvement in f1-score with as little as 30 training examples from the target area. This is a crucial quality of the proposed method as it allows to fine-tune models to regions where OSM data is scarce.
Detecting OpenStreetMap missing buildings by transferring pre-trained deep neural networks
Conference Paper
Sven Lautenbach
Benjamin Herfort
Alexander Zipf
Accurate and complete geographic data of human settlements is crucial for effective emergency response, humanitarian aid and sustainable development. Open-StreetMap (OSM) can serve as a valuable source of this data. As there are still many areas missing in OSM, deep neural networks have been trained to detect such areas from satellite imagery. However, in regions where little or no training data is available, training networks is problematic. In this study, we proposed a method of transferring a building detection model, which was previously trained in an area well-mapped in OSM, to remote data-scarce areas. The transferring was achieved via fine-tuning the model on limited training samples from the original training area and the target area. We validated the method by transferring deep neural networks trained in Tanzania to a site in Cameroon with straight distance of over 2600 km, and tested multiple variants of the proposed method. Finally, we applied the fine-tuned model to detect 1192 buildings missing OSM in a selected area in Cameroon. The results showed that the proposed method led to a significant improvement in f1-score with as little as 30 training examples from the target area. This is a crucial quality of the proposed method as it allows to fine-tune models to regions where OSM data is scarce.
Centaur VGI: A Hybrid Human–Machine Approach to Address Global Inequalities in Map Coverage
Jonathan J. Huck
Chris Perkins
Billy T. Haworth
Emmanuel B. Moro
Despite advances in mapping technologies and spatial data capabilities, global mapping inequalities are not declining. Inequalities in the coverage, quality, and currency of mapping persist, with significant gaps in remote and rural parts of the Global South. These regions, representing some of the most economically and resource-disadvantaged societies in the world, need high-quality mapping to aid in the delivery of essential services, such as health care, in response to severe challenges such as poverty, conflict, and global climate change. Volunteered geographic information (VGI) has shown potential as a solution to mapping inequalities. Contributions have largely been made in urban areas or in response to acute emergencies (e.g., earthquakes or floods), however, leaving rural regions that suffer from chronic humanitarian crises undermapped. An alternative solution is needed that harnesses the power of volunteer mapping more effectively to address regions in most need. Machine learning holds promise. In this article we propose centaur VGI, a hybrid system that combines the spatial cognitive abilities of human volunteers with the speed and efficiency of a machine. We argue that centaur VGI can contribute to mitigating some of the political and technological factors that produce inequalities in VGI mapping coverage and do so in the context of a case study in Acholi, northern Uganda, an inadequately mapped region in which the authors have been working since 2017 to provide outreach health care services to victims of major limb loss during conflict.
Proceedings of the Academic Track at State of the Map 2020
Serena Coetzee
Exploration of OpenStreetMap Missing Built-up Areas using Twitter Hierarchical Clustering and Deep Learning in Mozambique
Accurate and detailed geographical information digitizing human activity patterns plays an essential role in response to natural disasters. Volunteered geographical information, in particular OpenStreetMap (OSM), shows great potential in providing the knowledge of human settlements to support humanitarian aid, while the availability and quality of OSM remains a major concern. The majority of existing works in assessing OSM data quality focus on either extrinsic or intrinsic analysis, which is insufficient to fulfill the humanitarian mapping scenario to a certain degree. This paper aims to explore OSM missing built-up areas from an integrative perspective of social sensing and remote sensing. First, applying hierarchical DBSCAN clustering algorithm, the clusters of geo-tagged tweets are generated as proxies of human active regions. Then a deep learning based model fine-tuned on existing OSM data is proposed to further map the missing built-up areas. Hit by Cyclone Idai and Kenneth in 2019, the Republic of Mozambique is selected as the study area to evaluate the proposed method at a national scale. As a result, 13 OSM missing built-up areas are identified and mapped with an over 90% overall accuracy, being competitive compared to state-of-the-art products, which confirms the effectiveness of the proposed method.
| https://www.researchgate.net/figure/Workflow_fig3_332980026 |
Overall risk of birth defects appears low for women taking antiretrovirals during early pregnancy | EurekAlert! Science News
Among pregnant women infected with HIV, the use of antiretroviral medications early in pregnancy to treat their HIV or to prevent mother-to-child transmission of HIV does not appear to increase the risk of birth defects in their infants, according to a new study led by Harvard School of Public Health.
Overall risk of birth defects appears low for women taking antiretrovirals during early pregnancy
Boston, MA - Among pregnant women infected with HIV, the use of antiretroviral (ARV) medications early in pregnancy to treat their HIV or to prevent mother-to-child transmission of HIV does not appear to increase the risk of birth defects in their infants, according to a new study led by Harvard School of Public Health (HSPH). It is one of the largest studies to date to look at the safety of ARV use during pregnancy.
While the study found that overall risk was low--in keeping with previous research that has found ARV use in pregnancy to be generally safe--the researchers did find that one ARV drug, atazanavir, was associated with increased risk of birth defects and they said it should be studied further.
"This study suggests that the benefits of using ARVs during pregnancy still far outweigh the risks for HIV-infected women, although they also indicate a need for continued monitoring," said Paige Williams, senior lecturer on biostatistics at HSPH and the study's lead author.
The study will appear online November 10, 2014 in JAMA Pediatrics.
While the use of combination ARV regimens among HIV-infected pregnant women has helped substantially reduce the number of HIV-infected infants, there remain concerns about the safety of in utero exposures to these medications--particularly as newer drugs are approved and as an increasing percentage of women become pregnant while already taking ARVs.
The researchers looked at first-trimester exposures to ARVs in a group of 2,580 HIV-exposed, uninfected children enrolled between 2007 and 2012 in an ongoing U.S. study that follows HIV-infected pregnant women and their children--the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study.
Few individual ARVs and no classes of drugs were associated with increased risk of birth defects, the researchers found. However, when atazanavir was used by mothers during pregnancy, risk of birth defects appeared to increase by about two-fold, particularly musculoskeletal and skin anomalies. Since most women receive a combination of three or more ARV drugs during pregnancy, the researchers also looked at what other drugs were commonly used together with atazanavir. When atazanavir was used with newer drugs, such as tenofovir or emtricitabine, the risk of birth defects remained higher, but there was no significant elevation in risk when atazanavir was used with older ARV drugs like zidovudine or lamivudine.
"As World Health Organization 2013 ARV guidelines are implemented globally, an increasing percentage of women with HIV will be expected to enter pregnancy already receiving ARVs. This heightens the need to identify optimal regimens based on their safety profiles as well as their effectiveness in preventing HIV transmission," said Williams.
###
Senior author of the paper was D. Heather Watts of the Office of the U.S. Global AIDS Coordinator, U.S. Department of State; Cenk Yildirim, statistical programmer for the Center for Biostatistics in AIDS Research (CBAR) at HSPH, also participated in the study.
Funding for the study came from the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with Harvard School of Public Health (HD052102, 3 U01 314 HD052102-05S1, 3 U01 HD052102-06S3) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1).
"Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus-Exposed Uninfected Infants, Paige L. Williams, Marilyn J. Crain, Cenk Yildirim, Rohan Hazra, Russell B. Van Dyke, Kenneth Rich, Jennifer S. Read, Emma Stuard, Mobeen Rathore, Hermann A. Mendez, and D. Heather Watts, for the Pediatric HIV/AIDS Cohort Study, JAMA Pediatrics, online Nov. 10, 2014, doi: 10.1001/jamapediatrics.2014.1889
Harvard School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives--not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at HSPH teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America's oldest professional training program in public health.
Keywords
| https://archive.eurekalert.org/pub_releases/2014-11/hsop-oro110714.php |
Comparing recruitment strategies in a study of acupuncture for chronic back pain-ICH GCP
Sherman KJ, Hawkes RJ, Ichikawa L, Cherkin DC, Deyo RA, Avins AL, Khalsa PS. Comparing recruitment strategies in a study of acupuncture for chronic back pain. BMC Med Res Methodol. 2009 Oct 27;9:69. doi: 10.1186/1471-2288-9-69.。 ICH GCP。
Comparing recruitment strategies in a study of acupuncture for chronic back pain
Karen J Sherman, Rene J Hawkes, Laura Ichikawa, Daniel C Cherkin, Richard A Deyo, Andrew L Avins, Partap S Khalsa, Karen J Sherman, Rene J Hawkes, Laura Ichikawa, Daniel C Cherkin, Richard A Deyo, Andrew L Avins, Partap S Khalsa
Abstract
Background:Meeting recruitment goals is challenging for many clinical trials conducted in primary care populations. Little is known about how the use of different recruitment strategies affects the types of individuals choosing to participate or the conclusions of the study.
Methods:A secondary analysis was performed using data from participants recruited to a clinical trial evaluating acupuncture for chronic back pain among primary care patients in a large integrated health care organization. We used two recruitment methods: mailed letters of invitation and an advertisement in the health plan's magazine. For these two recruitment methods, we compared recruitment success (% randomized, treatment completers, drop outs and losses to follow-up), participant characteristics, and primary clinical outcomes. A linear regression model was used to test for interaction between treatment group and recruitment method.
Results:Participants recruited via mailed letters closely resembled those responding to the advertisement in terms of demographic characteristics, most aspects of their back pain history and current episode and beliefs and expectations about acupuncture. No interaction between method of recruitment and treatment group was seen, suggesting that study outcomes were not affected by recruitment strategy.
Conclusion:In this trial, the two recruitment strategies yielded similar estimates of treatment effectiveness. However, because this finding may not apply to other recruitment strategies or trial circumstances, trials employing multiple recruitment strategies should evaluate the effect of recruitment strategy on outcome.
Trial registration:Clinical Trials.govNCT00065585.
References
Foy R, Parry J, Duggan A, Delaney B, Wilson S, Lewin-Van Den Broek NT, Lassen A, Vickers L, Myres P. How evidence based are recruitment strategies to randomized controlled trials in primary care? Experience from seven studies. Fam Pract. 2003;20(1):83–92. doi: 10.1093/fampra/20.1.83.
Watson JM, Torgerson DJ. Increasing recruitment to randomised trials: a review of randomised controlled trials. BMC Med Res Methodol. 2006;6:34. doi: 10.1186/1471-2288-6-34.
Geraets JJ, de Groot IJ, Goossens ME, de Bruijn CP, de Bie RA, Heuvel WJ van den, Dinant GJ. Comparison of two recruitment strategies for patients with chronic shoulder complaints. Br J Gen Pract. 2006;56(523):127–133.
Cherkin DC, Sherman KJ, Avins AL, Erro JH, Ichikawa L, Barlow WE, Delaney K, Hawkes R, Hamilton L, Pressman A. A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain. Arch Intern Med. 2009;169(9):858–866. doi: 10.1001/archinternmed.2009.65.
Cherkin DC, Sherman KJ, Hogeboom CJ, Erro JH, Barlow WE, Deyo RA, Avins AL. Efficacy of acupuncture for chronic low back pain: protocol for a randomized controlled trial. Trials. 2008;9:10. doi: 10.1186/1745-6215-9-10.
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Carey TS, Garrett J, Jackman A, McLaughlin C, Fryer J, Smucker DR. The outcomes and costs of care for acute low back pain among patients seen by primary care practitioners, chiropractors, and orthopedic surgeons. The North Carolina Back Pain Project. N Engl J Med. 1995;333(14):913–917. doi: 10.1056/NEJM199510053331406.
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Source:PubMed
| https://ichgcp.net/zh/clinical-trials-registry/publications/79283-comparing-recruitment-strategies-in-a-study-of-acupuncture-for-chronic-back-pain |
Designer foods as an effective approach to enhance disease preventative properties of food through its health functionalities | Request PDF
Request PDF | Designer foods as an effective approach to enhance disease preventative properties of food through its health functionalities | Designer foods provide health functions in addition to the typical essential nutrients, such as vitamins and minerals. These health functions are... | Find, read and cite all the research you need on ResearchGate
January 2022
DOI: 10.1016/B978-0-323-91001-9.00031-1
In book: Future Foods (pp.469-497)
Authors:
Lee-Hoon Ho
Lee-Hoon Ho
This person is not on ResearchGate, or hasn't claimed this research yet.
Thuan-Chew Tan
Universiti Sains Malaysia
Li-Choo Chong
Taylor's University
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Abstract
Designer foods provide health functions in addition to the typical essential nutrients, such as vitamins and minerals. These health functions are naturally present in food or added through fortification. Designer foods are often consumed as part of the human diet to promote health due to their disease preventative ability. This chapter highlighted the recent progress in designer foods processed from four major sources: plants, animals, insects, and bacteria. It also discussed the effect of fortification on the disease preventative ability of food with the aid of advanced technologies. Available benefits, such as nutraceutical, medicinal, and pharmacological values of designer foods to human health were also examined. Information in this chapter could be of great interest and use to both research and medical-nutrition communities, as well as food industries for the development of designer foods that are expected to benefit consumers.
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New insights into functional cereal foods as an alternative for dairy products: A review Article
Jun 2023
Kouadio Jean Eric-Parfait Kouamé Awa Fanny Massounga Bora Xiaodong li
Muhammad Hussain
View
Biofortification of Three Cultivated Mushroom Species with Three Iron Salts—Potential for a New Iron-Rich Superfood Article Full-text available
Apr 2022 MOLECULES
Sylwia Budzyńska Marek Siwulski
Monika Gąsecka Mirosław Mleczek
Mushrooms fortified with iron (Fe) can offer a promising alternative to counter the worldwide deficiency problem. However, the factors that may influence the efficiency of fortification have not yet been fully investigated. The aim of this study was to compare the effects of three Fe forms (FeCl3 6H2O, FeSO4 7H2O, or FeHBED) in three concentrations (5, 10, or 50 mM) for three mushroom species (Pleurotus eryngii, P. ostreatus, or Pholiota nameko) on their chemical composition, phenolic compounds, and organic acid production. The most effective metal accumulation of all the investigated species was for the 50 mM addition. FeCl3 6H2O was the most favorable additive for P. eryngii and P. nameko (up to 145 and 185% Fe more than in the control, respectively) and FeHBED for P. ostreatus (up to 108% Fe more than in control). Additionally, P. nameko showed the highest Fe accumulation among studied species (89.2 ± 7.51 mg kg−1 DW). The creation of phenolic acids was generally inhibited by Fe salt supplementation. However, an increasing effect on phenolic acid concentration was observed for P. ostreatus cultivated at 5 mM FeCl3 6H2O and for P. eryngii cultivated at 5 mM FeCl3 6H2O and 5 mM FeSO4 7H2O. In the case of organic acids, a similar situation was observed. For P. ostreatus, FeSO4 7H2O and FeHBED salts increased the formation of the determined organic acids in fruiting bodies. P. eryngii and P. nameko were characterized by a much lower content of organic acids in the systems supplemented with Fe. Based on the obtained results, we recommend starting fortification by preliminarily indicating which form of the element is preferred for the species of interest for supplementation. It also seems that using an additive concentration of 50 mM or higher is most effective.
View Show abstract
Urban poverty and nutrition challenges associated with accessibility to a healthy diet: a global systematic literature review Article Full-text available Jan 2021 Mireya Vilar-Compte Soraya Burrola-Méndez Annel Lozano Rafael Pérez-Escamilla Background
There is an increasing global trend towards urbanization. In general, there are less food access issues in urban than rural areas, but this “urban advantage” does not benefit the poorest who face disproportionate barriers to accessing healthy food and have an increased risk of malnutrition.
Objectives
This systematic literature review aimed to assess urban poverty as a determinant of access to a healthy diet, and to examine the contribution of urban poverty to the nutritional status of individuals.
Methods
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) methodology, our review included quantitative and qualitative studies published in English or in Spanish between 2000 and 2019. The articles were eligible if they focused on nutrition access (i.e. access to a healthy diet) or nutrition outcomes (i.e., anemia, overweight and obesity, micronutrient deficiency, micronutrient malnutrition) among urban poor populations. Articles were excluded if they did not meet pre-established criteria. The quality of the quantitative studies was assessed by applying Khan et al.’s methodology. Similarly, we assessed the quality of qualitative articles through an adapted version of the National Institute for Health and Care Excellence (NICE) methodology checklist. Finally, we systematically analyzed all papers that met the inclusion criteria based on a qualitative content and thematic analysis.
Results
Of the 68 papers included in the systematic review, 55 used quantitative and 13 used qualitative methods. Through the analysis of the literature we found four key themes: (i) elements that affect access to healthy eating in individuals in urban poverty, (ii) food insecurity and urban poverty, (iii) risk factors for the nutritional status of urban poor and (iv) coping strategies to limited access to food. Based on the systematization of the literature on these themes, we then proposed a conceptual framework of urban poverty and nutrition.
Conclusions
This systematic review identified distinct barriers posed by urban poverty in accessing healthy diets and its association with poorer nutrition outcomes, hence, questioning the “urban advantage”. A conceptual framework emerging from the existing literature is proposed to guide future studies and policies.
Systematic review registration
PROSPERO Registration number: CRD42018089788 . View Show abstract Functional food products in Japan: A review Article Full-text available Jun 2019 Shun Iwatani Naoyuki Yamamoto Japan has a long history of using foods with health benefits and Japanese people are well-known for their longevity. In 1991, the Ministry of Health, Labor and Welfare introduced a functional food regulation called “foods for specified health uses” (FOSHU) in Japan. After the introduction of the functional food system, many clinically proven FOSHU products with health benefits have been developed and launched in the market. As a result, the net sales of FOSHU products reached 6.2 billion dollars in 2007. Most of the health claims relate to improving gastro-intestinal health using probiotics. Triglycerides, high blood pressure, high LDL-cholesterol, and high blood glucose are mainly associated with the related health claims. After 2007, the market for FOSHU products was almost saturated. However, a novel functional regulatory system\called “Foods with Function Claims” was established in 2015 based on the Dietary Supplement Health and Education Act system established in the USA. Major health claims in the new regulation system are associated with fatigue, eyes, memory, stress, sleep, joints, blood flow, body temperature, muscles, and Body Mass Index. After the introduction of the new system, the total sales for functional foods including FOSHU products reached 8 billion dollars in 2018. The new functional regulatory system is more flexible in terms of health claims, the protocol for clinical studies, and the required results. Therefore, the market for new regulatory products is still growing. In the present paper, the potential of both regulatory systems and some related issues will be discussed. View Show abstract Effect of Heat Treatment and Light Exposure on the Antioxidant Activity of Flavonoids Article Full-text available Sep 2020 Irina Ioannou Leila Chekir-Ghedira Moh Ghoul The application of food processes can lead to a modification of both the structure and the activities of flavonoids. In this article, the effect of heat treatment and exposure to light on the antioxidant activity of 6 model flavonoid solutions (rutin, naringin, eriodictyol, mesquitol, luteolin, and luteolin 7-O-glucoside) was studied. The evolution of the antioxidant activity measured after heat treatment of 130 °C at 2 h and an exposure to visible light for 2 weeks is measured by the ABTS (2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt) method and represented by a new parameter called ΔTEAC. The model solution of Mesquitol showed the highest increase in ΔTEAC after a heat treatment, a value of 200 mM was obtained. The increase in ΔTEAC is always greater with thermal treatment than with light exposure. Thus, temperature and light lead to different degradation pathways of the flavonoid. In vivo measurements were carried out with solutions of naringin, erodictyol, and luteolin 7-O-glucoside. Heated solutions of flavonoids do not exhibit toxicity on cells. The specific activities of superoxide dismutase and glutathione peroxide have been determined and have shown an increased impact on the potential anti-cancer of these solutions by enhancing their cellular antioxidant activity, as well as modulation of the oxidative stress. View Show abstract Production and processing of antioxidant bioactive peptides: A driving force for the functional food market Article Full-text available Aug 2020 Solomon Abebaw Tadesse Shimelis Admassu Emire Recently, the demand for functional foods in the global market has increased rapidly due to the increasing occurrences of non-communicable diseases and technological advancement. Antioxidant peptides have been suggested as ingredients used to produce health-promoting foods. These peptides are encrypted from various food derived protein sources by chemical and enzymatic hydrolysis, and microbial fermentation. However, the industrial-scale production of antioxidant peptides is hampered by different problems such as high production cost, and low yield and bioactivity. Accordingly, novel processing technologies, such as high pressure, microwave and pulsed electric field, have been recently emerged to overcome the problems associated with the conventional hydrolysis methods. This particular review, therefore, discussed the current processing technologies used to produce antioxidant peptides. The review also suggested further perspectives that should be addressed in the future. View Show abstract Bioavailability of Micronutrients From Nutrient-Dense Whole Foods: Zooming in on Dairy, Vegetables, and Fruits Article Full-text available Jul 2020 Alida Melse In order to fully exploit the nutrient density concept, thorough understanding of the biological activity of single nutrients in their interaction with other nutrients and food components from whole foods is important. This review provides a narrative overview of recent insights into nutrient bioavailability from complex foods in humans, highlighting synergistic and antagonistic processes among food components for two different food groups, i.e., dairy, and vegetables and fruits. For dairy, bioavailability of vitamins A, B2, B12 and K, calcium, phosphorous, magnesium, zinc and iodine are discussed, whereas bioavailability of pro-vitamin A, folate, vitamin C and K, potassium, calcium, magnesium and iron are discussed for vegetables and fruits. Although the bioavailability of some nutrients is fairly well-understood, for other nutrients the scientific understanding of uptake, absorption, and bioavailability in humans is still at a nascent stage. Understanding the absorption and bioavailability of nutrients from whole foods in interaction with food components that influence these processes will help to come to individual diet scores that better reflect absorbable nutrient intake in epidemiologic studies that relate dietary intake to health outcomes. Moreover, such knowledge may help in the design of foods, meals, and diets that aid in the supply of bioavailable nutrients to specific target groups. View Show abstract Targeted Nutrition in Chronic Disease Article Full-text available Jun 2020 Peter Bergman Susanna Brighenti Today, chronic disease is a major public health problem around the world that is rapidly increasing with a growing and aging population [...] View Show abstract Antiviral and Immunomodulatory Properties of Antimicrobial Peptides Produced by Human Keratinocytes Article Full-text available Jun 2020 Céline Chessa Charles Bodet Clément Jousselin Magali Garcia Keratinocytes, the main cells of the epidermis, are the first site of replication as well as the first line of defense against many viruses such as arboviruses, enteroviruses, herpes viruses, human papillomaviruses, or vaccinia virus. During viral replication, these cells can sense virus associated molecular patterns leading to the initiation of an innate immune response composed of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Human keratinocytes produce and secrete at least nine antimicrobial peptides: human cathelicidin LL-37, types 1–4 human β-defensins, S100 peptides such as psoriasin (S100A7), calprotectin (S100A8/9) and koebnerisin (S100A15), and RNase 7. These peptides can exert direct antiviral effects on the viral particle or its replication cycle, and indirect antiviral activity, by modulating the host immune response. The purpose of this review is to summarize current knowledge of antiviral and immunomodulatory properties of human keratinocyte antimicrobial peptides. View Show abstract Bioactive Compounds in Fermented Sausages Prepared from Beef and Fallow Deer Meat with Acid Whey Addition Article Full-text available May 2020 MOLECULES Anna Kononiuk M. Karwowska The present study examined the effect of the type of meat (beef and fallow deer) and the addition of freeze-dried acid whey on nutritional values and the content of bioactive compounds (peptides, L-carnitine, glutathione, and conjugated linoleic acid (CLA)) in uncured fermented sausages. The antioxidant properties of isolated peptides (ABTS, DPPH radical scavenging activity, and ferric-reducing antioxidant power) were also evaluated. The results showed that fallow deer sausages had higher peptide content than beef products. The addition of acid whey caused a decrease in the content of peptides, especially in fallow deer sausages. The glutathione content in beef sausages (22.91–25.28 mg 100 g−1 of sausage) was quite higher than that of fallow deer sausages (10.04–11.59 mg 100 g−1 of sausage). The obtained results showed a significantly higher content of CLA in beef sausages than in products from fallow deer meat. In conclusion, products prepared from fallow deer meat have generally higher nutritional value because of the content of peptides, their antioxidant properties, and the content of L-carnitine, while beef products have higher levels of CLA and glutathione. View Show abstract A review on bioactive peptides derived from various sources of meat and meat by-products Article Full-text available Dec 2019 Bayu Rezaharsamto Edy Subroto Bioactive peptides are short polymers from proteins that have a positive impact functionally for human health. This paper provi des a review of bioactive peptides derived from various sources of meat and the generation of bioactive peptides. Bioactive peptides can be produced from a variety of animal species, such as bovine, poultry, and porcine. They can be obtained by hydrolysis from their parent protein sequence to release bioactive peptides. Some of the methods are enzymatic hydrolysis using enzymes from animals, commercial proteinase, or enzymes from plants. In addition, microorganism fermentation with starter lactic acid bacteria may also be used. Some of the functions of bioactive peptides that are beneficial for humans health include antimicrobials, antithrombotic drugs such as the prevention of blood clots and strokes, antioxidants that counteract free radicals, and antihypertensive drugs that can lower blood pressure. View Show abstract Progress in microencapsulation of probiotics: A review Article Full-text available Feb 2020 COMPR REV FOOD SCI F Mingfei Yao Jiaojiao Xie Hengjun Du Lanjuan Li The potential health benefits of probiotics may not be realized because of the substantial reduction in their viability during food storage and gastrointestinal transit. Microencapsulation can be used to enhance the resistance of probiotics to unfavorable conditions. A range of oral delivery systems has been developed to increase the level of probiotics reaching the colon including embedding and coating systems. This review introduces emerging strategies for the microencapsulation of probiotics and highlights the key mechanisms of their stress–tolerance properties. Recent in vitro and in vivo models for evaluation of the efficiency of probiotic delivery systems are also reviewed. Encapsulation technologies are required to maintain the viability of probiotics during storage and within the human gut so as to increase their ability to colonize the colon. These technologies work by protecting the probiotics from harsh environmental conditions, as well as increasing their mucoadhesive properties. Typically, the probiotics are either embedded inside or coated with food‐grade materials such as biopolymers or lipids. In some cases, additional components may be coencapsulated to enhance their viability such as nutrients or protective agents. The importance of having suitable in vitro and in vivo models to evaluate the efficiency of probiotic delivery systems is also emphasized. View Show abstract Potential Health-Promoting Benefits of Paraprobiotics, Inactivated Probiotic Cells Article Full-text available Jan 2020 J Microbiol Biotechnol Shahina Akter Jong Hyun Park Hoo Kil Jung Viability plays an important role in the beneficial microbes (probiotics) to produce health benefits. However, this idea has been changed after the invention of the term, paraprobiotics, indicating that non-viable microbes could produce health benefits that are similar to those produced by live probiotics. Occasionally, it might be dangerous to administer live probiotics to people with weak immunity. In such cases, ingestion of paraprobiotics could be a potential alternative. The definition of paraprobiotics refers to the use of inactivated (non-viable) microbial cells or cell fractions to provide health benefits to the consumer. Paraprobiotics have attracted much attention because of their long shelf life, safety, and beneficial effects, such as modulation of immunity, modification of biological responses, reduction of cholesterol, anti-inflammatory, and antiproliferative properties. These features indicate that paraprobiotics may play a vital role in improving the health of the consumer by enhancing particular physiological functions, even though the exact underlying mechanisms have not yet been completely elucidated. In this mini-review, we briefly discuss the historical backgrounds of paraprobiotics and evidence of their health-promoting effects, prophylactic, and therapeutic properties. View Show abstract Glycemic Index, Starch, and Protein Digestibility in Tempeh Gembus Cookies Article Full-text available Jan 2020 J FOOD QUALITY Valentina A. Manullang Ayu Rahadiyanti Niniek Lely Pratiwi Diana Nur Afifah Diabetes mellitus is directly related to diet and lifestyle. Control of blood glucose levels is needed to reduce the risk of complications, and one way is to choose foods with a low glycemic index. Cookies made from tempeh gembus / tempeh gembus flour are expected to be eaten as a snack and are safe for people with diabetes. The aim of this research was to analyze glycemic index (GI), glycemic load (GL), dietary fiber, in vitro starch, and protein digestibility of cookies with tempeh gembus flour substitution. Completely randomized design research with one primary factor used cookies with variations of 0%, 25%, and 50% tempeh gembus flour substitution. GI was calculated using the Incremental Area Under the Blood Glucose Response Curve (IAUC) method. Dietary fiber concentration analysis was done by enzymatic methods. The starch and protein digestion rates were calculated using the in vitro method. GI, GL, dietary fiber, starch digestion rate, and protein digestion rate data were analyzed with descriptive methods. Cookies with lowest GI (47.01 ± 11.08%) and GL (6.90 ± 1.63) were found in cookies with 50% tempeh gembus flour substitution. The highest dietary fiber content (24.61 ± 0.41%), digestibility of starch (48.07 ± 0.01%), and protein (20.27 ± 0.43%) cookies were found in cookies with 50% tempeh gembus flour substitution. The higher tempeh gembus flour substitution produced low GI and GL while its dietary fiber, in vitro starch, and protein digestibility were highest. View Show abstract A Review of the Role of the Gut Microbiome in Personalized Sports Nutrition Article Full-text available Jan 2020 Riley Hughes The gut microbiome is a key factor in determining inter-individual variability in response to diet. Thus, far, research in this area has focused on metabolic health outcomes such as obesity and type 2 diabetes. However, understanding the role of the gut microbiome in determining response to diet may also lead to improved personalization of sports nutrition for athletic performance. The gut microbiome has been shown to modify the effect of both diet and exercise, making it relevant to the athlete's pursuit of optimal performance. This area of research can benefit from recent developments in the general field of personalized nutrition and has the potential to expand our knowledge of the nexus between the gut microbiome, lifestyle, and individual physiology. View Show abstract Consumer preference for nutrition and health claims: A multi-methodological approach Article Full-text available Dec 2019 FOOD QUAL PREFER Marija Klopčič Polona Slokan Karmen Erjavec To understand consumers’ acceptance and preference in relation to Nutrition and Health Claims (NHCs) on food products and the reasons for their (non)acceptance in an Eastern European country with a weak tradition in NHC, and an enormous increase in the number of foods with NHCs in recent years, this study aimed to fill a research gap by applying a multi-methodological approach combining a survey and conjoint analysis (n = 204) and a focus group (n = 45). The survey demonstrated that Slovenian consumers in general are moderately doubtful of NHCs. Conjoint analysis showed that when Slovenians choose their breakfast cereals, NHCs are more important than whether visual images are present. Visual images convince only the youngest consumers. The study revealed the importance of social perception and trust in the social system for accepting foods with NHCs/images. Consumers who did not trust the political and economic system also did not accept foods with NHCs/images. View Show abstract Is reduction in appetite beneficial for body weight management in the context of overweight and obesity? Yes, according to the SATIN (Satiety Innovation) study Article Full-text available Nov 2019 Thea Toft Hansen Bethan Mead Jesús Francisco García-Gavilán Anders Sjödin New dietary-based concepts are needed for treatment and effective prevention of overweight and obesity. The primary objective was to investigate if reduction in appetite is associated with improved weight loss maintenance. This cohort study was nested within the European Commission project Satiety Innovation (SATIN). Participants achieving ≥8% weight loss during an initial 8-week low-energy formula diet were included in a 12-week randomised double-blind parallel weight loss maintenance intervention. The intervention included food products designed to reduce appetite or matching controls along with instructions to follow national dietary guidelines. Appetite was assessed by ad libitum energy intake and self-reported appetite evaluations using visual analogue scales during standardised appetite probe days. These were evaluated at the first day of the maintenance period compared with baseline (acute effects after a single exposure of intervention products) and post-maintenance compared with baseline (sustained effects after repeated exposures of intervention products) regardless of randomisation. A total of 181 participants (forty-seven men and 134 women) completed the study. Sustained reduction in 24-h energy intake was associated with improved weight loss maintenance ( R 0·37; P = 0·001), whereas the association was not found acutely ( P = 0·91). Suppression in self-reported appetite was associated with improved weight loss maintenance both acutely ( R −0·32; P = 0·033) and sustained ( R −0·33; P = 0·042). Reduction in appetite seems to be associated with improved body weight management, making appetite-reducing food products an interesting strategy for dietary-based concepts. View Show abstract Comparative Characterization of Protein Hydrolysates from Three Edible Insects: Mealworm Larvae, Adult Crickets, and Silkworm Pupae Article Full-text available Nov 2019 Sungwon Yoon Nathan A. K. Wong Minki Chae Joong-Hyuck Auh A comparative characterization of proteins from three edible insects—Tenebrio molitor (mealworm) larvae, Gryllus bimaculatus (cricket), and Bombyx mori (silkworm) pupae—was performed in this study. Proteins were extracted from edible insects and their hydrolysates were prepared through enzymatic hydrolysis with commercial enzymes (Flavourzyme: 12%; Alcalase: 3%). Solubility was significantly higher following enzymatic hydrolysis, while foamability was lower compared to those of the protein control. Angiotensin-converting enzyme was significantly inhibited after enzymatic hydrolysis, especially following Alcalase treatment, with IC50 values of 0.047, 0.066, and 0.065 mg/mL for G. bimaculatus, T. molitor larvae, and B. mori pupae, respectively. Moreover, the Alcalase-treated group of B. mori pupae and the T. molitor larvae group treated with a mixture of enzymes showed the effective inhibition of α-glucosidase activity. The anti-inflammatory activity of the insect hydrolysates was assessed via nitric oxide production from macrophages, and B. mori pupae samples exhibited significant activity regardless of the method of hydrolysis. These results indicate the functional properties of protein and hydrolysates from three species of edible insects, which may be useful in their future exploitation. View Show abstract Arabinogalactan-Proteins from the Liverwort Marchantia polymorpha L., a Member of a Basal Land Plant Lineage, Are Structurally Different to Those of Angiosperms Article Full-text available Oct 2019 Happ Birgit Classen The thalloid liverwort Marchantia polymorpha as a member of a basal land plant lineage has to cope with the challenge of terrestrial life. Obviously, the plant cell wall has been strongly involved in the outstanding evolutionary process of water-to-land-transition. AGPs are signaling glycoproteins of the cell wall, which seem to be ubiquitous in seed plants and might play a role in adaption to abiotic and biotic stress situations. Therefore, we investigated the cell wall composition of Marchantia polymorpha with special focus on structural characterization of arabinogalactan-proteins. The Marchantia AGP shows typical features known from seed plant AGPs like precipitation with β-glucosyl-Yariv’s reagent, a protein moiety with hydroxyproline and a carbohydrate part with 1,3,6-linked galactose and terminal arabinose residues. On the other hand, striking differences to AGPs of angiosperms are the occurrence of terminal 3-O-methyl-rhamnose and a highly branched galactan lacking appreciable amounts of 1,6-linked galactose. Binding of different AGP-antibodies (JIM13, KM1, LM2, LM6, LM14, LM26, and MAC207) to Marchantia AGP was investigated and confirmed structural differences between liverwort and angiosperm AGP, possibly due to deviating functions of these signaling molecules in the different taxonomic groups. View Show abstract Resistant Starch from Exotic Fruit and Its Functional Properties: A Review of Recent Research Chapter Full-text available Oct 2019 Lee-Hoon Ho Shi-Yun Wong View n-3 PUFA Sources (Precursor/Products): A Review of Current Knowledge on Rabbit Article Full-text available Oct 2019 María Rodríguez Francisco Pilar García Rebollar Simona Mattioli Cesare Castellini This review compares the effects of different n-3 polyunsaturated fatty acid (PUFA) sources on biological activity, physiological/reproductive endpoints, and health implications with a special emphasis on a rabbit case study. Linoleic acid (LA) and α-linolenic acid (ALA) are members of two classes of PUFAs, namely the n-6 and n-3 series, which are required for normal human health. Both are considered precursors of a cascade of molecules (eicosanoids), which take part in many biological processes (inflammation, vasoconstriction/vasodilation, thromboregulation, etc.). However, their biological functions are opposite and are mainly related to the form (precursor or long-chain products) in which they were administered and to the enzyme–substrate preference. ALA is widely present in common vegetable oils and foods, marine algae, and natural herbs, whereas its long-chain PUFA derivatives are available mainly in fish and animal product origins. Recent studies have shown that the accumulation of n-3 PUFAs seems mostly to be tissue-dependent and acts in a tissue-selective manner. Furthermore, dietary n-3 PUFAs widely affect the lipid oxidation susceptibility of all tissues. In conclusion, sustainable sources of n-3 PUFAs are limited and exert a different effect about (1) the form in which they are administered, precursor or derivatives; (2) their antioxidant protections; and (3) the purpose to be achieved (health improvement, physiological and reproductive traits, metabolic pathways, etc.). View Show abstract The “Grass-Fed” Milk Story: Understanding the Impact of Pasture Feeding on the Composition and Quality of Bovine Milk Article Full-text available Aug 2019 Mohammad Alothman Tom F O'Callaghan Sean A. Hogan Kieran N Kilcawley Milk is a highly nutritious food that contains an array of macro and micro components, scientifically proven to be beneficial to human health. While the composition of milk is influenced by a variety of factors, such as genetics, health, lactation stage etc., the animal’s diet remains a key mechanism by which its nutrition and processing characteristics can be altered. Pasture feeding has been demonstrated to have a positive impact on the nutrient profile of milk, increasing the content of some beneficial nutrients such as Omega-3 polyunsaturated fatty acids, vaccenic acid, and conjugated linoleic acid (CLA), while reducing the levels of Omega-6 fatty acids and palmitic acid. These resultant alterations to the nutritional profile of “Grass-Fed” milk resonate with consumers that desire healthy, “natural”, and sustainable dairy products. This review provides a comprehensive comparison of the impact that pasture and non-pasture feeding systems have on bovine milk composition from a nutritional and functional (processability) perspective, highlighting factors that will be of interest to dairy farmers, processors, and consumers. View Show abstract Sources, Extraction and Biomedical Properties of Polysaccharides Article Full-text available Aug 2019 Samee Ullah Anees Ahmed Khalil Faryal Shaukat Yuanda Song In the recent era, bioactive compounds from plants have received great attention because of their vital health-related activities, such as antimicrobial activity, antioxidant activity, anticoagulant activity, anti-diabetic activity, UV protection, antiviral activity, hypoglycemia, etc. Previous studies have already shown that polysaccharides found in plants are not likely to be toxic. Based on these inspirational comments, most research focused on the isolation, identification, and bioactivities of polysaccharides. A large number of biologically active polysaccharides have been isolated with varying structural and biological activities. In this review, a comprehensive summary is provided of the recent developments in the physical and chemical properties as well as biological activities of polysaccharides from a number of important natural sources, such as wheat bran, orange peel, barely, fungi, algae, lichen, etc. This review also focused on biomedical applications of polysaccharides. The contents presented in this review will be useful as a reference for future research as well as for the extraction and application of these bioactive polysaccharides as a therapeutic agent. View Show abstract Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health Article Full-text available Aug 2019 APPL MICROBIOL BIOT Andrea Monteagudo-Mera Robert A. Rastall Glenn R Gibson Afroditi Chatzifragkou Adhesion ability to the host is a classical selection criterion for potential probiotic bacteria that could result in a transient colonisation that would help to promote immunomodulatory effects, as well as stimulate gut barrier and metabolic functions. In addition, probiotic bacteria have a potential protective role against enteropathogens through different mechanisms including production of antimicrobial compounds, reduction of pathogenic bacterial adhesion and competition for host cell binding sites. The competitive exclusion by probiotic bacteria has a beneficial effect not only on the gut but also in the urogenital tract and oral cavity. On the other hand, prebiotics may also act as barriers to pathogens and toxins by preventing their adhesion to epithelial receptors. In vitro studies with different intestinal cell lines have been widely used along the last decades to assess the adherence ability of probiotic bacteria and pathogen antagonism. However, extrapolation of these results to in vivo conditions still remains unclear, leading to the need of optimisation of more complex in vitro approaches that include interaction with the resident microbiota to address the current limitations. The aim of this mini review is to provide a comprehensive overview on the potential effect of the adhesive properties of probiotics and prebiotics on the host by focusing on the most recent findings related with adhesion and immunomodulatory and antipathogenic effect on human health. View Show abstract High dietary total antioxidant capacity is associated with a reduced risk of hypertension in French women Article Full-text available Jun 2019 Nutr J Paola Villaverde Martin Lajous Conor-James MacDonald Marie-Christine Boutron-Ruault Background:
Although there is evidence for a reduced risk of hypertension associated with fruit and vegetable consumption, the relationship between the total antioxidant capacity of the diet (TAC) and the risk of hypertension has not been previously examined. We aimed to evaluate that association in the large E3N French prospective cohort of women.
Methods:
Dietary TAC was estimated using total radical-trapping ability parameter (TRAP) assay food values; self-reported incident hypertension cases were validated. Cox regression models were adjusted for conventional risk factors, body mass index, physical activity, energy, sodium, magnesium, omega-3 fatty acids, and alcohol.
Results:
After an average 12.7 years of follow up, there were 9350 incident cases of hypertension among 40,576 women. Dietary TAC was inversely associated with the risk of hypertension with a 15% lower risk of hypertension in those in the fifth vs. first quintile (HRQ5 0.85 [CI 95% 0.74; 0.95] p-trend 0.03) An inverse dose-effect relationship was observed for dietary TAC excluding coffee (HRQ5 0.85 [CI 95% 0.74; 0.95], p-trend 0.0008), while for dietary TAC from coffee, only the highest quintile was inversely associated with risk (HRQ5 0.86 [0.75, 0.97], p-trend 0.20). In a fully partitioned model with major dietary TAC contributors, TAC from fruit/vegetables, wine, and miscellaneous sources was inversely associated with risk, while associations with TAC from coffee, tea, and chocolate were not statistically significant.
Conclusions:
In a large prospective cohort, the risk of incident hypertension in women was inversely associated with the antioxidant capacity of the diet, suggesting that promoting a diet naturally rich in antioxidants might help prevent the development of hypertension. View Show abstract Effects of the resistant starch on glucose, insulin, insulin resistance, and lipid parameters in overweight or obese adults: a systematic review and meta-analysis Article Full-text available Dec 2019 Yong Wang Jing Chen Ying-Han Song Xiao-Ting Wu Background:
The role of resistant starch (RS) in glucose, insulin, insulin resistance or sensitivity, and lipid parameters have been reported in several studies and remained controversial. A pooled analysis which assessed these parameters has not been performed. Thus, we conducted a meta-analysis to sum up existing evidence about the issue.
Methods:
We searched in MEDLINE and PUBMED for studies that were published before November 2018. Meta-analysis of diabetics and nondiabetics trials were performed by use of a random-effects model.
Results:
A total of 13 case-control studies that included 428 subjects with body mass index ≥25 were identified. RS supplementation reduced fasting insulin in overall and stratified (diabetics and nondiabetics trials) analysis (SMD = -0.72; 95% CI: -1.13 to -0.31; SMD = -1.26; 95% CI: -1.66 to -0.86 and SMD = -0.64; 95% CI: -1.10 to -0.18, respectively), and reduced fasting glucose in overall and stratified analysis for diabetic trials (SMD = -0.26; 95% CI: -0.5 to -0.02 and SMD = -0.28; 95% CI: -0.54 to -0.01, respectively). RS supplementation increased HOMA-S% (SMD = 1.19; 95% CI: 0.59-1.78) and reduced HOMA-B (SMD =-1.2; 95% CI: -1.64 to -0.77), LDL-c concentration (SMD =-0.35; 95% CI: -0.61 to -0.09), and HbA1c (SMD = -0.43; 95% CI: -0.74 to -0.13) in overall analysis.
Conclusions:
This meta-analysis has provided evidence that RS supplementation can improve fasting glucose, fasting insulin, insulin resistance and sensitivity, especially for diabetic with overweight or obesity. However, owing to potential sophistication, individual difference and composition of intestinal microbiota, this result should be carefully taken into account. View Show abstract Dietary Fiber, Atherosclerosis, and Cardiovascular Disease Article Full-text available May 2019 Ghada A Soliman Observational studies have shown that dietary fiber intake is associated with decreased risk of cardiovascular disease. Dietary fiber is a non-digestible form of carbohydrates, due to the lack of the digestive enzyme in humans required to digest fiber. Dietary fibers and lignin are intrinsic to plants and are classified according to their water solubility properties as either soluble or insoluble fibers. Water-soluble fibers include pectin, gums, mucilage, fructans, and some resistant starches. They are present in some fruits, vegetables, oats, and barley. Soluble fibers have been shown to lower blood cholesterol by several mechanisms. On the other hand, water-insoluble fibers mainly include lignin, cellulose, and hemicellulose; whole-grain foods, bran, nuts, and seeds are rich in these fibers. Water-insoluble fibers have rapid gastric emptying, and as such may decrease the intestinal transit time and increase fecal bulk, thus promoting digestive regularity. In addition to dietary fiber, isolated and extracted fibers are known as functional fiber and have been shown to induce beneficial health effects when added to food during processing. The recommended daily allowances (RDAs) for total fiber intake for men and women aged 19–50 are 38 gram/day and 25 gram/day, respectively. It is worth noting that the RDA recommendations are for healthy people and do not apply to individuals with some chronic diseases. Studies have shown that most Americans do not consume the recommended intake of fiber. This review will summarize the current knowledge regarding dietary fiber, sources of food containing fiber, atherosclerosis, and heart disease risk reduction. View Show abstract Phytochemicals screening and anti-oxidant activity of hydroethanolic extracts of Ruellia tuberosa L Article Full-text available May 2019 Anna Safitri Anna Roosdiana Istoria Rosyada Resti Rachmawanti View Development of fermented beverage with water kefir in water-soluble coconut extract (Cocos nucifera L.) with inulin addition Article Mar 2021 LWT-FOOD SCI TECHNOL Vanessa Alves Thamarys Scapini Aline Frumi Camargo Helen Treichel The use of water-soluble plant-based extracts is a viable option of a non-dairy substrate in developing new food products, such as for kefir fermented beverage. The aim of this study was to develop a vegan fermented beverage with water kefir in the water-soluble coconut extract (WSCE), with inulin. A factorial design 2³ was applied, with independent variables: coconut sugar (2.0; 6.0 and 10.0% w/v); inulin (2.0, 2.5 and 3.0% w/v) and xanthan gum (0.0; 0.13 and 0.26% w/v) and dependent variables: growth of kefir grains, fermented beverage yield and lactic acid. The growth of kefir grains was higher when the concentrations of inulin were close to 2.8 and 3.0% (w/v) and xanthan gum up to 0.26% (w/v), influencing in 90% the rate growth. Fermented beverage yield and lactic acid were between 80 to 82.5% and 1.2 to 1.25%, respectively, when of xanthan gum and coconut sugar were between 0.26 and 10.0% (w/v). Still, fermentative process was significant in terms of nutritional and enzymatic contents. The water kefir showed great potential for adaptation to WSCE in 24 hours of fermentation, favoring the development of a non-dairy fermented beverage that may prove to be an alternative for lactose intolerant, allergic and vegans. View Show abstract Physicochemical, textural and structural characteristics of wheat gluten-soy protein composited meat analogues prepared with the mechanical elongation method Article Feb 2021 Jie Hong Chiang Wesley Tay Dayna Shu Min Ong Jeya Henry This study investigated the effect of mechanical elongation method by combining wheat gluten (WG) and soy protein isolate (SPI) (at the ratio of 100:0, 80:20, 60:40 and 40:60% w/w dry protein basis), and studied the physicochemical, textural and structural characteristics of meat analogues (∼52% moisture). The meat analogues were analysed and compared against commercial control samples of firm tofu, mock chicken, and steamed chicken. Meat analogues made with 100%WG showed the lowest hardness and chewiness. Analysis of meat analogues by scanning electron microscopy (SEM) showed their unique compact ultrastructure which was distinct from the commercial control samples. However, the proportional concentration of WG had an insignificant impact on the ultrastructure. Increasing SPI concentrations improved lysine contents of meat analogues but were still significantly lower (p<0.05) than steamed chicken. The results from protein solubility analysis suggested that hydrogen bonds, disulphide bonds and hydrophobic interactions were the forces responsible for the formation, stabilisation and retention of the structures within the meat analogues. It was concluded that the use of WG and WG-SPI produced acceptable doughs that could be used for the development of meat analogues using the mechanical elongation method. View Show abstract Inulin as an ingredient for improvement of glycemic response and sensory acceptance of breakfast cereals Article May 2021 FOOD HYDROCOLLOID Suzane Martins Ferreira Vanessa Dias Capriles Ana Carolina Conti-Silva Inulin-type fructans have been used as an ingredient to partially replace starchy flours in foods such as pasta, confectionery, breads, sauces and desserts, as they have the potential to improve technological properties, nutritional quality of the products and reduce glycemic response. Therefore, this study aimed evaluating the impact of inulin on the physical properties, proximate composition, glycemic response and sensory acceptance of corn breakfast cereals. A mixture of corn grits and inulin was extruded in a single screw extruder, at a feed rate of 247 g/min, temperatures in the shearing zones at 140 °C and screw speed of 192 rpm. The addition of inulin did not impair the physical properties of breakfast cereals, such as expansion ratio, density, instrumental force and color. Moreover, inulin did not affect the acceptance of products, as well as having a positive impact on them. Extrudates with inulin presented a high fiber level and moderate glycemic load, in contrast to the control extrudate that had low fiber level and high glycemic load. Therefore, the addition of inulin in breakfast cereals is promising and may contribute to increasing the consumption of products with aggregated nutritive value.
Share Link: https://authors.elsevier.com/c/1cMs1,65-xVdbW 50 days' free access to the article, February 25, 2021 View Show abstract Gelation of a combination of insect and pork proteins as affected by heating temperature and insect:meat ratio Article Nov 2020 FOOD RES INT Jana Scholliers Liselot Steen Ilse Fraeye In order to better understand structure formation in hybrid meat products containing insects, viscoelastic properties, protein aggregation and surface hydrophobicity of extracted insect and meat proteins in different insect:meat nitrogen ratios (100:0, 75:25, 50:50, 25:75 and 0:100) at different heating temperatures (from 20 to 80 °C) were studied. During heating, meat proteins showed best gelling properties. This was probably associated with the formation of hydrophobic interactions, as was confirmed by the strong increase in surface hydrophobicity of the meat proteins upon heating. Insect proteins, on the other hand, formed a considerable amount of additional structure during cooling, resulting in gels with high gel strength, although their gel stability was low. As for the mixtures of insect and meat proteins, they showed lower final gel strengths compared to the pure insect and meat protein samples. Furthermore, proteins with molecular weights of 230 and 16 kDa, that aggregated in the pure samples, did not aggregate in the mixtures. Although the mechanism of the latter effect remains to be elucidated, it probably explains the lower gel strength observed in the protein mixtures. View Show abstract Development of a functional whey cheese (ricotta) enriched in phytosterols: Evaluation of the suitability of whey cheese matrix and processing for phytosterols supplementation Article Oct 2020 LWT-FOOD SCI TECHNOL Astride Franks Kamgang Nzekoue Alessandro Alesi Sauro Vittori Giovanni Caprioli This study aims to evaluate the suitability of whey cheese (ricotta) matrix and production process for phytosterols-enrichment. Therefore, the phytosterols stability of ricotta cheese was assessed during cheese processing (85 • C for 60 min) and storage (4 • C for 4 weeks). Given the novelty of the food matrix used, it was necessary to develop an innovative analytical method for sterols determination in enriched ricotta cheese. The developed HPLC-DAD method showed good linearity (R 2 ≥ 0.9956) and reproducibility (0.4-7.6%), while extraction recoveries ranged between 83.7% and 84.6%. Phytosterols showed a good heat-stability in ricotta cheese matrix during cheese processing (87.0-89.7) %. Moreover, the functional cheese showed a homogeneous phytosterols distribution and maintained its potential bioactivity during its shelf-life since no significant variation of phytosterols levels was observed during storage (0.83 ± 0.03) g/100 g. View Show abstract Bioactive peptides: A review Article Mar 2017 Adrian Sanchez Alfredo Vázquez View Risk profile related to production and consumption of insects as food and feed Article Oct 2015 EFSA Scientific Committee The present opinion has the format of a risk profile and presents potential biological and chemical hazards as well as allergenicity and environmental hazards associated with farmed insects used as food and feed taking into account of the entire chain, from farming to the final product. The opinion also addresses the occurrence of these hazards in non-processed insects, grown on different substrate categories, in comparison to the occurrence of these hazards in other non-processed sources of protein of animal origin. When currently allowed feed materials are used as substrate to feed insects, the possible occurrence of microbiological hazards is expected to be comparable to their occurrence in other non-processed sources of protein of animal origin. The possible occurrence of prions in non-processed insects will depend on whether the substrate includes protein of human or ruminant origin. Data on transfer of chemical contaminants from different substrates to the insects are very limited. Substrates like kitchen waste, human and animal manure are also considered and hazards from insects fed on these substrates need to be specifically assessed. It is concluded that for both biological and chemical hazards, the specific production methods, the substrate used, the stage of harvest, the insect species and developmental stage, as well as the methods for further processing will all have an impact on the occurrence and levels of biological and chemical contaminants in food and feed products derived from insects. Hazards related to the environment are expected to be comparable to other animal production systems. The opinion also identifies the uncertainties (lack of knowledge) related to possible hazards when insects are used as food and feed and notes that there are no systematically collected data on animal and human consumption of insects. Studies on the occurrence of microbial pathogens of vertebrates as well as published data on hazardous chemicals in reared insects are scarce. Further data generation on these issues are highly recommended. View Show abstract Synthetic Phenolic Antioxidants: A Review of Environmental Occurrence, Fate, Human Exposure, and Toxicity Article Sep 2020 ENVIRON SCI TECHNOL Runzeng Liu Scott A Mabury Synthetic phenolic antioxidants (SPAs) are widely used in various industrial and commercial products to retard oxidative reactions and lengthen product shelf life. In recent years, numerous studies have been conducted on the environmental occurrence, human exposure, and toxicity of SPAs. Here, we summarize the current understanding of these issues and provide recommendations for future research directions. SPAs have been detected in various environmental matrices including indoor dust, outdoor air particulates, sea sediment, and river water. Recent studies have also observed the occurrence of SPAs, such as 2,6-di-tert-butyl-4-methylphenol (BHT) and 2,4-di-tert-butyl-phenol (DBP), in humans (fat tissues, serum, urine, breast milk, and fingernails). In addition to these parent compounds, some transformation products have also been detected both in the environment and in humans. Human exposure pathways include food intake, dust ingestion, and use of personal care products. For breastfeeding infants, breast milk may be an important exposure pathway. Toxicity studies suggest some SPAs may cause hepatic toxicity, have endocrine disrupting effects, or even be carcinogenic. The toxicity effects of some transformation products are likely worse than those of the parent compound. For example, 2,6-di-tert-butyl-p-benzoquinone (BHT-Q) can cause DNA damage at low concentrations. Future studies should investigate the contamination and environmental behaviors of novel high molecular weight SPAs, toxicity effects of co-exposure to several SPAs, and toxicity effects on infants. Future studies should also develop novel SPAs with low toxicity and low migration ability, decreasing the potential for environmental pollution. View Show abstract Omega-3 rich foods: Durum wheat spaghetti fortified with Portulaca oleracea Article Aug 2020 Maria GRAZIA Melilli Antonella Pagliaro Salvatore Scandurra Vita Di Stefano Portulaca oleracea is an annual succulent herb (purslane) with high antioxidant properties and high content of essential ω-3 and ω-6 fatty acids, ascorbic acid, α-tocopherol and β-carotene. In the present study, sensorial and chemical analyses of uncooked and cooked durum wheat pasta fortified with purslane from three different Sicilian areas and at three different concentrations (5, 10 and 15%) were estimated. The sensorial analysis showed that the scores of the overall acceptance decreased considerably in pasta with 15% purslane, while consumers appreciated pasta samples with 10% purslane. Chemical analysis highlighted that the addition of purslane gave pasta samples the potential to be a functional food, due α-linonenic fatty acid concentration, antioxidant activity and total phenols content. The influence of the origin of purslane used to enrich pasta was evident: the “Cassibile” purslane supplemented spaghetti showed the highest content of linoleic and α-linolenic acids and the highest antioxidant activity. View Show abstract Italian consumers’ attitudes towards entomophagy: Influence of human factors and properties of insects and insect-based food Article Aug 2020 FOOD RES INT Fabio Tuccillo Mattia Gianfranco Marino Luisa Torri Studies on consumers’ perceptions towards entomophagy have recently gained popularity. However, the use of the general term “insect” represents a limitation of previous research, due to the need for more precise terminology. This study assessed attitudes towards specific insects, their gastronomic preparations, their relationships with human factors and the characteristics of insects as a food source. Using a survey, socio-demographics, personality traits, willingness to eat (WTE) six edible insects and their relative insect-based products or dishes (IBPD) and the emotions associated with entomophagy were collected from 400 Italians. Compared with females, males were found to be more positive towards insects, less influenced by the species and level of processing of insects and more willing to eat insects for reasons of taste. Eating insects evoked adventurous, daring and wild emotions, while disgust and food neophobia represented the main factors in refusal to eat insects. WTE was: crickets > bee larvae and grasshoppers > mealworms and silkworms > giant water bugs. A similar result was obtained considering the respective IBPD. On average, adult insects were preferred over larvae. Three subject groups, namely “In favour of eating insects” (41%), “Picky towards eating insects” (32%) and “Against eating insects” (27%) were found. A sensory evaluation performed on three cricket-based samples with 52 Italians revealed that a low level of insect visibility was preferred.
This study gives new insights into the variables related to the acceptance of entomophagy by determining the characteristics of a potential consumer and of a probable insect product for the market. View Show abstract Development of β-glucan enriched wheat bread using soluble oat fiber Article Jul 2020 Maria Ortiz de Erive Fuli He Tao Wang Guibing Chen Soluble oat fiber (SOF) containing 70% oat β-glucan was incorporated into wheat bread by replacing 10, 12, and 14% of flour in wheat bread formulas. At each level of SOF, bread was made at the farinograph water content defined by the amount of water required to develop a dough consistency of 500 Brabender Units in farinograph tests, and 10 and 20% extra water above the farinograph water content. At the farinograph water content, bread formulated at each level of SOF exhibited lower specific volume and porosity, darker color, higher hardness, and lower springiness and cohesiveness than the control white bread. These negative effects were effectively counteracted by optimizing the water content in bread formulas. For the three levels of bran addition, when the water content was increased by 20% above the farinograph water content, the obtained loaves exhibited similar loaf volume, microstructure, textural properties, and crumb porosity to the control white bread. A serving (28 g) of the developed bread contained respectively 0.95, 1.12, and 1.28 g of β-glucan, which substantially exceed the minimum standard for approved health claims. View Show abstract Vacuum Impregnation: Emerging Technology for Osmotic Dehydration of Fruits and Vegetables Article Dec 2016 R Sasireka Shunmugam Ganapathy In the osmotic treatment of foods, Vacuum Impregnation (VI) is the emerging technique that improves the air drying and osmotic dehydration (OD) of a porous product with a consequent change in food composition. Due to the action of hydrodynamic mechanisms (HDM) promoted by pressure changes, VI technique exchanges the internal gas or liquid occluded in open pores to an external liquid phase that consequently enhances the quality of the food by changing its composition. With the unique advantage of incorporating both osmosis and diffusion during its process, VI has a broad application in fruit and vegetable processing industries. This paper provides an overall review about the process and equipment details of the VI and their application in food industries. Also, the main factors affecting the process and the response of porous fruits and vegetables to VI processing has been discussed. View Show abstract Effects of probiotics and paraprobiotics on subjective and objective sleep metrics: a systematic review and meta-analysis Article May 2020 EUR J CLIN NUTR Christopher Garry Irwin Danielle Mccartney Ben Desbrow Saman Khalesi Inadequate sleep (i.e., duration and/or quality) is becoming increasingly recognized as a global public health issue. Interaction via the gut-brain axis suggests that modification of the gut microbial environment via supplementation with live microorganisms (probiotics) or nonviable microorganisms/microbial cell fractions (paraprobiotics) may improve sleep health. This systematic review and meta-analysis aimed to clarify the effect of consuming probiotics/paraprobiotics on subjective and objective sleep metrics. Online databases were searched from 1980 to October 2019 for studies involving adults who consumed probiotics or paraprobiotics in controlled trials, during which, changes in subjective and/or objective sleep parameters were examined. A total of 14 studies (20 trials) were included in meta-analysis. Random effects meta-analyses indicated that probiotics/paraprobiotics supplementation significantly reduced Pittsburgh Sleep Quality Index (PSQI) score (i.e., improved sleep quality) relative to baseline (−0.78-points, 95% confidence interval: 0.395–1.166; p < 0.001). No significant effect was found for changes on other subjective sleep scales, nor objective parameters of sleep (efficiency/latency) measured using polysomnography or actigraphy. Subgroup analysis for PSQI data suggested that the magnitude of the effect was greater (although not statistically) in healthy participants than those with a medical condition, when treatment contained a single (rather than multiple) strain of probiotic bacteria, and when the duration of treatment was ≥8 weeks. Probiotics/paraprobiotics supplementation may have some efficacy in improving perceived sleep health, measured using the PSQI. While current evidence does not support a benefit of consuming probiotics/paraprobiotics when measured by other subjective sleep scales, nor objective measures of sleep; more studies using well-controlled, within-subject experimental designs are needed. View Show abstract Kinetic study of staling in breads with high-amylose resistant starch Article Mar 2020 FOOD HYDROCOLLOID Carlos Gabriel Arp María Jimena Correa Cristina Ferrero High-amylose resistant starch breads were long-stored (11 days) at 20 °C for kinetic analysis of different aspects of the staling process. Bread products were formulated on a French-bread recipe basis and replacing wheat flour by type II resistant starch at different levels: 0% (control), 10% (HM10), 20% (HM20) and 30% (HM30). Experiments included measurements of water activity, moisture loss, amylopectin retrogradation by DSC, crystallinity changes by X-ray diffraction, and firmness by texture analysis. In the presence of resistant starch water loss was slower, allowing amylopectin retrogradation to be more extensive. However, HM10 and HM20 had similar firming behavior to the control, likely due to the similar and adequate quality that these breads showed initially (at day 0). In contrast, samples with high resistant starch content such as HM30 presented a poor-quality and highly filled crumb that led to the highest firmness during storage. View Show abstract An international regulatory review of food health-related claims in functional food products labeling Article May 2020 Laura Domínguez Virginia Fernández-Ruiz M. Cámara Consumers are increasingly aware of the importance of diet in human health and they preferably choose functional food products. The present work is focused on describing the current status of the international regulatory framework for health-related claims in functional food products and the state of the art regarding these products market focusing on those with health-related claims. Specific regulation must control the use of these claims in the labeling of functional products. Although the European, American and Japanese claims are partly similar in nature, but the approval and use procedures and the regulatory framework are different. Consumers generally accept functional products with health-related claims, and most of them include more than one claim. This review could help consumers for making better-informed food decisions; food industry in marketing its products with a focus on international trade; and scientists in order to put in value their research work. View Show abstract Effect of Water-Soluble Dietary Fiber Resistant Dextrin on Flour and Bread Qualities Article Feb 2020 FOOD CHEM Zheng Huang Jing Jing Wang Yu Chen Song-Qing Hu A new water-soluble resistant dextrin (WSRD), fabricated by thermal-acid treatment following amylase hydrolysis from corn starch, was expected to strengthen the dietary fibers intake of flour products. This study was to investigate the effects of WSRD on flour processing quality, and further dissect its improvement mechanisms by farinographic and rheological analysis, SDS-PAGE, Fourier transform infrared spectroscopy, texture analyzer, etc. Results showed that WSRD greatly improved the viscoelasticity and strength of dough, which was predominantly contributed by its formation of gel-like networks. Meanwhile, the WSRD-induced increase of gluten aggregates and β-sheet conformation provided the structural basis for enhancing dough quality. Notably, WSRD greatly promoted the sensory appearance and crumb quality of baked breads. Moreover, the WSRD-treated breads resisted the hydrolysis of digestive fluid and enzymes. Therefore, WSRD can strengthen the processing qualities and nutritional values of flour products, which will broaden the application of the novel dietary fiber in flour industry. View Show abstract Lesser mealworm (Alphitobius diaperinus) powder as a novel baking ingredient for manufacturing high-protein, mineral-dense snacks Article May 2020 FOOD RES INT Andrea Roncolini Vesna Milanovic Lucia Aquilanti Andrea Osimani Increasing interest in consuming foods that are high in protein, vitamin, amino acid, and mineral contents is steering growth in the market for fortified snacks. The aim of the present study was to evaluate the use of lesser mealworm (Alphitobius diaperinus) powder (LP) (at 10 or 30% substitution for wheat flour) for the protein and mineral fortification of crunchy snacks (rusks). Hence, the technological, microbiological, nutritional, and sensory characteristics of the fortified rusks were evaluated. The protein content was enriched up to 99.3% in rusks with 30% substitution; moreover, a notable increase in the essential amino acids content was observed, with histidine fortification reaching up to 129.1% in rusks with 30% substitution. The incorporation of LP has led to an enrichment of almost all the minerals considered here, and especially Fe, P and Zn, with Zn showing fortification percentages of up to 300% in rusks with 30% substitution for LP. The experimental rusks showed pleasant sensory traits and low aw values. In view of the potential industrial manufacturing of insect-based rusks, the proposed product can be assigned to level 4 (validation in a laboratory environment) of the Technology Readiness Level (TRL) scale, and it is thus ready to be tested in a simulated production environment. View Show abstract Potential risks of phytonutrients associated with high-dose or long-term use Chapter Jan 2020 Ipek Süntar Ömer Faruk Yakıncı View Functional Foods: Product Development, Technological Trends, Efficacy Testing, and Safety Article Mar 2020 Daniel Granato Francisco J. Barba Danijela Bursać Kovačević Predrag Putnik Functional foods is a very popular term in the social and scientific media; consequently, food producers have invested resources in the development of processed foods that may provide added functional benefits to consumers’ well-being. Because of intrinsic regulation and end-of-use purposes in different countries, worldwide meanings and definitions of this term are still unclear. Hence, here we standardize this definition and propose a guideline to attest that some ingredients or foods truly deserve this special designation. Furthermore, focus is directed at the most recent studies and practical guidelines that can be used to develop and test the efficacy of potentially functional foods and ingredients. The most widespread functional ingredients, such as polyunsaturated fatty acids (PUFAs), probiotics/prebiotics/synbiotics, and antioxidants, and their technological means of delivery in food products are described. The review discusses the steps that food companies should take to ensure that their developed food product is truly functional.
Expected final online publication date for the Annual Review of Food Science and Technology, Volume 11 is March 25, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. View Show abstract Beneficial role of insect-derived bioactive components against inflammation and its associated complications (colitis and arthritis) and cancer Article Sep 2019 CHEM-BIOL INTERACT Prachurjya Dutta Ravi Kumar Sahu Tapan Dey Jatin Kalita Insect-based bioactive components are emerging as novel sources of drugs, effective against various diseases. Inflammation is considered to be an innate immune response developed by different organisms against foreign pathogens and cellular stress. However, repetitive elevated inflammation is considered to be responsible for development of many other diseases including colitis and arthritis. Due to the limited activities and side effects of non-steroidal anti-inflammatory drugs, researchers are continuously looking for alternative sources of drug molecules to alleviate the inflammatory related complications. Recently, insect-based bioactive components, such as venoms, haemocytes, cecropin A, papiliocin, N-acetyldopamine dimers, cecropin-TY1 peptide, cop A3 peptide, glycosaminoglycan, coprisin peptide, silk fibroin microparticles, and silk fibroin nanoparticles have been found to be active against different inflammatory mechanisms and associated diseases. Cancers, are some of the deadliest diseases, which are mainly treated by chemotherapy, radiation therapy and surgery. However, such treatments, mainly chemotherapy, is associated with enormous side effects. Therefore, as an alternative, less hazardous option, compounds from insects with anti-cancerous activity are being explored. Insect-derived compounds, such as cantharidin, norcantharidin, isocoumarin, plancyols A, plancypyrazine A, pancratistatin, narciclasine, and ungeremine, show potential anti-cancerous activity. In this review, we will be discussing the role of different potential drug molecules of insect origin with special emphasis on anti-inflammation and their association with health disorders and cancer. View Show abstract Low-glycemic index diets as an intervention for diabetes: A systematic review and meta-analysis Article Aug 2019 AM J CLIN NUTR Mohammad Ishraq Zafar Kerry Elizabeth Mills Juan Zheng Lu-Lu Chen Background:
Low-glycemic index (GI) diets are thought to reduce postprandial glycemia, resulting in more stable blood glucose concentrations.
Objective:
We hypothesized that low-GI diets would be superior to other diet types in lowering measures of blood glucose control in people with type 1 or type 2 diabetes, or impaired glucose tolerance.
Methods:
We searched PubMed, the Cochrane Library, EMBASE, and clinical trials registries for published and unpublished studies up until 1 March, 2019. We included 54 randomized controlled trials in adults or children with impaired glucose tolerance, type 1 diabetes, or type 2 diabetes. Continuous data were synthesized using a random effects, inverse variance model, and presented as standardized mean differences with 95% CIs.
Results:
Low-GI diets were effective at reducing glycated hemoglobin (HbA1c), fasting glucose, BMI, total cholesterol, and LDL, but had no effect on fasting insulin, HOMA-IR, HDL, triglycerides, or insulin requirements. The reduction in fasting glucose and HbA1c was inversely correlated with body weight. The greatest reduction in fasting blood glucose was seen in the studies of the longest duration.
Conclusions:
Low-GI diets may be useful for glycemic control and may reduce body weight in people with prediabetes or diabetes. View Show abstract Cricket powder (Gryllus assimilis) as a new alternative protein source for gluten-free breads Article Jun 2019 INNOV FOOD SCI EMERG Carolina da Rosa Machado Roberta Cruz Silveira Thys Gluten elimination in bakery goods is a technological challenge since the absence of gluten generates breads with poor capacity to retain gas during leavening, which can be minimised with the use of gluten-free proteins in combination with hydrocolloids and/or enzymes. Due to the increasing world population and scarce land resources to expand current food production, it is necessary to find alternative and sustainable ways of growing food. This study aimed to characterise cricket (Gryllus assimilis) powder as a new protein source for gluten-free breads in comparison with the use of lentil and buckwheat flours. Cricket powder presented high water and oil holding capacities and appropriate microbiological features for human consumption. Results confirm that the enrichment with cricket powder can lead to the production of gluten-free bread with acceptable technological properties and high protein content. As the addition of cricket powder increases lipid contents, for better nutritional and functional results, the use of oil-free formulations is recommended.
Industrial relevance
Considering the rising world population and the scarce water and land resources, it is extremely important to find new and sustainable ways to produce food. Edible insects are particularly interesting due to its high protein content and lower environmental impacts compared to traditional livestock. This study evaluated the use of cricket powder as protein source for the production of gluten-free bread in comparison with two other protein sources: buckwheat and lentil flours. Results confirm that the enrichment with cricket powder can lead to the production of gluten free bread with acceptable technological properties and high protein content. View Show abstract Microencapsulation of Probiotic Lactobacillus acidophilus KBL409 by Extrusion Technology to Enhance Survival under Simulated Intestinal and Freeze-Drying Conditions Article May 2019 J Microbiol Biotechnol YunJung Lee Yu Ra Ji Sumi Lee Youngjae Cho The probiotic Lactobacillus acidophilus KBL409 was encapsulated with alginate (Al) and alginate-chitosan (Al/Chi) through extrusion method. The sizes and zeta potentials of microspheres were measured to confirm encapsulation. To evaluate the protective effect of microspheres against gastrointestinal fluids, all the samples were exposed to simulated gastric fluids (SGFs, pH 1.5) at 37°C for 1 or 2 h, followed by incubation with simulated intestinal fluids (SIFs, pH 6.5) for 2 h. The mucoadhesive ability of microspheres was evaluated using the intestinal epithelial cell line HT29-MTX. To extend the shelf-life of probiotics, lyoprotectants such as disaccharide and polysaccharide were mixed with free or encapsulated cells during the freeze-drying process. The size of the microspheres demonstrated a narrow distribution, while the zeta potentials of Al and Al/Chi-microspheres were -17.9 ± 2.3 and 20.4 ± 2.6 mV, respectively. Among all the samples, Al/Chi-encapsulated cells showed the highest survival rate even after exposure to SGF and SIF. The mucoadhesive abilities of Al and Al/Chi-microspheres were higher than 94%, whereas the free L. acidophilus showed 88.1% mucoadhesion. Ten percent of sucrose showed over 80% survival rate in free or encapsulated cells. Therefore, L. acidophilus encapsulated with Al and Al/Chi-microspheres showed higher survival rates after exposure to the gastrointestinal tract and better mucoadhesive abilities than the free cells. Also, sucrose showed the highest protective effect of L. acidophilus during the freeze-drying process. View Show abstract Sacha inchi oil encapsulation: Emulsion and alginate beads characterization Article May 2019 FOOD BIOPROD PROCESS Klycia Silva Ana Gabriela da Silva Carvalho Renata S. Rabelo Miriam Hubinger The sacha inchi oil (SIO) has about 82% polyunsaturated fatty acids and micronutrients, as tocopherol and phenolic compounds. This work investigated the combination of encapsulation techniques (emulsification and ionic gelation) in order to produce food ingredients with SIO to the enrichment of foodstuffs, as well as to promote its protection against lipid oxidation. For the SIO encapsulation processes, sodium alginate and nonionic surfactants (Tween 20 and 80) were used as encapsulating/gelation and stabilizers agents, respectively. Emulsions exhibited high electronegativity (≈ −80 mV) and pseudoplastic behavior. Control emulsions showed low kinetics stability with increased oil concentration. With polysorbates addition, an increase in the stability of these emulsions and a significant decline in droplet size, span and electronegativity values were observed. Systems with 1.0 wt% Tween 20 were preferred for particles formation due to the low presence of drops agglomerates. The wet Ca (II) - alginate beads showed characteristic results of ionic gelation technique for moisture content (>85 ± 1%) and water activity (>0.996 ± 0.001), with size ranging from 407 ± 11 to 448 ± 33 μm and high encapsulation efficiency (>99%). The combination of encapsulation methods allowed the improvement of oxidative stability of SIO from 132 ± 9 meq O 2. kg ⁻¹ to values lower than 44 ± 18 meq O 2. kg ⁻¹ . View Show abstract Show more
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June 2023
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[...] Rishi Kumar Bharti
Background: Didactic lecture is most commonly used method to teach medical students in Family and Community Medicine. However, considering its demerits and the need to integrate theoretical knowledge into practice, the objective of this paper is to review the contribution of role play in medical education and to propose it’s applications to deliver healthcare services in community more
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November 2021
· Blood
Farhana Ferdousi Masud Alam
Risa Araki [...] Hiroko Isoda
Background:
Anemia is one of the major public health problems that affected 2.36 billion individuals worldwide in 2015. Half of all causes of anemia are iron or other nutrient deficiency anemia (WHO, 2015). Currently available treatment options for anemia include iron or other nutrient supplementation, nutritional interventions in the form of food fortification, blood transfusion, and ... [Show full abstract]
erythropoietic agent infusion. However, conventional treatments are not without adverse effects. In this context, medicinal plants with bioactive components have been receiving considerable attention from researchers as natural hematinic agents complemented with or alternatives to conventional treatment.
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Additionally, we have reported that long-term consumption of OLE tea increased RBC count, Hb%, and hematocrit (Ht) in female volunteers aged between 40 - 70 years old (Ferdousi et al., 2019). However, none of the participants were anemic at the baseline. Therefore, in the present study, we aimed to investigate the effects of oral intake of OLE on hematological parameters in healthy to mildly anemic young adults.
Study Design and Methods
A double-blinded, randomized, placebo-controlled study will be conducted in Bangladesh. Total 165 apparently healthy adults with Hb level at least 10g/dl for females (nonpregnant, non-breastfeeding) and 11g/dl for males, and aged between 18 to 59 years will be enrolled from the local community. Major exclusion criteria will include currently pregnant women or breastfeeding mothers, moderate to severe anemia (Hb concentration < 10 g / dL for women and < 11 g / dL for men), any medical condition, such as hematological diseases, malignant tumors, aplastic anemia, uncontrolled hypertension, chronic kidney disease, irritable bowel syndrome, and cardiovascular diseases, and currently taking medicine for diabetes or hypertension and taking regular iron or other supplements, etc.
After providing informed written consent, study participants will be randomly assigned to placebo, 250 mg OLE and 500 mg OLE groups. Participants will take OLE or placebo capsules in two divided doses every day for 12 weeks. Hematological parameters, Hb concentration, RBC count, WBC count, Ht, MCV, MCH, MCHC, serum Fe and ferritin levels will be investigated at baseline and after 6 and 12 weeks of intervention. Liver and renal function tests will be conducted for safety assessment. Additionally, lipid profile will be investigated to understand how lipid parameters will be regulated if anemia condition is improved by OLE intervention (Araki et al., 2019). Given that fatigue is one of the most common symptoms of anemia, we will also evaluate the effect of OLE on the score of each item of the Fatigue Assessment Scale (FAS) questionnaire during the intervention.
The analysis will be carried out on an intention-to-treat basis involving all the participants who will consume the test samples at least once. We will replace the missing data from dropouts using the baseline observation carried forward method. ANOVA with Bonferroni's post hoc test will be used for normally distributed data; otherwise, the Mann-Whitney U test or Kruskal-Wallis H(K) test will be used. Categorical variables will be compared by the Chi-square or Fisher's exact test. A one-way repeated-measures ANOVA with Bonferroni's post hoc test (Within-group) and ANOVA followed by Bonferroni's post hoc test (between-group) will be performed. Significance is at p < 0.05.
This protocol is registered with UMIN-CTR Clinical Trial (UMIN000039023), and has been approved by University of Tsukuba Hospital Clinical Research Ethics Review Committee (R01-292) and the Ethical Review Committee of icddr,b (PR-21017). This study is funded by the Japan Society for the Promotion of Science (19K20106) and partly by the Japan Science and Technology Agency-SATREPS (JPMJSA1506).
Disclosures
Suidasari: Nutrition Act Co. Ltd.: Current Employment. Yokozawa: Nutrition Act Co. Ltd.: Current Employment. Yamauchi: Nutrition Act Co. Ltd.: Current Employment.
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Diertary Intake of Micronutrients in Non-Indigenous Womens in the Cities of Khanty-Mansiysk and Sale...
September 2021
L. N. Bikbulatova Vladimir Korchin
[...] T.Ya. Korchina
Introduction: Healthy nutrition is an important determinant of physical and mental wellbeing. A significant amount of evidence has been accumulated on the effect of nutrition on health promotion, disease prevention, resiliance to unfavorable climatic factors, longevity and life quality. Insufficient intake of micronutrients is often combined with an excess intake of macronutrients, particularly
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Exploring food fortification potential of neglected legume and oil seed crops for improving food and...
March 2021
· Journal of Agriculture and Food Research
Marongwe F. Desire Blessing Masamha Nyakudya Elijah [...]
Nyamadzawo George
A systematic review of literature on value-addition and food fortification of cereals using neglected legume and oil seed crops among smallholder farming communities was done. There is scanty and very limited empirical evidence on the use of legumes in food fortification of cereals at the household level. This is largely because of a neglect of local micronutrient provision initiatives at the
... [Show full abstract]
household level, with much attention being done at policy and industrial scale food fortification levels. Besides, the current policies do not provide for the fortification of most food crops commonly grown in smallholder farming communities and there are very few initiatives that are in place to promote localised fortification options among rural communities. The paper consolidated existing knowledge on food fortification in general, value addition of small grains and neglected legume and oil seed crops. It explored fortification potential of sesame, cow pea and groundnuts and mapped existing gaps and missing links hampering the enhancement of food security and nutrition. This study recommends the promotion of groundnuts and sesame production, their value addition, and their use in the fortification of cereal food products to complement protein, Vitamins, Fe, K, Na, Mg, Zn, and Ca provision. This will significantly contribute to the alleviation of malnutrition among rural communities particularly in developing countries where agriculture is the mainstay of economies.
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Sustainable binders for concrete: A structured approach from waste screening to binder composition development | Request PDF
Request PDF | Sustainable binders for concrete: A structured approach from waste screening to binder composition development | Worldwide, the building sector requires the production of 4 billion tonnes of cement annually, consuming more than 40% of global energy. Alkali... | Find, read and cite all the research you need on ResearchGate
Article
Sustainable binders for concrete: A structured approach from waste screening to binder composition development
Authors:
<here is a image e92fd35bbe42c179-2215f8286048052e>
Raffaele Vinai
University of Exeter
<here is a image dcd934fbc9959a81-f654d7444684c4b7>
Chrysa Panagiotopoulou
National Technical University of Athens
<here is a image 31a427a4e74ebf6a-e72a852c3c4c5188>
Marios Soutsos
Queen's University Belfast
<here is a image f149e4016ee7b2be-c890be01debd738a>
Maria Taxiarchou
National Technical University of Athens
Abstract
Worldwide, the building sector requires the production of 4 billion tonnes of cement annually, consuming more than 40% of global energy. Alkali activated "cementless" binders have recently emerged as a novel eco-friendly construction material with a promising potential to replace ordinary Portland cement. These binders consist of a class of inorganic polymer formed mainly by the reaction between an alkaline solution and an aluminosilicate source. Precursor materials for this reaction can be found in secondary material streams from different industrial sectors, from energy to agro-alimentary. However, the suitability of these materials in developing the polymerisation reaction must be assessed through a detailed chemical and physical characterisation, ensuring the availability of required chemical species in the appropriate quantity and physical state. Furthermore, the binder composition needs to be defined in terms of proper alkali activation dosages, water content in the mix, and curing conditions. The mix design must satisfy mechanical requirements and compliance to desired engineering properties (workability, setting time) for ensuring the suitability of the binder in replacing Portland cement in concrete applications. This paper offers a structured approach for the development of secondary material-based binders, from their identification to mix design and production procedure development. Essential features of precursor material can be determined through chemical and physical characterisation methods and advanced microscope techniques. Important mixing parameters and binder properties requirements are examined and some examples of developed binders are reported.
... Secondary raw materials such as fly ash, slag and perlite tailings are in sufficient large quantities available to serve as cement replacement
[Vinai, 2015]
. Sustainable binders, such as alkali activated fly ash, slag or combinations of these, have been shown to develop a higher compressive strength than a similarly composed concrete based on a Portland cement binder and gravel and sand as aggregates [Provis, 2014, Bernal, 2011. ...
... All binders have been described in detail in
Vinai [2015]
, including the concentration and type of activators. ...
... The initial design of the concrete was based on the (theoretical) density of concrete. All binder / aggregate combinations were tested, with the optimum binder compositions as formulated by
Vinai [2015]
. As most of the available aggregates reduced the workability, the biggest challenge in the fresh concrete design was to make the concrete as light as possible while maintaining a sufficient workability. ...
Sustainable concrete: Design and testing
Article
Full-text available
Jan 2015
<here is a image 17cfd59b2ab5b92f-e30d6998dcd34396> Johanna Hendrica Maria Visser
<here is a image c9a2b8ca49fbe4cb-9f4e2448a856b3bd> Sandra Couto
Anoop Gupta
<here is a image 31a427a4e74ebf6a-e72a852c3c4c5188> Marios Soutsos
Producing concrete with secondary raw materials is an excellent way to contribute to a more sustainable world, provided that this concrete has at least the same performance during its service life as concrete made with the primary raw materials it replaces. Secondary raw materials for Light Weight (LW) aggregates (rigid polyurethane foams, shredded tire rubber and mixed plastic scraps) have been combined with secondary raw materials for the binder (fly ash, slag and perlite tailings) making sustainable concretes that were investigated for their suitability as LW, highly insulating concrete for four different types of applications. Compliance to desired engineering properties (workability, setting time) was not always feasible: it was mostly the low workability of the mixtures that limited their application. Contrary to well established cements, steering the workability by adding water was not an option for these binders that rely on alkali-activation. Eight successful mixtures have been tested further. The results have shown that it is possible to produce a non-structural sustainable concrete with good mechanical and thermal insulation properties. Design of concrete made with novel materials is currently not feasible without extensive experimentation as no design rules exist other than empirically derived rules based on traditional materials. As a radical different approach, a flexible concrete mix design has been developed with which the concrete can be modelled in the fresh and hardened state. The numerical concrete mix design method proves a promising tool in designing concrete for performance demands such as elasticity parameters and thermal conductivity.
... Cement is the major binding material in the concrete works
[1]
. The strength and durability of the concrete mainly depends on the quality of the cement, which is significantly affected by the storage and age of the cement [2]. ...
... Bended mortar mixes were prepared using cement and standard sand adopting a proportion of 1: 3 by weight (1800gm cement and 5400gm standard sand). As recommended by IS 4031: 1988 [7], the amount of water used in the mortar (W) was obtained by using Equation
1
. ...
An Experimental Study on Strength Loss of Nepalese Ordinary Portland Cements with Storage Time
Article
Full-text available
Nov 2019
<here is a image 72190d4496a65912-bfb3aaafbb6875ba> Naresh Prasad Dangol
<here is a image 3d8b5edc1d8b1364-56c9033df5614dfc> Rajendra Prasad Bohara
<here is a image 83f08116d86153f8-577879016b1901d8> Sujan Tripathi
<here is a image fe1a1ad65e0506ab-db353a78add8cb68> Santosh Kumar Shrestha
A cement bag undergoes different storage and climatic conditions before its use in the construction site. A long storage-time of the cement causes adverse effects on its strength. Therefore, the variation of the strength of the cement with storage time is required to be investigated. This paper aims to study the strength variation of three randomly selected Nepalese Ordinary Portland Cements (OPCs) with increasing storage time. The appropriate age of the OPCs for general concrete works is determined experimentally. A series of mortar cubes made of the OPCs of different ages were tested under a compressive load. The 3-day, 7-day and 28-day compressive strengths of the mortar cubes were tested using a universal testing machine. Based on the test results, strength development of different types of cement and strength loss with increasing storage time were scrutinized. The obtained results were compared with recommendations from Nepal Standard (NS). It was revealed that all the investigated OPCs satisfied the minimum strength requirements from NS. However, a variation in the strength loss was exhibited by the cements. The examined cements showed an average strength loss of 17.71% (in the range of 16.28% to 18.91%) in 14 weeks. All of the investigated cements are suitable for the normal concrete construction works within 14 weeks after being manufactured.
... Czynniki te sprawiają, że kierunki rozwoju technologii spoiw są nieco odmienne w różnych strefach geograficznych, a nawet w krajach o różnych strukturach gospodarki. Poszukiwania nowych, zrównoważonych spoiw
[18]
powinny obejmować kompleksową analizę racjonalności ich stosowania, uwzględniającą nie tylko podstawowe surowce, ale także używane w relatywnie małych ilościach, lecz niezbędne, składniki drugorzędne, których charakterystyki ekologiczne należy również uwzględnić w całkowitym bilansie w odniesieniu do produktu końcowego. I tak na przykład: zastąpienie klinkieru w cemencie materiałem odpadowym w bilansie łącznym prowadzi do obniżenia śladu węglowego spoiwa, ale już użycie tego samego materiału odpadowego w spoiwie geopolimerowym, w którym konieczny jest alkaliczny aktywator, może zasadniczo zmienić pogląd na rolę odpadu w tworzeniu spoiwa zrównoważonego. ...
... Potencjał przydatności materiałów mineralnych różnego pochodzenia, jako surowców do wytwarzania geopolimerów powinien być oceniany na podstawie złożonych badań, obejmujących między innymi: -fluorescencję rentgenowską (XRF), do elementarnej analizy ilościowej służącej określeniu czy materiał zawiera wystarczające ilości Si i al, -dyfraktometrię rentgenowską (XRD), do identyfikacji krzemowych i glinowych faz mineralnych, decydujących o reaktywności składników, Vinai i inni
[18]
zaproponowali ogólną procedurę, która pozwala oszacować potencjał aplikacyjny surowców mineralnych do wytwarzania geopolimerów (rys. 3). ...
Kierunki rozwoju spoiw mineralnych - geopolimerowe kompozyty budowlane
Article
Mar 2018
<here is a image 84d4a11d0becc9e7-318aa8aaab1b9e44> Grzegorz Adamczewski
... Other major bands were attributed to the stretching (approximately 3,450 cm −1 ) and bending (approximately 1,650 cm −1 ) vibration of absorbed H 2 O [12]. Some studies pointed out that the bands at approximately 600-450 cm −1 were due to Si-O-Si, Al-O-Si, and O-Si-O bending vibrations [26,
27]
. Figure 2B illustrates the FTIR transmittance spectra of GSC after curing for 1 day, 3 days, and 7 days. ...
Silty Clay Stabilization Using Metakaolin-Based Geopolymer Binder
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Shengnian Wang
Honglei Hui
Geopolymer binders are adjudged as the latest wave of sustainable alkali-activated materials for soil stabilization due to their excellent bonding properties. This study applied metakaolin as a precursor for synthesizing the geopolymer binder by employing the mixture of quicklime and sodium bicarbonate as an alkali activator. The optimal mass mixing ratio of the alkali activator, metakaolin, and silty clay was determined by unconfined compression tests. The stabilization mechanisms of the geopolymer binder were measured by x-ray diffraction and Fourier transform infrared spectroscopy. The microstructural characteristics of the geopolymer-stabilized silty clay were observed by scanning electron microscopy with an energy dispersive x-ray spectroscopy and mercury intrusion porosimetry test for understanding the strengthening mechanism of the silty clay after the treatment. Results indicate that the optimal mass mixing ratio of the alkali activator, metakaolin, and silty clay is 1:2:17, and the unconfined compressive strength of the geopolymer-stabilized silty clay reaches the maximum value of 0.85 MPa with adding 15 wt% of the geopolymer binder. Diffraction patterns show an insufficient polymerization of the geopolymer binder in the silty clay in the early days but a rapid synthesis of aluminosilicate gels after that. The new asymmetrical stretching vibration peaks signified the formation of aluminosilicate networks and are responsible for the strength improvement of the silty clay. Microstructural analyses further confirm the formation of aluminosilicate gels and their positive impacts on the structure of the silty clay over curing age.
... Until 2014, world production of cement has reached 4 billion tons, which accounted for 8% of total CO2 gas emissions. Half of the gas emissions are the result of combustion of fossil fuels, while the other half is due to calcination of limestone
[1]
. ...
Concrete Performance with Ground Granulated Blast Furnace Slag as Supplementary Cementitious Materials
<here is a image f10ec44702cac230-f3efcb83512c929c> Rizki A. T. Cahyani
Supplementary Cementitious Materials (SCMs) are materials that contribute to the hardened concrete properties through hydraulic or pozzolanic activities. The use of Ground Granulated Blast Furnace Slag (GGBFS) as SMCs or partial replacement of cementitious components in concrete provides benefits both in terms of economy and performance improvement. However, GGBFS is not widely known in Indonesia, hence the available research for this product is still limited. In this study, the performance of concrete with GGBFS as a partial replacement for cement was investigated, with the percentage of GGBFS varying by 0%, 30%, 50% and 70% of cement weight. The mechanical properties of concrete being observed are compressive strength and elastic modulus. Porosity testing is carried out to assess the durability aspect of concrete. Compressive tests are carried out when the concrete age reached 7, 28, 56 and 90 days to assess the strength development of GGBFS based concrete. From the study, it was found that GGBFS can replace cement up to a percentage of 50%, with its compressive strength comparable to conventional concrete. However, the addition of GGBFS in concrete mixes slowed the development of concrete compressive strength at early age. Concrete modulus of elasticity decreases with increasing GGBFS, but not significantly. The increasing percentage of GGBFS causes the pore volume to decrease, indicating the greater durability of GGBFS based concrete compared with the conventional one.
... compressive strength, thermal properties, durability). Results were successful as SUS-CON binder-based products showed properties equal or even superior to OPC-based products (
Vinai et al. 2015
). ...
Towards Greener Concrete: The Challenges of SUS-CON Project
Portland cement production is an energy-intensive process responsible for a significant share of the total CO2 production. Its replacement with low carbon binders from by-products of industrial processes is a sustainable alternative for innovative construction materials. In addition, the combination of low carbon binders with recycled aggregates results in a more sustainable concrete, also contributing to reduce waste amounts sent to landfills or incinerators. SUS-CON (SUStainable, innovative and energy-efficient CONcrete, based on the integration of all-waste materials) project (Funded by EC under FP7 (call EeB-NMP.2011-1/3, grant agreement no. 285463).), aimed at developing new concepts and technologies to integrate secondary raw materials in the concrete production cycle, resulting in cost-effective, lightweight and insulating concretes with reduced embodied energy and CO2 footprint. This paper presents a comprehensive overview of the technical work carried out during the Project. The work was structured in three major phases: 1. material research, leading to set-up and assess eco-sustainable concretes with recycled aggregates (e.g. waste polyurethane foams, mixed plastic scraps, end-of-life tyres and plastics from electrical and electronic equipment) and low carbon alkali activated binders (e.g. pulverized fly ash from power stations and blast furnace slags from steel plants); 2. industrial implementation, validating the developed technologies in industrially relevant environment through pre-cast components and ready-mixed concrete production and pilot buildings construction; 3. industrial uptake, creating the bases for transferring results and methodologies by environmental and economical assessments (LCA, LCC, HSE) and certification issues. Mechanical, insulation and fire resistance properties of SUS-CON components were tested; energy efficiency performances of SUS-CON pilot buildings were also monitored.
Oxidation of Aldehydes to Carboxylic Acids over Geopolymer Supported CuO
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Swayam PRABHA Misra
Potential of Portland pozzolana cement in the stabilization of an expansive soil subjected to alternate cycles of wetting and drying
<here is a image 10892d05cf0328b2-ebfa75b6e3649dd7> Jijo James
Anupriya Natesan
Aswini Manohar
Vishvaa Subramanian
Cement/lime stabilization of soils is one of the common techniques adopted for improving its geotechnical properties. Lately, the focus of investigation has shifted to blended stabilization with industrial wastes as auxiliary additives. However, the role of blended cement in stabilization of soil has been studied insufficiently despite the fact that it is manufactured under controlled conditions. This investigation deals with the use of Portland pozzolana cement (PPC) instead of ordinary Portland cement (OPC) in the stabilization of an expansive soil subjected to alternate cycles of wetting and drying. Unconfined compression strength (UCS) test specimens of dimensions 38mm x 76mm were cast and cured for periods of 7, 14 and 21 days. Then, the specimens were subjected to 1, 2 and 3 cycles of wetting and drying and the UCS of the specimens were determined. Based on the results of the investigation, it was found that OPC performed significantly better than PPC under normal conditions. However, under conditions of wetting and drying, PPC stabilized soil performed much better than OPC stabilized soil when sufficient binder content was available.
Sustainable concrete: Design and testing
Producing concrete with secondary raw materials is an excellent way to contribute to a more sustainable world, provided that this concrete has at least the same performance during its service life as concrete made with the primary raw materials it replaces. Secondary raw materials for Light Weight (LW) aggregates (rigid polyurethane foams, shredded tire rubber and mixed plastic scraps) have been combined with secondary raw materials for the binder (fly ash, slag and perlite tailings) making sustainable concretes that were investigated for their suitability as LW, highly insulating concrete for four different types of applications. Compliance to desired engineering properties (workability, setting time) was not always feasible: it was mostly the low workability of the mixtures that limited their application. Contrary to well established cements, steering the workability by adding water was not an option for these binders that rely on alkali-activation. Eight successful mixtures have been tested further. The results have shown that it is possible to produce a non-structural sustainable concrete with good mechanical and thermal insulation properties. Design of concrete made with novel materials is currently not feasible without extensive experimentation as no design rules exist other than empirically derived rules based on traditional materials. As a radical different approach, a flexible concrete mix design has been developed with which the concrete can be modelled in the fresh and hardened state. The numerical concrete mix design method proves a promising tool in designing concrete for performance demands such as elasticity parameters and thermal conductivity.
The Role of Water Content and Paste Proportion on Physico-mechanical Properties of Alkali Activated Fly Ash–Ggbs Concrete
The growth of the construction industry worldwide poses a serious concern on the sustainability of the building material production chain, mainly due to the carbon emissions related to the production of Portland cement. On the other hand, valuable materials from waste streams, particularly from the metallurgical industry, are not used at their full potential. Alkali-activated concrete (AAC) has emerged in the last years as a promising alternative to traditional Portland cement-based concrete for some applications. However, despite showing remarkable strength and durability potential, its utilisation is not widespread, mainly due to the lack of broadly accepted standards for the selection of suitable mix recipes fulfilling design requirements, in particular workability, setting time and strength. In this paper, a contribution towards the design development of AAC synthesised from pulverised fuel ash (60 %) and ground granulated blast furnace slag (ggbs) (40 %) activated with a solution of sodium hydroxide and sodium silicate is proposed. Results from a first batch of mixes indicated that water content influences the setting time and that paste content is a key parameter for controlling strength development and workability. The investigation indicated that, for the given raw materials and activator compositions, a minimum water-to-solid (w/s) ratio of 0.37 was needed for an initial setting time of about 1 h. Further work with paste content in the range of 30–33 % determined the relationship between workability and strength development and w/s ratio and paste content. Strengths in the range of 50–60 MPa were achieved.
Valorisation of wastes by alkali-activation: Progress, Opportunities and pitfalls
Influence of Sodium Oxide on Properties of Fresh and Hardened Paste of Alkali-Activated Blast-Furnace Slag
| https://www.researchgate.net/publication/309088165_Sustainable_binders_for_concrete_A_structured_approach_from_waste_screening_to_binder_composition_development |
Weighing the Impact of Long-term Safety and Efficacy Data for Ibrutinib in the Treatment of CLL
Continued data for the first-generation BTK inhibitor have demonstrated its expanding utility amid a growing treatment arsenal.
BTK Inhibitors: In-Focus : Episode 1
Weighing the Impact of Long-term Safety and Efficacy Data for Ibrutinib in the Treatment of CLL
Targeted Oncology
Continued data for the first-generation BTK inhibitor have demonstrated its expanding utility amid a growing treatment arsenal.
In recent years, the treatment landscape for chronic lymphocytic leukemia (CLL) has been marked by a significant increase in agents that target various mechanisms of B-cell differentiation and growth. Among the most prominent of these mechanisms is Bruton tyrosine kinase (BTK), an essential component of the B-cell receptor (BCR) signaling pathway required for proliferation, differentiation, development, trafficking, chemotaxis, adhesion, and cell survival. 1Autophosphorylation of BTK on the BCR activates its kinase activity, which subsequently sets in motion a cascade of downstream effects. 2The absence or inhibition of BTK has been correlated with a high rate of apoptosis in various B-cell lineages. Malignant B cells, as in the setting of CLL, upregulate BTK expression, making BTK an actionable therapeutic target to initiate malignant B-cell death. 2,3
Ibrutinib, which covalently binds to the cysteine-481 moiety within the active site of the ATP-binding domain of BTK, is an oral, first-generation BTK inhibitor that was approved in 2014 for the treatment of CLL in patients who have received one prior therapy. Having since been evaluated for a variety of other applications in patients with CLL, ibrutinib is the first BTK inhibitors with FDA approvals for the first-line treatment of CLL as well as for patients with CLL who carry the deletion in chromosome 17 (del(17p)), a high-risk prognostic category. 4-7
The approval of ibrutinib in the first-line setting was based on findings of the phase 3 RESONATE-2 trial, an international, open-label, randomized study in which investigators compared ibrutinib to chlorambucil in patients with treatment-naive CLL or small lymphocytic lymphoma who were aged 65 years or older. Patients (N=269) were randomly assigned 1:1 to either ibrutinib (420 mg/d taken orally) or chlorambucil (administered on days 1 and 15 of a 28-day cycle for up to 12 cycles). The primary efficacy end point, as assessed by an independent review committee, was progression-free survival (PFS). Those in the ibrutinib arm experienced a significantly prolonged median PFS compared with those in the chlorambucil arm (not reached vs 18.9 months, respectively; HR for progression or death, 0.16; 95% CI, 0.09-0.28), with an estimated PFS rate at 24 months of 98% vs 85%, respectively. 8
Results published in a 5-year follow-up analysis of RESONATE-2 demonstrated that the significant treatment benefit of ibrutinib was sustainable through at least 60 months. Median PFS remained not reached in the ibrutinib arm and was 15 months in the chlorambucil arm (HR, 0.146; 95% CI, 0.098-0.218), with an estimated PFS rate at 60 months of 70% vs 12%, respectively. 9In addition, ibrutinib was associated with significantly improved PFS in a subgroup analysis of those with a high prognostic risk (defined as a TP53mutation, 11q mutation, and/or unmutated IGHV. These patients were nearly 92% less likely to experience disease progression or death compared with those who received chlorambucil (HR, 0.083; 95% CI, 0.047-0.145). 9This finding was particularly promising because of the treatment-induced mutations, which have been previously reported in the literature with shorter-term use of ibrutinib.10 Of note, new long-term safety and efficacy data from the RESONATE-2 are expected to be presented at an upcoming medical meeting.
More recently, data from patients with CLL bearing TP53aberrations or del(17p) who had received ibrutinib-based therapy in the first-line setting (n=89) were pooled from 4 different studies, and the findings were reported at the 62nd American Society of Hematology Annual Meeting and Exposition. The analysis revealed that PFS and overall survival at 4 years were 79% and 88%, respectively, which the investigators noted was highly promising for a population with historically poor outcomes. 11Median duration of ibrutinib-based treatment was 46 months, with 46% of patients remaining on ibrutinib therapy at the time of the analysis. Adverse events of grade 3 or higher noted over the 8-year time span across the 4 studies were infection (22%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%)—all of which are consistent with the safety profile observed in other clinical trials of ibrutinib. 12These results are indicative of sustained efficacy in those with del(17p) or TP53or mutations among patients treated with ibrutinib. 11
In consideration of the broader profile of ibrutinib since its initial United States Food and Drug Administration approval in 2014, the long-term safety and efficacy data coupled with study results showing its potential in specific patient populations suggest that the role of this agent is both flexible and evolving in the overall spectrum of CLL treatment.
References
Ibrutinib. Prescribing information. Pharmacyclics; 2020. Accessed April 1, 2021. https://www.imbruvica.com/files/prescribing-information.pdf
Li CJ, Jiang C, Liu Y, et al. Pleiotropic action of novel Bruton's tyrosine kinase inhibitor BGB-3111 in mantle cell lymphoma. Mol Cancer Ther . 2019;18(2):267-277. doi:10.1158/1535-7163.MCT-18-0478
Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol . 2019;26(2):e233-e240. doi:10.3747/co.26.4345
Lymphoma Research Foundation. Chronic lymphocytic leukemia/small lymphocytic lymphoma: FDA updates. Accessed April 2, 2021. https://lymphoma.org/aboutlymphoma/cll/cllfdaupdates/
Seiler T, Dreyling M.Bruton’s tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives. Expert Opin Investig Drugs . 2017;26(8):909-915. doi:10.1080/13543784.2017.1349097
Kim HO. Development of BTK inhibitors for the treatment of B-cell malignancies. Arch Pharm Res. 2019;42(2):171-181.doi:10.1007/s12272-019-01124-1
NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2021. Accessed April 2, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388
Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x
Woyach JA, Ruppert AS, Guinn D, et al. BTK C481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282
Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 mutation): a pooled analysis from 4 clinical trials. Blood. 2020;136 (suppl 1):23–24. doi:10.1182/blood-2020-134431.
Strati P, O’Brien SM. BTK inhibitors for the treatment of chronic lymphocytic leukemia. Oncol Times. 2019;41(17):1,6-8,29. doi:10.1097/01.COT.0000581600.17621.64
| https://www.targetedonc.com/view/weighing-the-impact-of-long-term-safety-and-efficacy-data-for-ibrutinib-in-the-treatment-of-cll |
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HAL API platform L'écologie politique : une idéologie de classes moyennes. Political ecology: a middle-class ideology Hubert Billemont ed4c3919883a622b3c0950eeaeaf3b7b education.gouv.fr 837355 185881-837355 Hubert Billemont ed4c3919883a622b3c0950eeaeaf3b7b education.gouv.fr 2007-01-02 15:28:03 2023-04-17 14:36:07 2007-01-02 19:20:54 2006-01-12 2007-01-02 contributor Hubert Billemont ed4c3919883a622b3c0950eeaeaf3b7b education.gouv.fr CCSD tel-00122490 https://theses.hal.science/tel-00122490 billemont:tel-00122490 Sociologie. Université d'Evry-Val d'Essonne, 2006. Français. <a target="_blank" href="https://www.theses.fr/">⟨NNT : ⟩</a> Sociologie. Université d'Evry-Val d'Essonne, 2006. Français. ⟨NNT : ⟩ Sciences de l'Homme et de la Société Université d'Evry-Val d'Essonne Archives ouvertes de la Sociologie SOCIOLOGIE Centre Pierre Naville L'écologie politique : une idéologie de classes moyennes. Political ecology: a middle-class ideology Hubert Billemont ed4c3919883a622b3c0950eeaeaf3b7b education.gouv.fr 837355 185881-837355 2006-01-12 Université d'Evry-Val d'Essonne Sciences de l'homme des politiques et du territoire Jean-Pierre Durand([email protected]) M. Louis Chauvel, Professeur de Sociologie à l'IEP Paris (Sciences Po) Mme Joëlle Deniot, Professeur de Sociologie à l'Université de Nantes M. Jean Pierre Durand, Professeur de Sociologie à l'Université d'Evry M. Guy Groux, Directeur de Recherche au CEVIPOF-CNRS (Sciences Po) M. Frederik Mispelblom, Professeur de Sociologie à l'Université d'Evry French intellectuals lifestyle class war ideology dominated sectors of the dominating class ecologism political ecology écologisme écologie politique intellectuels mode de vie lutte de classes nature idéologie fractions dominées de la classe dominante Humanities and Social Sciences/Sociology Theses Theses Theses
This thesis is devoted to the lifestyles and social and political representations of ecological militants and sympathisers in France. The analysis focuses on the semi-intellectual sectors of the salaried middle classes, which are overrepresented among ecologists. The main argument seeks to demonstrate that multiple attitudes and modes of thought conveyed by ecologists may be attributed to the ambivalent social positions of these subaltern intellectuals.
La thèse est consacrée aux modes de vie et aux représentations sociales et politiques des militants et sympathisants écologistes en France. L'analyse porte sur l'étude des fractions semi-intellectuelles de la classe moyenne salariée qui sont sur-représentées parmi les écologistes. Il s'agit de montrer que nombre d'attitudes et de schèmes de pensées véhiculées par les écologistes sont imputables aux positions sociales ambivalentes de cette catégorie sociale d'intellectuels subalternes. 073354953 199814071H Centre Pierre Naville CPN 1994-01-01 2019-12-31 UFR de Sciences de l'Homme et de la Société 2 rue du Facteur Cheval 91000 EVRY http://cpn.univ-evry.fr/ https://ror.org/00e96v939 Université d'Évry-Val-d'Essonne UEVE 1991-07-22 Boulevard François Mitterrand 91025 Evry Cedex http://www.univ-evry.fr
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Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study - Full Text View - ClinicalTrials.gov
Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04115072 Recruitment Status :
Completed First Posted : October 3, 2019 Last Update Posted : May 18, 2020
Sponsor:
Charite University, Berlin, Germany
Leiden University Medical Center
Nagasaki University
Umeå University
Merck Serono International SA
Ministry of Health, Madagascar
Information provided by (Responsible Party):
Vendsyssel Hospital
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
Female genital schistosomiasis (FGS) is a frequent manifestation of the infection with Schistosoma haematobium or mansoni. FGS is probably the most neglected gynaecological condition in the tropics.
Inflammation of genital tissue persists as long as adult worms are present in the circulation, and new eggs are released. Hence, lesions can only heal if the inflammation is abated and a normal immune response is restored
A randomized controlled study will be carried out to compare the efficacy of the standard treatment with that of five repeated doses of praziquantel.
Outcome measure is the disappearance/regression of clinical pathology at the cervix, in the vagina/vulva.
Detailed Description:
Female genital schistosomiasis (FGS) is a frequent manifestation of the infection with Schistosoma haematobium or mansoni. It occurs in women of all age groups, including young girls and is associated with important, frequently debilitating and stigmatizing morbidity. It may develop into a life-threatening condition. FGS is probably the most neglected gynaecological condition in the tropics.
Depending on where eggs are released the clinical pathology develops in vulva and vagina, cervix, uterus, Fallopian tubes and the ovaries. All genital organs may be affected simultaneously. Women with FGS report spontaneous, or post-coital bleeding, vaginal discharge, pain during sexual intercourse, pelvic pain, irregular menstruation and infertility. Vaginal discharge and itching, pain during sexual intercourse, spontaneous + post-coital bleeding, as well as menstruation abnormalities are attributed by the women to STIs. This results in shame, mental strain and distress, eventually causes stigmatization and social exclusion leading to an impaired life quality.
Clinical, histopathological, immunological and epidemiological evidence suggests that there is a cause-effect relationship between FGS and HIV infection. There are hints of a cause effect relationship between FGS and HPV. The association of FGS with HIV /HPV infection underlines the pivotal importance for an effective treatment of FGS.
Clinical pathology is the result of a complex inflammatory response to antigens released by adult worms and viable eggs. The inflammation of genital tissue persists as long as adult worms are present in the circulation, and new eggs are released and become trapped. Hence, lesions can only heal if the inflammation is abated and a normal immune response is restored. This means that all worms have to be eliminated and reinfection has to be prevented for some time to allow complete healing of genital organs.
Based on this rationale, five doses of praziquantel will be given over a period of 10 weeks to ensure that all existing worms will be eliminated. The first three doses aim to kill all adult worms. The fourth dose will kill schistosomula which will mature in the following weeks. The last dose will prevent women from re-infection.
A randomized controlled study will be carried out to compare the efficacy of the standard treatment with that of repeated doses of praziquantel. Since a placebo is not available, the study will not be blinded. Outcome measure is the disappearance/regression of clinical pathology at the cervix, in the vagina/vulva.
The result of this study has important implications for the sexual health of millions of women in sub-Saharan Africa.
The aim of the study is to compare standard treatment of schistosomiasis as recommended by WHO (a single dose of praziquantel 40 mg/kg)- with a treatment based on a new rationale: five doses of praziquantel 40 mg/kg
1 x 40 mg/kg after enrollment in the study (D1, H0) plus two single doses (40 mg/kg) after 12 and 24 hours after the first treatment
1 x 40 mg/kg five weeks following the 1st PZQ treatment
1 x 40 mg/kg ten weeks following the 1st PZQ treatment
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 116 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: Treatment of Female Genital Schistosomiasis (FGS) With Praziquantel: A Proof-of-Concept Study Actual Study Start Date : September 3, 2019 Actual Primary Completion Date : February 21, 2020 Actual Study Completion Date : February 21, 2020
Resource links provided by the National Library of Medicine
Drug Information available for: Praziquantel
Genetic and Rare Diseases Information Center resources: Schistosomiasis Helminthiasis
U.S. FDA Resources
Arm Intervention/treatment Active Comparator: A - Single dose og PZQ Single dose of Praziquantel 40 mg/kg Standard treatment of schistosomiasis as recommended by WHO Drug: Praziquantel 600Mg Oral Tablet x 1 Single dose of Praziquantel 40 mg/kg Other Name: PZQ Experimental: B - Five doses of PZQFive doses of Praziquantel1 x 40 mg/kg Praziquantel after enrollment in the study plus two single doses (40 mg/kg) after 12 and 24 hours after the first treatment1 x 40 mg/kg Praziquantel five weeks following the 1st dose1 x 40 mg/kg Praziquantel ten weeks following the 1st dose Drug: Praziquantel 600Mg Oral Tablet x 5 Five doses of Praziquantel 40 mg/kg Other Name: PZQ
Outcome Measures
Primary Outcome Measures
:
Pathognomonic sign(s) in the cervix [ Time Frame: 15 weeks ]
Changes is quantitatively measured by the comparison of the number of sectors of the cervix affected by a pathognomonic sign before treatment and at the end of the study.
Secondary Outcome Measures
:
Gynaecological complaint score [ Time Frame: 15 weeks ]
Gynaecologial symptoms assessed by a questionnaire (Lower abdominal pain, Itching of vagina/vulva, Vaginal discharge with a strange odor, Pain/abnormal sensation during sexual intercourse, Bleeding after sexual intercourse, Abnormal sensation when touching vulva/vagina, Spontaneous bleeding (outside menstruation), Irregular menstruation, Infertility (primary or secondary) after two years without contraception, Pain during micturition, Blood in urine outside menstruation).
Vaginal Schistosome DNA [ Time Frame: 15 weeks ]
Concentration of schistosome DNA in vaginal fluid
Vaginal Pro-inflammatory Th2-dependent cytokines /chemokines [ Time Frame: 15 weeks ]
Concentration of selected pro-inflammatory Th2-dependent cytokines /chemokines in vaginal fluid
Vaginal ECP [ Time Frame: 15 weeks ]
Eosinophilic cationic protein (ECP) in vaginal lavage fluid
Cytobrush Schistosome DNA [ Time Frame: 15 weeks ]
Concentration of schistosome DNA in cytobrush material from vagina
Eligibility Criteria
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 15 Years to 35 Years (Child, Adult) Sexes Eligible for Study: Female Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:
Women 15 to 35 years of age with a gynaecological/urinary/lower abdominal complaint
The woman has signed the informed consent form (IFC); in the case of minors, the IFC has to be signed by parent or guardian.
The woman does not plan to leave the area within 6 months and accept to come to the CSB regularly following the scheduled follow-up (at week 5,10 and 15).
The woman with confirmed diagnosed of FGS (as described in section 6.3.1)
The woman agrees to be examined clinically and gynaecologically including taking specimens from the genital tract (collection of vaginal lavage fluid, collection of cells with a cytobrush).
The woman agrees to provide a urine and a stool sample.
The woman agrees that a venous blood sample for laboratory assessments is taken.
The woman accepts to stay at the hospital for 2 days follow-up after the first dose of PZQ.
Exclusion Criteria:
Virgin (assessed by gynaecologist)
Pregnancy (determined by pregnancy test)
Tumor of vulva, vagina, uterus (diagnosed by gynaecologist)
Treatment with praziquantel during the last 3 months
Hysterectomy
Known HIV positive prior to enrollment
Any severe medical condition requiring hospitalization
The woman is unable to comprehend the nature and objectives of the study
The woman is judged by the investigators to be unlikely to participate regularly in the follow-up
The woman is taking any drug that might affect the metabolism of PZQ and that is contraindicated the last two weeks before the enrollment. These drugs are as follows: rifampin; phenytoin, carbamazepine, phenobarbital; dexamethasone;
The woman is taking a drug which decreases the activity of praziquantel metabolizing enzymes (P450 inhibitors) the last two weeks before the enrollment, for example cimetidine, ketoconazole, itraconazole, erythromycin.
All contraindications to Praziquantel
Layout table for location information Madagascar K'Olo Vanona Ambanja, Diana, Madagascar, 203
Leiden University Medical Center
Nagasaki University
Umeå University
Merck Serono International SA
Ministry of Health, Madagascar
Investigators
Layout table for investigator information Study Director: Peter Leutscher, PhD Centre for Clinical Research, North Denmark Regional Hospital, Denmark Principal Investigator: Bodo S Randrianasolo, MD K'OLO VANONA; Antananarivo, Madagascar
Schuster A, Randrianasolo BS, Rabozakandraina OO, Ramarokoto CE, Bronnum D, Feldmeier H. Knowledge, experiences, and practices of women affected by female genital schistosomiasis in rural Madagascar: A qualitative study on disease perception, health impairment and social impact. PLoS Negl Trop Dis. 2022 Nov 7;16(11):e0010901. doi: 10.1371/journal.pntd.0010901. eCollection 2022 Nov.
Arenholt LTS, Aaroe KK, Norderud K, Lumholdt M, Randrianasolo BS, Ramarokoto CE, Rabozakandraina O, Broennum D, Feldmeier H, Leutscher PDC. Cervical lesion proportion measure using a digital gridded imaging technique to assess cervical pathology in women with genital schistosomiasis. PLoS Negl Trop Dis. 2022 Jul 5;16(7):e0009995. doi: 10.1371/journal.pntd.0009995. eCollection 2022 Jul.
Layout table for additonal information Responsible Party: Vendsyssel Hospital ClinicalTrials.gov Identifier: NCT04115072 History of Changes Other Study ID Numbers: RHN_PCL_01 First Posted: October 3, 2019 Key Record Dates Last Update Posted: May 18, 2020 Last Verified: May 2020 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: No
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Vendsyssel Hospital:
Schistosomiasis Praziquantel Gynaecology Female
For Study Record Managers
| https://clinicaltrials.gov/ct2/show/study/NCT04115072 |
Example usage for java.io BufferedWriter write
Example usage for java.io BufferedWriter write
List of usage examples for java.io BufferedWriter write
Introduction
In this page you can find the example usage for java.io BufferedWriter write.
Prototype
public void write( int c) throws IOException
Source Link
Document
Writes a single character.
Usage
From source file:
edu.iu.kmeans.regroupallgather.KMUtil.java
/**
* Generate centroids and upload to the cDir
* / * f r o m w w w . j a v a 2 s . c o m * / * @param numCentroids
* @param vectorSize
* @param configuration
* @param random
* @param cenDir
* @param fs
* @throws IOException
*/ static void generateCentroids( int numCentroids, int vectorSize, Configuration configuration, Path cenDir, FileSystem fs) throws IOException { Random random = new Random (); double [] data = null; if (fs.exists(cenDir))
fs.delete(cenDir, true); if (!fs.mkdirs(cenDir)) { throw new IOException ( "Mkdirs failed to create " + cenDir.toString());
}
data = new double [numCentroids * vectorSize]; for ( int i = 0; i < data.length; i++) { // data[i] = 1000; data[i] = random.nextDouble() * 1000;
} Path initClustersFile = new Path (cenDir, Constants.CENTROID_FILE_NAME); System .out.println( "Generate centroid data." + initClustersFile.toString());
FSDataOutputStream out = fs.create(initClustersFile, true); BufferedWriter bw = new BufferedWriter ( new OutputStreamWriter (out)); for ( int i = 0; i < data.length; i++) { if ((i % vectorSize) == (vectorSize - 1)) { bw.write(data[i] + "" ); bw.newLine();
} else {
bw.write(data[i] + " " );
}
}
bw.flush();
bw.close(); System .out.println( "Wrote centroids data to file" );
}
From source file:
com.vmware.identity.interop.PlatformUtils.java
private static boolean renameFileOnWindows( File oldFile, File newFile) { String sCurrentLine = "" ; try { / * f r o m w w w . j a v a 2 s . c o m * / BufferedReader bufReader = new BufferedReader ( new FileReader (oldFile.getAbsoluteFile())); BufferedWriter bufWriter = new BufferedWriter ( new FileWriter (newFile.getAbsoluteFile())); while ((sCurrentLine = bufReader.readLine()) != null) { bufWriter.write(sCurrentLine); bufWriter.newLine();
}
bufReader.close();
bufWriter.close();
oldFile.delete(); return true;
} catch ( Exception e) { return false;
}
}
From source file:
com.sciaps.utils.Util.java
public static void saveCSVFile( StringBuilder strBuilder) { JFileChooser chooser = new JFileChooser (); int retrival = chooser.showSaveDialog(Constants.MAIN_FRAME); if (retrival == JFileChooser .APPROVE_OPTION) {
ProgressStatusPanel progressbar = new ProgressStatusPanel(); final CustomDialog progressDialog = new CustomDialog(Constants.MAIN_FRAME, "Exporting CSV file" ,
progressbar, CustomDialog.NONE_OPTION);
progressDialog.setSize(400, 100); SwingUtilities .invokeLater( new Runnable () {
@ Override / / f r o m w w w . j a v a 2 s . c o m public void run() {
progressDialog.setVisible(true);
}
}); try { String fileName = chooser.getSelectedFile().toString(); if (!fileName.endsWith( ".csv" ) && !fileName.endsWith( ".CSV" )) {
fileName = fileName + ".csv" ;
} FileWriter fw = new FileWriter (fileName); BufferedWriter bw = new BufferedWriter (fw); bw.write(strBuilder.toString()); bw.close();
} catch ( Exception ex) {
ex.printStackTrace(); System .out.println(ex.getMessage());
}
progressDialog.dispose();
}
}
From source file:
com.example.makerecg.NetworkUtilities.java
/**
* Perform 2-way sync with the server-side ADSampleFrames. We send a request that
* includes all the locally-dirty contacts so that the server can process
* those changes, and we receive (and return) a list of contacts that were
* updated on the server-side that need to be updated locally.
*
* @param account The account being synced
* @param authtoken The authtoken stored in the AccountManager for this
* account / * f r o m w w w . j a v a 2 s . c o m * / * @param serverSyncState A token returned from the server on the last sync
* @param dirtyFrames A list of the frames to send to the server
* @return A list of frames that we need to update locally
*/ public static List <ADSampleFrame> syncSampleFrames(Account account, String authtoken, long serverSyncState, List <ADSampleFrame> dirtyFrames) throws JSONException, ParseException , IOException , AuthenticationException { List <JSONObject> jsonFrames = new ArrayList <JSONObject>(); for (ADSampleFrame frame : dirtyFrames) {
jsonFrames.add(frame.toJSONObject());
}
JSONArray buffer = new JSONArray(jsonFrames);
JSONObject top = new JSONObject();
top.put( "data" , buffer); // Create an array that will hold the server-side ADSampleFrame // that have been changed (returned by the server). final ArrayList <ADSampleFrame> serverDirtyList = new ArrayList <ADSampleFrame>(); // Send the updated frames data to the server //Log.i(TAG, "Syncing to: " + SYNC_URI); URL urlToRequest = new URL (SYNC_ URI ); HttpURLConnection conn = ( HttpURLConnection ) urlToRequest.openConnection();
conn.setDoOutput(true);
conn.setDoInput(true);
conn.setRequestMethod( "POST" );
conn.setRequestProperty( "Content-Type" , "application/json" );
conn.setRequestProperty( "Authorization" , "Bearer " + authtoken); OutputStream os = conn.getOutputStream(); BufferedWriter writer = new BufferedWriter ( new OutputStreamWriter (os, "UTF-8" )); writer.write(top.toString(1)); writer.flush();
writer.close();
os.close(); //Log.i(TAG, "body="+top.toString(1)); int responseCode = conn.getResponseCode(); if (responseCode == HttpsURLConnection .HTTP_OK) { // Our request to the server was successful - so we assume // that they accepted all the changes we sent up, and // that the response includes the contacts that we need // to update on our side... // TODO: Only uploading data for now ... String response = "" ; String line; BufferedReader br = new BufferedReader ( new InputStreamReader (conn.getInputStream())); while ((line = br.readLine()) != null) {
response += line;
}
br.close(); //Log.i(TAG, "response="+response); /*
final JSONArray serverContacts = new JSONArray(response);
Log.d(TAG, response);
for (int i = 0; i < serverContacts.length(); i++) {
ADSampleFrame rawContact = ADSampleFrame.valueOf(serverContacts.getJSONObject(i));
if (rawContact != null) {
serverDirtyList.add(rawContact);
}
}
*/ } else { if (responseCode == HttpsURLConnection .HTTP_UNAUTHORIZED) {
Log.e(TAG, "Authentication exception in while uploading data" ); throw new AuthenticationException ();
} else {
Log.e(TAG, "Server error in sending sample frames: " + responseCode); throw new IOException ();
}
} return null;
}
From source file:
ProxyAuthTest.java
private static void generateData() throws Exception { String fileData[] = { "1|aaa" , "2|bbb" , "3|ccc" , "4|ddd" , "5|eee" , }; File tmpFile = File .createTempFile(tabName, ".data" );
tmpFile.deleteOnExit(); / / f r o m w w w . j a v a 2 s . c o m tabDataFileName = tmpFile.getPath(); FileWriter fstream = new FileWriter (tabDataFileName); BufferedWriter out = new BufferedWriter (fstream); for ( String line : fileData) { out.write(line); out.newLine();
}
out.close();
tmpFile.setWritable(true, true);
}
From source file:
net.arccotangent.pacchat.net.Client.java
public static void sendMessage( String msg, String ip_address) {
client_log.i( "Sending message to " + ip_address);
client_log.i( "Connecting to server..." ); PublicKey pub; / / w w w . j a v a 2 s . c o m PrivateKey priv; Socket socket; BufferedReader input; BufferedWriter output;
client_log.i( "Checking for recipient's public key..." ); if ( KeyManager .checkIfIPKeyExists(ip_address)) {
client_log.i( "Public key found." );
} else {
client_log.i( "Public key not found, requesting key from their server." ); try { Socket socketGetkey = new Socket ();
socketGetkey.connect( new InetSocketAddress ( InetAddress .getByName(ip_address), Server.PORT), 1000); BufferedReader inputGetkey = new BufferedReader ( new InputStreamReader (socketGetkey.getInputStream())); BufferedWriter outputGetkey = new BufferedWriter ( new OutputStreamWriter (socketGetkey.getOutputStream())); outputGetkey.write( "301 getkey" ); outputGetkey.newLine();
outputGetkey.flush(); String pubkeyB64 = inputGetkey.readLine(); byte [] pubEncoded = Base64.decodeBase64(pubkeyB64);
X509 EncodedKeySpec pubSpec = new X509 EncodedKeySpec (pubEncoded); KeyFactory keyFactory = KeyFactory .getInstance( "RSA" );
outputGetkey.close();
inputGetkey.close(); KeyManager .saveKeyByIP(ip_address, keyFactory.generatePublic(pubSpec));
} catch ( IOException | NoSuchAlgorithmException | InvalidKeySpecException e) {
client_log.e( "Error saving recipient's key!" );
e.printStackTrace();
}
} try {
socket = new Socket ();
socket.connect( new InetSocketAddress ( InetAddress .getByName(ip_address), Server.PORT), 1000);
input = new BufferedReader ( new InputStreamReader (socket.getInputStream()));
output = new BufferedWriter ( new OutputStreamWriter (socket.getOutputStream()));
} catch ( SocketTimeoutException e) {
client_log.e( "Connection to server timed out!" );
e.printStackTrace(); return ;
} catch ( ConnectException e) {
client_log.e( "Connection to server was refused!" );
e.printStackTrace(); return ;
} catch ( UnknownHostException e) {
client_log.e( "You entered an invalid IP address!" );
e.printStackTrace(); return ;
} catch ( IOException e) {
client_log.e( "Error connecting to server!" );
e.printStackTrace(); return ;
} try { Thread .sleep(100);
} catch ( InterruptedException e) {
e.printStackTrace();
}
pub = KeyManager .loadKeyByIP(ip_address);
priv = Main.getKeypair().getPrivate(); String cryptedMsg = MsgCrypto.encryptAndSignMessage(msg, pub, priv); try {
client_log.i( "Sending message to recipient." );
output.write( "200 encrypted message" );
output.newLine();
output.write(cryptedMsg);
output.newLine();
output.flush(); String ack = input.readLine(); switch (ack) { case "201 message acknowledgement" :
client_log.i( "Transmission successful, received server acknowledgement." ); break ; case "202 unable to decrypt" :
client_log.e( "Transmission failure! Server reports that the message could not be decrypted. Did your keys change? Asking recipient for key update." );
kuc_id++;
KeyUpdateClient kuc = new KeyUpdateClient(kuc_id, ip_address);
kuc.start(); break ; case "203 unable to verify" :
client_log.w( "**********************************************" );
client_log.w( "Transmission successful, but the receiving server reports that the authenticity of the message could not be verified!" );
client_log.w( "Someone may be tampering with your connection! This is an unlikely, but not impossible scenario!" );
client_log.w( "If you are sure the connection was not tampered with, consider requesting a key update." );
client_log.w( "**********************************************" ); break ; case "400 invalid transmission header" :
client_log.e( "Transmission failure! Server reports that the message is invalid. Try updating your software and have the recipient do the same. If this does not fix the problem, report the error to developers." ); break ; default :
client_log.w( "Server responded with unexpected code: " + ack);
client_log.w( "Transmission might not have been successful." ); break ;
}
output.close();
input.close();
} catch ( IOException e) {
client_log.e( "Error sending message to recipient!" );
e.printStackTrace();
}
}
From source file:
com.orange.atk.results.logger.documentGenerator.GraphGenerator.java
/**
* Save the data of a plot list into a file. A divisor value coould be apply
* to X, ie values would be dived by Xdivisor value are
* stored on each line as :<br/> (x_i-x_0)/Xdivisor \t y <br/>
* format, the first value is shifted to 0.
* / * f r o m w w w . j a v a 2 s . c o m * / * @param plotList
* plot list to save
* @param fileName
* file name where plot list would be saved
* @param Xdivisor
* divisor for the X axis
* @param Ydivisor
* divisor for the Y axis
* @throws ArrayIndexOutOfBoundsException
* @throws IOException
*/ public static void dumpInFile(PlotList plotList, String fileName) throws ArrayIndexOutOfBoundsException , IOException { int iXListSize = plotList.getSize(); if (iXListSize > 0) { // get the first value to translate the x scale // x rep SimpleDateFormat spf = new SimpleDateFormat ( "yyyy-MM-dd HH:mm:ss SSS" ); SimpleDateFormat year = new SimpleDateFormat ( "yyyy-MM-dd" ); SimpleDateFormat hour = new SimpleDateFormat ( "HH:mm:ss" ); SimpleDateFormat ms = new SimpleDateFormat ( "SSS" ); // double initialValue = ((Long) plotList.getX(0)).doubleValue(); File fichier = new File (fileName); BufferedWriter bufferedWriter = new BufferedWriter ( new OutputStreamWriter ( new FileOutputStream (fichier))); bufferedWriter.write( "# " + spf.format( new Date (plotList.getX(0))) + "-" + Platform.LINE_SEP); bufferedWriter.write( "# yyyy-MM-dd, HH:mm:ss:SSS,value" + Platform.LINE_SEP); for ( int i = 0; i < iXListSize; i++) { // Logger.getLogger(this.getClass() ).debug(((plotList.getX(i)).floatValue()) + " - " // + initialValue); long xval = ((( Long ) plotList.getX(i))); float yval = plotList.getY(i).floatValue();
bufferedWriter.write(year.format( new Date (xval)) + ", " + hour.format( new Date (xval)) + ":" + ms.format( new Date (xval)) + "," + yval + Platform.LINE_SEP); // Logger.getLogger(this.getClass() ).debug(xval + "\t" + yval ); }
bufferedWriter.close();
}
}
From source file:
com.dc.util.file.FileSupport.java
public static void appendToFile( File file, String data) throws IOException { FileWriter fileWriter = null; BufferedWriter bufferedWriter = null; try { / * f r o m w w w . j a v a 2 s . c o m * / fileWriter = new FileWriter (file, true);
bufferedWriter = new BufferedWriter (fileWriter); bufferedWriter.write(data); bufferedWriter.flush();
} finally { if (fileWriter != null) {
fileWriter.close();
} if (bufferedWriter != null) {
bufferedWriter.close();
}
}
}
From source file:
com.dc.util.file.FileSupport.java
public static void writeTextFile( String folderPath, String fileName, String data, boolean isExecutable) throws IOException { File dir = new File (folderPath); if (!dir.exists()) {
dir.mkdirs(); / * f r o m w w w . j a v a 2 s . c o m * / } File file = new File (dir, fileName); FileWriter fileWriter = null; BufferedWriter bufferedWriter = null; try {
fileWriter = new FileWriter (file);
bufferedWriter = new BufferedWriter (fileWriter); bufferedWriter.write(data); bufferedWriter.flush(); if (isExecutable) {
file.setExecutable(true);
}
} finally { if (fileWriter != null) {
fileWriter.close();
} if (bufferedWriter != null) {
bufferedWriter.close();
}
}
}
From source file:
com.jaceace.utils.Bundle.java
public static boolean write(Bundle bundle, OutputStream stream) { try { / / f r o m w w w . j a v a 2 s . c o m BufferedWriter writer = new BufferedWriter ( new OutputStreamWriter (stream)); writer.write(bundle.data.toString()); writer.close(); return true;
} catch ( IOException e) { return false;
}
}
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| http://www.java2s.com/example/java-api/java/io/bufferedwriter/write-1-24.html |
U.S. Census Bureau QuickFacts: Telfair County, Georgia; United States; Dawson County, Georgia; Whitfield County, Georgia; Baldwin County, Georgia
Frequently requested statistics for: Telfair County, Georgia; United States; Dawson County, Georgia; Whitfield County, Georgia; Baldwin County, Georgia
U.S. Census Bureau QuickFacts: Telfair County, Georgia; United States; Dawson County, Georgia; Whitfield County, Georgia; Baldwin County, Georgia
Please note that new Connecticut county level geographies are not availabe within the map.
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Telfair County, Georgia; United States; Dawson County, Georgia; Whitfield County, Georgia; Baldwin County, Georgia
QuickFacts provides statistics for all states and counties, and for cities and towns with a
population of 5,000 or more
.
-- Select a fact -- Population Estimates, July 1, 2022, (V2022) Population estimates base, April 1, 2020, (V2022) Population, percent change - April 1, 2020 (estimates base) to July 1, 2022, (V2022) Population, Census, April 1, 2020 Population, Census, April 1, 2010 Persons under 5 years, percent Persons under 18 years, percent Persons 65 years and over, percent Female persons, percent White alone, percent Black or African American alone, percent (a) American Indian and Alaska Native alone, percent (a) Asian alone, percent (a) Native Hawaiian and Other Pacific Islander alone, percent (a) Two or More Races, percent Hispanic or Latino, percent (b) White alone, not Hispanic or Latino, percent Veterans, 2017-2021 Foreign born persons, percent, 2017-2021 Housing units, July 1, 2022, (V2022) Owner-occupied housing unit rate, 2017-2021 Median value of owner-occupied housing units, 2017-2021 Median selected monthly owner costs -with a mortgage, 2017-2021 Median selected monthly owner costs -without a mortgage, 2017-2021 Median gross rent, 2017-2021 Building permits, 2022 Households, 2017-2021 Persons per household, 2017-2021 Living in same house 1 year ago, percent of persons age 1 year+, 2017-2021 Language other than English spoken at home, percent of persons age 5 years+, 2017-2021 Households with a computer, percent, 2017-2021 Households with a broadband Internet subscription, percent, 2017-2021 High school graduate or higher, percent of persons age 25 years+, 2017-2021 Bachelor's degree or higher, percent of persons age 25 years+, 2017-2021 With a disability, under age 65 years, percent, 2017-2021 Persons without health insurance, under age 65 years, percent In civilian labor force, total, percent of population age 16 years+, 2017-2021 In civilian labor force, female, percent of population age 16 years+, 2017-2021 Total accommodation and food services sales, 2017 ($1,000) (c) Total health care and social assistance receipts/revenue, 2017 ($1,000) (c) Total transportation and warehousing receipts/revenue, 2017 ($1,000) (c) Total retail sales, 2017 ($1,000) (c) Total retail sales per capita, 2017 (c) Mean travel time to work (minutes), workers age 16 years+, 2017-2021 Median household income (in 2021 dollars), 2017-2021 Per capita income in past 12 months (in 2021 dollars), 2017-2021 Persons in poverty, percent Total employer establishments, 2021 Total employment, 2021 Total annual payroll, 2021 ($1,000) Total employment, percent change, 2020-2021 Total nonemployer establishments, 2019 All employer firms, Reference year 2017 Men-owned employer firms, Reference year 2017 Women-owned employer firms, Reference year 2017 Minority-owned employer firms, Reference year 2017 Nonminority-owned employer firms, Reference year 2017 Veteran-owned employer firms, Reference year 2017 Nonveteran-owned employer firms, Reference year 2017 Population per square mile, 2020 Population per square mile, 2010 Land area in square miles, 2020 Land area in square miles, 2010
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Table
Map
Telfair County, Georgia United States Dawson County, Georgia Whitfield County, Georgia Baldwin County, Georgia
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Population Estimates, July 1, 2022, (V2022)
- - - - -
Populations below 5,000 are not in QuickFacts and therefore Not Selectable
Selectable
Not Selectable
Value Notes
Estimates are not comparable to other geographic levels due to methodology differences that may exist between different data sources.
Some estimates presented here come from sample data, and thus have sampling errors that may render some apparent differences between geographies statistically indistinguishable. ]
Click the Quick Info
icon to the left of each row in TABLE view to learn about sampling error.
In Vintage 2022, as a result of the formal request from the state, Connecticut transitioned from eight counties to nine planning regions. For more details,
please see the Vintage 2022 release notes available here:
Release Notes.
The vintage year (e.g., V2022) refers to the final year of the series (2020 thru 2022). Different vintage years of estimates are not comparable.
Users should exercise caution when comparing 2017-2021 ACS 5-year estimates to other ACS estimates.
For more information, please visit the
2021 5-year ACS Comparison Guidance
page.
Fact Notes
(a) Includes persons reporting only one race
(c) Economic Census - Puerto Rico data are not comparable to U.S. Economic Census data
(b) Hispanics may be of any race, so also are included in applicable race categories
Value Flags
- Either no or too few sample observations were available to compute an estimate, or a ratio of medians cannot be calculated because one or both of the median estimates falls in the lowest or upper interval of an open ended distribution.
F Fewer than 25 firms
D Suppressed to avoid disclosure of confidential information
N Data for this geographic area cannot be displayed because the number of sample cases is too small.
FN Footnote on this item in place of data
X Not applicable
S Suppressed; does not meet publication standards
NA Not available
Z Value greater than zero but less than half unit of measure shown
QuickFacts data are derived from: Population Estimates, American Community Survey, Census of Population and Housing, Current Population Survey, Small Area Health Insurance Estimates, Small Area Income and Poverty Estimates, State and County Housing Unit Estimates, County Business Patterns, Nonemployer Statistics, Economic Census, Survey of Business Owners, Building Permits.
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NO THANKS SUBMIT | https://www.census.gov/quickfacts/fact/map/telfaircountygeorgia,US,dawsoncountygeorgia,whitfieldcountygeorgia,baldwincountygeorgia/PST045222 |
Med Lagen som Verktyg | Independent Living Institute
Med Lagen som Verktyg
Culture and Identity
McLaughlin, Dara
.
2001.
Culture and Identity.
<here is a image 7f938d3eaa78b648-ea439bf4e688ce01>
<here is a image 4480518bb6cf610b-c6cc48e18622d94e> Dara McLaughlin is a writer and visual artist. Her award winning poetry and stories have been published in literary magazines and anthologies. Her autobiographical poetry collection, A Map of This World, was released in 1999. Dara teaches poetry, coordinates writing workshops, and is an advocacy speaker for disability issues and education. Raised in New York, Dara moved to New Mexico six years ago,and works from her studio on a mesa overlooking The Rio Grande.
Barriers in the built environment: The problems of barrier removal in the Czech Republic
Maxa, Miloslav
.
1991.
Barriers in the built environment: The problems of barrier removal in the Czech Republic.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Contents
Barriers in the built environment: The problems of barrier removal in the Czech Republic
Miloslav Maxa., Czechoslovak Building Centre Prague, Czech Republic
Access legislation in the Czech Republic
Maxa, Miloslav
.
1991.
Access legislation in the Czech Republic.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Access legislation in the Czech Republic
Miloslav Maxa., Czechoslovak Building Centre Prague, Czech Republic
Contents
Self-Managed Versus Agency-Provided Personal Assistance Care for Individuals With High Level Tetraplegia
Mattson Prince, Jane,Manley Scott M, Whiteneck Gale G
.
1995.
Self-Managed Versus Agency-Provided Personal Assistance Care for Individuals With High Level Tetraplegia.
Research brief
Self-Managed Versus
Agency-Provided Personal Assistance Care
for Individuals With High Level Tetraplegia
by Jane Mattson Prince, PhD; M. Scott Manley, EdD; Gale G. Whiteneck, PhD, 1995
På svenska
Abstract
Mattson Prince J, Manley MS, Whiteneck GG.
Self-managed versus agency-provided assistance care for individuals with high level tetraplegia. Arch Phys Med Rehabil 1995; 76:919-23.
Objective
Adaptive Technology for the Internet: Making Electronic Resources Accessible to All - The Online Version
Mates, Barbara T
.
2000.
Adaptive Technology for the Internet: Making Electronic Resources Accessible to All - The Online Version.
This document is from 2000 and most of the links to external resources no longer work after 17 years. TheW3C Web Accessibility Initiative (WAI)andWebAIM (web accessibility in mind)are the place to find out more in 2017.
--Table of Contents--
Epigraph
Preface
Acknowledgments
Chapter 1
Could Helen Keller Use Your Library?
Chapter 2
Click (W)Here(?)—Basic Document Design
Chapter 3
Large-Print Access to the Internet
Chapter 4
Access legislation and enforcement mechanisms
Masutha, Michael
.
1992.
Access legislation and enforcement mechanisms.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Harare 1992
Access legislation and enforcement mechanisms in South Africa
Michael Masutha, DPSA, South Africa
Contents
Independent Living in the U.S. & Canada
Martinez, Kathy
.
2003.
Independent Living in the U.S. & Canada.
by Kathy Martinez, 2003,
edited by Barbara Duncan
Contents
1. Origins of the Movement (1970-1980)
1.1. Background
1.2. Summary of the Early Years of the IL Movement in the U.S. and Canada
Out of the Public Eye
Windows of Enlightenment
1.3. 20th Century Developments
Education as a Catapult into the Community
The African View of Independent Living
Malinga, Joshua T
.
2003.
The African View of Independent Living.
by Joshua T. Malinga, 2003,
Secretary General: Pan African Federation of the Disabled (PAFOD),
Past World Chairperson: Disabled Peoples' International (DPI).
Contents
1. Introduction
2. Independent Living Concept in Africa
2.1. Activities Leading to Independent Living
2.2. Political Participation as the Incipient Independent Living Movement
Ett problem eller en utmaning? Att anpassa offentliga byggnader för rörelsehindrade
Könkkölä, Maija
.
1994.
Ett problem eller en utmaning? Att anpassa offentliga byggnader för rörelsehindrade
FÖRORD
Rethinking Disability and Discrimination - A social and economic approach (Comparative Study)
Konczei, Gyorgy
.
1999.
Rethinking Disability and Discrimination - A social and economic approach (Comparative Study).
Essay Contest: Disabled High School Students Can Win an All Expences Paid Trip to Japan
International Convention for Disabled High School Students
.
2002.
Essay Contest: Disabled High School Students Can Win an All Expences Paid Trip to Japan.
Swedish disabled high school student Yasmin Jungestedt won an essay competition and a trip to Japan to take part in the 10th annual camp for high school students organized by the Japanese Independent Living Movement. Read her prize-winning essay, "How I, as elected Prime Minister, would change disability policy," and her account (link to anchor which sets browser at start of document) about the time she spent in Japan meeting other high school students with disabilities from Japan and around the world.
Below is information spread by the organizers at Mainstream before the 2002 event.
Perspectivas Globales Sobre Vida Independiente Para El Proximo Milenio. Washington, D.C. 21-25 de setiembre de 1999
Independent Living Research Utilization (ILRU) Program
.
1999.
Perspectivas Globales Sobre Vida Independiente Para El Proximo Milenio. Washington, D.C. 21-25 de setiembre de 1999.
Taxi för alla-projektets utvärdering - kvalitativ sammanfattning
.
2003.
Toward an Inclusive Definition of Disability
Imparato, Andrew J
.
1999.
Toward an Inclusive Definition of Disability.
As an attorney who has spent my career working to promote policies and laws that expand opportunities for the 54 million Americans with disabilities, I am deeply concerned that the U.S. Supreme Court totally missed the mark last week in three cases construing the definition of “disability” in the Americans with Disabilities Act (ADA). The Supreme Court has left me and millions of other Americans with significant mental or physical impairments unprotected against egregious discrimination.
Violence and Disabled Women
Iglesias, M,Gil G,Joneken A,Mickler B, Knudsen J S
.
1998.
Violence and Disabled Women.
by Iglesias, M.; Gil, G.; Joneken, A.; Mickler, B.; Knudsen,
J.S.,
METIS project, European Unión DAPHNE initiative, 1998
CONTENTS
INTRODUCTION
GENERAL ISSUES
Portrait
of a woman with disability
What
do we understand by violence?
Causes,
origins and consequences
Why
women?
Foreword to The Independent Living Movement: International Experiences
Heumann, Judith E
.
2003.
Foreword to The Independent Living Movement: International Experiences.
In 1949 when I had polio there was nothing resembling the Independent Living Movement. As was the case for disabled people across the US and throughout the world we were not seen as a individuals who could make contributions to our society. We were out of sight and out of mind. Few laws existed which made it illegal to discriminate against disabled people.
HELIOS II: Sammanfattning av undersökningen om service med personlig assistans i Europa. Beskrivning och utvärdering av den bästa servicen med personlig assistans i ditt land
HELIOS
.
1996.
HELIOS II: Sammanfattning av undersökningen om service med personlig assistans i Europa. Beskrivning och utvärdering av den bästa servicen med personlig assistans i ditt land.
Temagrupp nummer 5, Rapport 1996
In English
Innehållsförteckning
HELIOS II: Social Integration and Independent Living. The Elimination of Socio-psychological Barriers: Assistance in Daily Living
HELIOS
.
1996.
HELIOS II: Social Integration and Independent Living. The Elimination of Socio-psychological Barriers: Assistance in Daily Living.
Table of Contents
Policy Issues in Independent Living Rehabilitation
Galvin, Donald E
.
1980.
Policy Issues in Independent Living Rehabilitation.
by Donald E. Galvin, Ph.D., Director,
University Center for International Rehabilitation (UCIR), June 1980
This paper was presented at the 1980 World Congress of Rehabilitation International held in Winnipeg, Manitoba, Canada, June 22-27, 1980.
Independent Living Models
Frieden, Lex
.
1980.
Independent Living Models.
Frieden, Lex. 1980. "Independent Living Models." In: Rehabilitation Literature, Special Article, July-August, 1980, Vol 41, No. 7-8, pp. 169-173. A-289. Internet publication URL: www.independentliving.org/docs6/frieden1980.html.
by Lex Frieden**
Introduction
Att förneka eller acceptera funktionshinder
Finkelstein, Vic
.
1975.
Att förneka eller acceptera funktionshinder.
av Vic Finkelstein
In English
To Deny or Not to Deny Disability - What is disability?
Finkelstein, Vic
.
1975.
To Deny or Not to Deny Disability - What is disability?
by Vic Finkelstein
På svenska
The Disabled Consumer Movement: Policy Implications for Rehabilitation Service Provisions
Derksen, Jim
.
1980.
The Disabled Consumer Movement: Policy Implications for Rehabilitation Service Provisions.
Jim Derksen, Winnipeg, 1980
Contents
Abstract
Introduction
I. Service Provision and Ethics
1. Privately Funded Service Providers
A. The Volunteer/Charity Ethic
B. The Medical Ethic
Government Consults on Rail Accessibility - Press Notice: 372/ Transport
Department of the Environment, Transport and the Regions, UK
.
1998.
Government Consults on Rail Accessibility - Press Notice: 372/ Transport.
Date: 15 May 1998
Read the Disabled People's Direct Action Network (DAN) response to this Press Release
Trains and trams entering service after 31 December 1998 will be fully accessible to disabled people under plans set out today by Transport Minister, Glenda Jackson.
In a consultation document, the Government is seeking views on proposed regulations to ensure that the rail industry meets the needs of those with limited mobility under the provisions of the Disability Discrimination Act.
Commenting, Ms Jackson said:
About CIB, and Contents of Documents
CIB (International Council for Building Research)
.
1993.
Report of the Fifth International Expert Seminar on Building Non-Handicapping Environments: Access Legislation and Design Solutions, Harare, Zimbabwe, January 16-18, 1992
CIB (International Council for Building Research)
.
1992.
Report of the Fifth International Expert Seminar on Building Non-Handicapping Environments: Access Legislation and Design Solutions, Harare, Zimbabwe, January 16-18, 1992.
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Table of contents
Part I Presentation of Organizers
Report of the Third International Expert Seminar on Building Non-Handicapping Environments: Accessibility Issues in Developing Countries, Tokyo
CIB (International Council for Building Research)
.
1988.
Report of the Third International Expert Seminar on Building Non-Handicapping Environments: Accessibility Issues in Developing Countries, Tokyo.
<here is a image 021ecef52e8fd812-d2251ae09b8a84ac>
Table of contents
.
Report of the Second International Expert Seminar on Building Non-Handicapping Environments: Renewal of Inner Cities, Prague
CIB (International Council for Building Research)
.
1987.
Report of the Second International Expert Seminar on Building Non-Handicapping Environments: Renewal of Inner Cities, Prague.
<here is a image 021ecef52e8fd812-d2251ae09b8a84ac>
Report of the Second International Expert Seminar on Building Non-Handicapping Environments: Renewal of Inner Cities
Prague, October 15-17, 1987
Table of contents
Report of the International Expert Seminar Building Concept for the Handicapped Stockholm, Sweden, April 10-12, 1984
CIB (International Council for Building Research)
.
1984.
Report of the International Expert Seminar Building Concept for the Handicapped Stockholm, Sweden, April 10-12, 1984.
<here is a image 021ecef52e8fd812-d2251ae09b8a84ac>
PDF(92 KB)
Table of contents
Presentation of the organizers
.
Opening Address by Mr. Bengt Lindqvist, M.P.
CIB/W 84 Background and Purpose by Prof. Sven Thiberg.
Accessibility legislation - 1991
Christophersen, Jon
.
1991.
Accessibility legislation - 1991.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Contents
Towards European guidelines for an accessible built environment: An analysis of the "European Manual" from the Nordic experience
Örnhall, Hans
.
1991.
Towards European guidelines for an accessible built environment: An analysis of the "European Manual" from the Nordic experience.
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Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Contents
Towards European requirements and guidelines for an accessible built environment:
An analysis of the "European Manual" from the Nordic experience.
Hans Örnhall, Boverket, Sweden
The History of the Berkeley Center for Independent Living (CIL)
Zukas, H
.
1975.
The History of the Berkeley Center for Independent Living (CIL).
LanguageEnglish
The Center for Independent Living came into existence as a formal entity in March 1972, but its origins extend considerably further back in time and place; on occasion fortuitous circumstance has also played a role.
Helping One Another: A Speculative History of the Self-Help Movement
Zola, I K
.
1979.
Helping One Another: A Speculative History of the Self-Help Movement.
Abstract
Helping one another: speculative history of self-help movement, Archives of Physical Medicine and Rehabilitation 60: 452-456, 1979.
From an American legal practitioner's viewpoint
Wolinsky, Sid
.
1991.
From an American legal practitioner's viewpoint.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Contents
Science and Society - Critical Comments on the 1999 World Conference on Science, Budapest, Hungary
Wolbring, Gregor
.
1999.
Science and Society - Critical Comments on the 1999 World Conference on Science, Budapest, Hungary.
The Natural Sciences (biological/medical sciences) have a huge impact on society and within societies the biggest impacts are felt among disadvantaged/marginalized group. Among these groups we can count women, disabled people, ethnic minorities and indigenous people to name a few. I will look at the characteristic disability for the rest of the report but most of my reasoning and arguments can be extended to every disadvantaged group.
Independence Care System: Managed Care for People with Disabilities
Wilner, MaryAnn, Wyatt Ann
.
1998.
Independence Care System: Managed Care for People with Disabilities.
by MaryAnn Wilner, Ph.D. & Ann Wyatt, CSW, NHA, 1998
Dr. Wilner is Director of Health Policy, Paraprofessional Healthcare Institute, and works in collaboration with consumer, worker, and high quality provider agencies to educate state and federal policymakers about "the labor impact of healthcare policy." She also develops advanced educational programs for the home health aides in the Cooperative network. Ms. Wyatt is Director of Care Management, Independence Care System, and has been instrumental in designing Independence Care System.
På svenska
Independence Care System: Managed Care for People with Disabilities
Wilner, MaryAnn, Wyatt Ann
.
1998.
Independence Care System: Managed Care for People with Disabilities.
av MaryAnn Wilner, Ph.D. & Ann Wyatt, CSW, NHA, 1998
Dr.Wilner är chef för Health Policy, Paraprofessional Health Care Institute, tillsammans med konsumenter, anställda och högkvalitetsagenturer arbetar hon med att utbilda delstats och federala policyplanerare i "vårdpolicyns påverkan på arbetet” (the labor impact of healthcare policy”). Hon utvecklar också avancerade utbildningsprogram för hemhjälpsbiträden/vårdbiträden inom ramarna för the Cooperative network. Ms Wyatt är chef för Care Management, Independence Care System, och har varit en nyckelperson i utformningen av Independence Care Systems.
A People's History of the Independent Living Movement
Willig Levy, Chava
.
1998.
A People's History of the Independent Living Movement.
Table of Contents
RTC/IL Monographs in Independent Living is published by the Research and Training Center on Independent Living (RTC/lL), The University of Kansas.
Copyright 1988 by Research and Training Center on Independent Living (RTC/IL). University of Kansas, Lawrence, KS 66045.
"Wasn't That a Time," by Lee Hays. Quoted with permission.
"Talking Wheelchair Blues," by Fred Small. Quoted with permission.
Opportunities and challenges of barrier-free design consciousness - an evaluation of the application of barrier-free design principles in the socio-cultural circumstances in Ghana
Wellington, H N A
.
1992.
Opportunities and challenges of barrier-free design consciousness - an evaluation of the application of barrier-free design principles in the socio-cultural circumstances in Ghana.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Harare 1992
Dr. H. N. A. Wellington, Building & Road Research Institute and Dept. of Architecture, University of Science and Technology, Kumasi, Ghana
Contents
Steering Systems and Their Application
Weiss-Lindencrona, Hanne
.
1984.
Steering Systems and Their Application.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the International Expert Seminar
Building Concept for the Handicapped
Stockholm, Sweden, April 10-12, 1984
Contents
About the Center of Independent Living Zürich
Wehrli, Peter
.
1999.
About the Center of Independent Living Zürich.
<here is a image acb6ee1cfb098909-5e892881957991e9>
Zentrum für selbstbestimmt Leben
by Peter Wehrli, April 1999
Symposium on Disability and Human Rights
Wallace, Mary
.
1997.
Symposium on Disability and Human Rights.
<here is a image 9d61582dbcf23d30-a64b9aa5735b69ee>
Dublin, Ireland, 18th November, 1997
Closing address by Ms. Mary Wallace, T.D., Minister of State at the Department of Justice, Equality and Law Reform
Introduction
A Generic Orientation to Doing Attendant Work
Walker, Pamela
.
2001.
A Generic Orientation to Doing Attendant Work.
File attachments:
<here is a image 99f540ca7e0b7aeb-56dcf9690606b639> walker2001.pdf
The Growing Digital Divide in Access for People with Disabilities: Overcoming Barriers To Participation In The Digital Economy
Waddell, Cynthia D
.
1999.
The Growing Digital Divide in Access for People with Disabilities: Overcoming Barriers To Participation In The Digital Economy.
UNDERSTANDING THE DIGITAL ECONOMY
Data, Tools and Research
May 25 and 26, 1999
US Department of Commerce
Washington DC
THE GROWING DIGITAL DIVIDE IN ACCESS FOR PEOPLE WITH DISABILITIES:
OVERCOMING BARRIERS TO PARTICIPATION IN THE DIGITAL ECONOMY
By
EU programmes with relevance to persons with disabilities
Verney, Arthur
.
1996.
EU programmes with relevance to persons with disabilities.
<here is a image 9d61582dbcf23d30-a64b9aa5735b69ee>
Presentation by Arthur Verney
Development Worker, Disabled Peoples' International - European Union Committee
at the ENIL Meeting in Stockholm, 10 June 1996
Presentation of the "European Manual for an Accessible Built Environment
van Hek, Roy
.
1991.
Presentation of the "European Manual for an Accessible Built Environment.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Contents
Technical aids and accessibility problems
Uritsky, Felix M
.
1991.
Technical aids and accessibility problems.
<here is a image 4fd71e796f3201d0-0dd21f6d424cadce>
Report of the CIB Expert Seminar on Building Non-Handicapping Environments, Budapest 1991
Technical aids and accessibility problems
Felix M. Uritsky, Club "Contacts", Moscow, Russia
Seminar Contents
Americans With Disabilities Act PUBLIC LAW 101-336 JULY 26, 1990 104 STAT. 327
United States of America
.
1990.
Americans With Disabilities Act PUBLIC LAW 101-336 JULY 26, 1990 104 STAT. 327.
PDF, 135 KB
Pamphlet about the Act(HTML)
One Hundred First Congress of the United States of America
At the Second Session, Begun and held at the City of Washington on Tuesday, the twenty-third day of January, one thousand nine hundred and ninety.
An Act: To establish a clear and comprehensive prohibition of discrimination on the basis of disability.
Be it enacted by the Senate and House of Representatives of the United States of America in Congress assembled,
Declaration on the Rights of Disabled Persons Proclaimed by United Nations General Assembly resolution 3447 (XXX) of 9 December 1975
United Nations General Assembly
.
1975.
Declaration on the Rights of Disabled Persons Proclaimed by United Nations General Assembly resolution 3447 (XXX) of 9 December 1975.
The General Assembly,
Mindful of the pledge made by Member States, under the Charter of the United Nations to take joint and separate action in co-operation with the Organization to promote higher standards of living, full employment and conditions of economic and social progress and development,
Reaffirming its faith in human rights and fundamental freedoms and in the principles of peace, of the dignity and worth of the human person and of social justice proclaimed in the Charter,
Persons with Disabilities, International Day of Disabled Persons, 3 December 1992
United Nations, Division for Social Policy and Development
.
1992.
Persons with Disabilities, International Day of Disabled Persons, 3 December 1992.
| https://www.independentliving.org/mlsv/sv/sv/docs4/sexuality.html?page=10 |
The Infection Rate of the Coronavirus Disease 2019 (COVID-19) in Wuhan, China | medRxiv
medRxiv - The Preprint Server for Health Sciences
The Infection Rate of the Coronavirus Disease 2019 (COVID-19) in Wuhan, China
doi: https://doi.org/10.1101/2020.05.02.20088724
Now published in Journal of Medical Internet Research doi: 10.2196/20914
Abstract
Full Text
Info/History
Summary Box
What is already known about this subject?The Wuhan city in China had a much higher mortality rate (Feb 10 thstatistics: 748 death/18,454 diagnosis =4.05%; Apr 24 thstatistics: 3,869 death/50,333 diagnosis=7.69%) than the rest of China.
What are the new findings?Based on our analysis, the number of infected people in Wuhan is estimated to be 143,000 (88,000 to 242,000) in late January and early February, significantly higher than the published number of diagnosed cases.
What are the recommendations for policy and practice?Increased awareness of the original infection rates in Wuhan, China is critically important for proper public health measures at all levels, as well as to eliminate panic caused by overestimated mortality rate that may bias health policy actions by the authorities
The pandemic of the Coronavirus Disease 2019 (COVID-19) started in Wuhan, China in December 2019. Wuhan is a megacity with a population of about 11 millions. To prevent the spread of this alarming infectious disease, the whole city was locked down by the government since Jan 23 rd, 2020. However, despite the efforts, COVID-19 has spread to many countries across the world, and is causing an unprecedented pandemic as well as serious public health concern considering its high mortality rate. According to the large-sample analysis by Wu and McGoogan(1,2), the case-fatality rate (CFR) was 2.3% in China, i.e. 1023 of 44-672 confirmed cases by February 11, 2020 with a significant proportion of the cases from Wuhan. The large number of infected people in the city of Wuhan had put a tight strain on essential medical resources. The city had a much higher mortality rate (Feb 10 thstatistics: 748 death/18,454 diagnosis =4.05%; Apr 24 thstatistics: 3,869 death/50,333 diagnosis=7.69%) than the rest of China. Therefore, the overall CFR of 2.3% in China was likely overestimated, due to strained medical resources and a large number of undiagnosed patients. According to the most recent study, 78% infections were asymptomatic(3). Therefore, a large number of asymptomatic infections in Wuhan might have never been diagnosed, which contributed to the overestimated CFR. To get an accurate estimation of infections is therefore important to assess the CFR in Wuhan precisely.
Using Markov Chain Monte Carlo methods, Wu et al. estimated that 75,815 individuals (95% CI: 37,304, 130,330) had been infected in Wuhan as of Jan 25, 2020(4). After this study, a number of foreign governments evacuated their citizens and performed thorough etiological tests for these people. The evacuation of people can serve as a “random” sample to estimate the infection rate in Wuhan. Using these publicly available data (Table 1), we performed a combined analysis of the infection rates of these population samples, instead of a simple pooled calculation, considering potential different life styles and pathogen exposures across different populations. The combined analysis was done using the Comprehensive Meta-Analysis Software (CMA).
Table 1
Number of infected people from different countries
Shown in our analysis, there is no significant heterogeneity across different population samples (heterogeneity test P=0.491). The combined infection rate (95% CI)=0.013 (0.008, 0.022) (Fig.1). Based on these results, the number of infected people in Wuhan is estimated to be 143,000 (88,000 to 242,000), or significantly higher than the estimate by Wu et al(4). By our estimation, it is safe to say that a large number of infections in Wuhan, China have not been diagnosed (the number of undiagnosed in late January and early February is much more than the final diagnosed number 50,333 to date), causing the CFR being over-estimated. In addition, our estimation suggests that the lower CFR (0.51%) estimated by the Centre for Evidence-Based Medicine(2) doesn’t mean viral variants and loss of virulence. Taken together, increased awareness of the original infection rates in Wuhan, China is critically important for proper public health measures at all levels, as well as to eliminate panic caused by overestimated mortality rate that may bias health policy actions by the authorities.
Figure 1
Combined analysis of infection rates of different populations
Contributorship
H.Q.: literature search, study design, data collection, data analysis, data interpretation, writing
Z.J.C:data collection
Z.D.:data interpretation
L.T.:study design, data interpretation
H.H.:study design, data interpretation, writing
Funding
none.
Competing interests
none to declare.
Data sharing statement
no additional data.
Reference
1.
↵
Wu Z , McGoogan JM . Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72-314 Cases From the Chinese Center for Disease Control and Prevention . JAMA . 2020 .
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Oke J , Heneghan C . Global Covid-19 Case Fatality Rates UPDATED 7th April 2020 . Available from: https://www.cebm.net/covid-19/global-covid-19-case-fatality-rates/ .
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Day M . Covid-19: four fifths of cases are asymptomatic, China figures indicate . BMJ . 2020 ; 369 : m1375 .
4.
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Wu JT , Leung K , Leung GM . Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study . Lancet (London, England) . 2020 ; 395 ( 10225 ): 689 – 97 .
Hui-Qi Qu , Zhangkai J. Cheng , Zhifeng Duan , Lifeng Tian , Hakon Hakonarson
2020.05.02.20088724;
doi: https://doi.org/10.1101/2020.05.02.20088724
Now published in Journal of Medical Internet Research doi: 10.2196/20914
| https://www.medrxiv.org/content/10.1101/2020.05.02.20088724v1.full |
Pharmaceuticals | Free Full-Text | Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress.
Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation
by Hikaru Tsuchiya , Akinori Endo and Yasushi Saeki *
Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
Author to whom correspondence should be addressed.
Pharmaceuticals 2020 , 13 (6), 128; https://doi.org/10.3390/ph13060128
Received: 8 June 2020 / Revised: 19 June 2020 / Accepted: 22 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery )
Abstract
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress.
Keywords:
proteasome
;
protein degradation
;
proteasomal ubiquitin receptors
;
p97/VCP
;
liquid–liquid phase separation
1. Introduction
The ubiquitin–proteasome system is the primary degradation system in eukaryotic cells. The 26S proteasome is a huge enzyme complex composed of the 20S core particle (CP; also known as 20S proteasome) and one or two 19S regulatory particles (RPs). There are 33 distinct proteins, with a total of 66 subunits, which constitute 26S proteasome. The CP has a barrel-shaped structure that possesses two sets of three proteolytic active sites inside the cavity. The RP recognizes the polyubiquitin chains via intrinsic ubiquitin receptors (Rpn10, Rpn13, and Rpn1), unfolds the substrate proteins, and translocates them into the catalytic CP [
1
]. Besides the RP, the proteasome has alternative proteasome activators, such as PA28α/β (PSME1/2), PA28γ (PSME3), and PA200 (PSME4), which are involved in ubiquitin-independent protein degradation (reviewed by Kish–Trier et al.) [
2
]. Through the degradation of substrates, the proteasome plays an essential role in most cellular functions, such as cell cycle progression, transcription, signal transduction, and protein homeostasis [
3
]. In addition to the constitutive subunits, the proteasome has multiple transiently-associated proteins called proteasome-interacting proteins. Among them, substrate shuttling factors, ubiquitin ligases, and deubiquitylating enzymes modulate proteasome functions. It is now clear that ubiquitin-selective AAA-ATPase p97 and substrate shuttling factors like RAD23 and UBQLNs act to select and deliver ubiquitylated substrates upstream of the proteasome [
4
]. In this review, we describe the recent progress in our research on factors upstream of the proteasome, including substrate shuttling factors and p97, the selectivity of the ubiquitin chain for proteasomal degradation, and recently identified nuclear proteasome droplets that are formed under the hyperosmotic stress triggered by multivalent interactions between RAD23B and ubiquitylated proteins to be degraded. These findings underline the multi-step regulation of proteasome responding to the cellular environment.
2. Ubiquitin-Binding Proteins Related to the Proteasome: Proteasomal Ubiquitin Receptors, UBL–UBA Proteins, and p97
2.1. Proteasomal Ubiquitin Receptors (Rpn10, Rpn13, and Rpn1)
In proteasomal degradation, the recognition of ubiquitin chains is one of the most crucial steps. The proteasome has three defined intrinsic ubiquitin receptors, namely Rpn10, Rpn13, and Rpn1, that recognize ubiquitylated substrates on the proteasome. These ubiquitin receptors can also bind ubiquitin-like (UBL) domains and are therefore also known as UBL domain receptors ( Figure 1 ).
Figure 1. Proteasomal ubiquitin receptors. ( a ) Domain architectures of intrinsic proteasomal ubiquitin receptors. Known ubiquitin and ubiquitin-like (UBL) domain-binding domains are indicated by thick-bordered boxes. The prefix “h” indicates the human protein; “y” indicates the yeast protein; “a” indicates the arabidopsis protein. VWA, von Willebrand factor A. UIM, ubiquitin-interacting motif. Pru, Pleckstrin-like receptor for ubiquitin. DEUBAD, deubiquitinase adaptor. ( b ) Domain architectures of extrinsic ubiquitin receptors. UBL, ubiquitin-like. UBA, ubiquitin associated. HDD, helical domain of Ddi1. RVP, predicted retroviral protease-like. ( c ) The interaction map for ubiquitin and ubiquitin receptors. Known interactions are indicated by arrows. USP, ubiquitin-specific protease.
Rpn10 (also known as S5a/PSMD4) is composed of an N-terminal von Willebrand factor A (VWA) domain and C-terminal ubiquitin-interacting motif (UIM) domains. The VWA domain interacts with the proteasome and the UIM domain binds to ubiquitin chains. The UIM domain consists of a single alpha helix. Yeast Rpn10 has one UIM domain, but human and plant Rpn10 have two and three UIMs, respectively [ 5 ]. The additional UIM domain is thought to be the binding site for UBL domain-containing proteins. The UBL domain in RAD23A preferentially binds to UIM-2 in Rpn10 [ 6 ], whereas the UBL domain in UBQLN2 exhibits a 25-fold stronger affinity for the N-terminal UIM-1 over UIM-2 in hRpn10 [ 7 ]. In plants, UIM-2 specifically interacts with ATG8 for the autophagic turnover of the proteasome, or proteaphagy [ 8 ]. Interestingly, recent studies have suggested that the UBL domains in both RAD23 and UBQLN can activate the mammalian proteasome even though they bind to different UIMs in Rpn10 [ 9 , 10 ]. It remains unclear how these UIM domains are coordinated as a platform for ubiquitin chains and UBL domain-containing proteins. Mice lacking all the UIMs in Rpn10 exhibit embryonic lethality, suggesting the importance of UIMs in Rpn10 [ 11 ].
Rpn13/ADRM1 binds ubiquitin via a conserved antiparallel β-sheet region, termed the Pru domain (Pleckstrin-like receptor for ubiquitin), which itself binds to Lys48-linked diubiquitin with an affinity of ~90 nM [
12
]. Rpn13 Pru also binds to UBL domain-containing proteins. NMR analysis revealed that Rpn13 directly binds to RAD23A and UBQLN2, and the Kd value of Rpn13 Pru–RAD23A UBL domain is about 36 μM [
12
]. Rpn13 also binds to the Uch37/UCHL5 deubiquitylating enzyme via its carboxy-terminal domain, called the deubiquitinase adapter (DEUBAD) domain. Curiously, Rpn13 in budding yeast lacks both the DEUBAD domain and Uch37 [
13
]. By trimming the ubiquitin chains, Uch37 may remodel ubiquitin chains on ubiquitin receptors.
Rpn1 is a large proteasome subunit composed of 11 repeats of 30 to 40 residues, known as proteasome/cyclosome (PC) repeats, each of which forms a helix-turn-helix hairpin [ 14 , 15 ]. These PC repeats form a closed toroid domain consisting of T1 and T2 sites. T1 binds to both ubiquitin and the RAD23 UBL domain, and T2 recognizes the UBL domain of deubiquitylating enzyme Ubp6/USP14 [ 16 ]. Thus, the toroid domain in Rpn1 serves as the receptor not only for ubiquitylated proteins but also for shuttling factors and deubiquitylating enzymes.
It has been suggested that, to a certain extent, these ubiquitin receptors have functional redundancy in the ubiquitin recognition of the proteasome. Single gene mutation of the ubiquitin- and UBL domain-binding domains of these ubiquitin receptors is permissive in yeast. In addition, yeast cells that lack all three ubiquitin-binding sites are still viable, although they exhibit amino-acid analog sensitivity [
16
]. Using a well-defined model substrate and mutant proteasomes, Martinez–Fonts et al. elegantly demonstrated that Rpn10 is a primary receptor for Lys48-linked ubiquitylated substrates, and Rpn1 and Rpn13 are co-receptors for multi-ubiquitylated substrates [
17
]. Moreover, a recent study showed that Rpn1 binds Lys11/Lys48 branched ubiquitin chains more efficiently than Lys48-linked homotypic chains [
18
]. Thus, three receptors provide a versatile platform for various ubiquitin chain topologies. In mice, the liver-specific deletion of either RPN10 or RPN13 exhibited modest tissue impairment, but the simultaneous loss of both RPN10 and RPN13 caused severe liver injury accompanied by a massive accumulation of ubiquitin conjugates and UBL domain-containing proteins on the proteasome [
19
].
Other subunits, such as Rpt5 and Rpn15/Sem1/Dss1, were proposed to bind to ubiquitin [ 20 , 21 ]. However, this process is not yet fully understood.
2.2. UBL–UBA Proteins
Some ubiquitylated proteins are recognized and degraded by the proteasome with the help of UBL–UBA domain-containing proteins (UBL–UBA proteins). The main members of the UBL–UBA family are Rad23, also known as RAD23A/B in mammals; Dsk2, also known as UBQLN1~4 and L in mammals; and Ddi1/2. The UBL–UBA proteins contain a UBL domain in the N-terminus and one or two UBA domains in the C-terminus. These proteins simultaneously bind to ubiquitin via UBA domains [
22
,
23
] and to the proteasome via the UBL domain, and they shuttle ubiquitylated substrates to the proteasome. Like ubiquitin chains, the UBL domain binds to Rpn1, Rpn10, or Rpn13.
Rad23, which is conserved from yeast to humans, contains an N-terminal UBL domain, a stress inducible-1 (STI) domain (Rad4/XPC binding), and two UBA domains. Rad23 was originally identified as a nucleotide excision repair factor that is involved in DNA repair [
24
], and it is also characterized as a regulatory factor of intracellular protein degradation. The STI domain is also known to bind
N
-glycanase (Png1 in yeast, NGLY1/2 in mammals), suggesting the involvement of the proteasomal degradation of the glycoprotein that has leaked into the cytoplasm [
25
]. RAD23A and RAD23B in mammals show high homology in their amino acid sequences and therefore they can functionally compensate for one another’s roles in nucleotide excision repair [
26
]. Despite this functional redundancy of RAD23A and B, only RAD23B-deficient mice exhibited developmental impairment and growth retardation [
26
]. The susceptibility of each protein’s depletion in mice may be explained by the difference in protein expression levels in their tissues. Indeed, the expression level of RAD23B is 6- to 10-fold higher than that of RAD23A in cultured human cells, suggesting that the expression levels of these proteins are differentially controlled depending on cell or tissue type.
Dsk2 was originally identified, together with Rad23, as an essential factor for the duplication of the microtubule organization center [ 27 ]. Dsk2 contains a UBL domain, an STI domain that binds to heat shock proteins, and a UBA domain. Five UBQLN proteins (UBQLN1~4 and L) are encoded in the human genome. UBQLN1, 2, and 4 have some redundant functions [ 28 ], whereas UBQLN3 is mainly expressed in the testis, and UBQLN-L lacks the UBA domain. The STI domain of UBQLNs appears to directly recognize transmembrane proteins, and with their associated ubiquitin E3 ligases, UBQLNs target mislocalized transmembrane proteins that fail to be transported to the endoplasmic reticulum (ER) or mitochondria for proteasomal degradation [ 29 , 30 ]. In addition, the STI domain interacts with the disaggregase HSP70–HSP110 and shuttles aggregated proteins to the proteasome [ 31 ]. Notably, mutations in the UBQLN2 gene are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration [ 32 ]. UBQLN4 also participates in the export of ubiquitylated proteins from the nucleus to the cytoplasm through association with an nuclear export signal-containing protein, named POST, and may contribute to nuclear protein quality control [ 33 ]. Yeast Rad23 and Dsk2 play a redundant role in proteasomal degradation [ 34 , 35 ] and synergistically contribute to shuttling ubiquitylated substrates to the proteasome [ 4 ]. However, human RAD23A/B and UBQLN proteins seem to have some specific functions, e.g., RAD23B and UBQLN proteins contribute to droplet formation by the proteasome [ 36 ] (described below) and autophagosome [ 37 ], respectively.
Ddi1 (also known as DDI1/2 in mammals) remains less understood. Ddi1 has a helical domain of Ddi1 and a predicted retroviral protease-like domain that has a similar amino acid sequence to retroviral aspartyl proteases; for example, those encoded in HIV [ 38 , 39 ]. Interestingly, the UBL domain of Ddi1 can bind not only to the proteasome but also to ubiquitin, as can the UBA domain [ 40 , 41 ]. Interestingly, recent studies have revealed that yeast Ddi1 is a ubiquitin-dependent protease that preferentially recognizes long Lys48-linked ubiquitin chains and cleaves proteasome substrates [ 42 ]. In mammals, the cleavage of DDI2 activates an ER-resident Nrf1 transcription factor that regulates the gene expression of proteasome subunits to compensate for proteasome dysfunction [ 43 ].
2.3. Cdc48/p97/VCP-Ufd1-Npl4 Complex
Cdc48 (also known as p97 or VCP in mammals) is a hexameric AAA-type ATPase that is essential for cell survival. p97 functions in many cellular processes, such as ER-associated degradation (ERAD), selective autophagy, and DNA damage responses [ 44 , 45 ]. Multiple different cofactors regulate p97 and generate functional diversity [ 44 ]. The Ufd1 (UFD1L in humans)-Npl4 (NPLOC4 in humans) heterodimer is the best-characterized ubiquitin-binding cofactor in proteasomal degradation. Polyubiquitylated proteins which are embedded in membranes or assembled in multi-subunit complexes are extracted by the p97-Ufd1-Npl4 complex using ATP hydrolysis. Human Npl4 consists of an N-terminal ubiquitin-X (UBX)-like domain that binds to p97, a zinc-finger domain (ZF-Npl4), an Mpr1/Pad1 N-terminal (MPN) domain found in JAB1/MPN/Mov34 metalloenzyme (JAMM)-family deubiquitylating enzymes, a C-terminal domain (CTD), and an Npl4 zinc finger (NZF) domain ( Figure 2 ). In mammals, Npl4 binds to ubiquitin via the NZF domain without ubiquitin chain selectivity [ 46 , 47 , 48 ]. Interestingly, yeast Npl4 lacks the NZF domain, and instead, the ZF-Npl4-MPN-CTD is utilized for ubiquitin binding [ 4 , 47 ]. Since the MPN domain in Npl4 is topologically similar to the catalytic domain of JAMM-family deubiquitylating enzymes, the MPN domain was thought to be the binding site for ubiquitin. However, recent cryo-electron microscopy analysis has shown that the Lys48 ubiquitin chain does not interact with the groove of the MPN domain in yeast Npl4 but rather with the CTD domain and other regions of the MPN domain [ 49 ]. The crystal structures of yeast Npl4 in the complex with Lys48-linked diubiquitin revealed that the C-terminal helix and N-terminal loop of CTD mainly interact with the distal and proximal ubiquitin moieties, respectively [ 50 ]. Ufd1, rather than ubiquitin, occupies a hydrophobic groove of the MPN domain of Npl4 [ 50 ]. Ufd1 also has two short small heterodimer partner (SHP) motifs that bind to p97, and it contains the Ufd1 truncation 3 (UT3) domain that binds to ubiquitin.
Figure 2. Domain architectures of p97, Ufd1, and Npl4. Known interactions are indicated by arrows. UBXL, ubiquitin regulatory X (UBX)-like. ZF, Zinc finger. MPN, Mpr1/Pad1 N-terminal. CTD, C-terminal domain. NZF, Npl4 zinc finger. NBM, Npl4-binding motif. SHP, small heterodimer partner.
2.4. The Major Pathway for Proteasomal Degradation
Since the proteasome itself contains the ubiquitin receptors Rpn1, Rpn10, and Rpn13, it was thought that the proteasome directly recognizes ubiquitylated substrates. Nevertheless, the degradation of some ubiquitylated substrates requires the UBL–UBA proteins and p97 prior to recognition by the proteasome [ 34 , 35 , 51 , 52 ]. The importance of the UBL–UBA proteins and p97 in proteasomal degradation has been a long-standing question. Quantitative proteomics revealed that proteasome-bound ubiquitin chains were dramatically decreased in rad23 and dsk2 knockout cells [ 4 ], suggesting that most proteasome substrates are degraded through the Rad23- and Dsk2-dependent pathway. In a p97 temperature-sensitive mutant ( cdc48-3 ), ubiquitylated substrates showed significant accumulation on the proteasome. Surprisingly, this accumulation was almost completely abolished by the knockout of rad23 and dsk2 , suggesting that Rad23 and Dsk2 are downstream factors of p97, reminiscent of the escort model originally described by Richly et al. [ 34 ]. These findings indicated that the p97–Rad23/Dsk2 axis plays a major role in ubiquitin-dependent proteasomal degradation rather than in direct proteasomal recognition and degradation. Recently, two independent groups reported that the p97-Ufd1-Npl4 complex has unfoldase activity that relies on ATP hydrolysis and substrate ubiquitylation [ 53 , 54 ]. Moreover, efficient proteasomal degradation requires the presence of an unstructured region in substrates, which facilitates proteasomal engagement with the substrates and initiates unfolding and degradation [ 55 ]. Tomita et al. reported that calpain cleavage exposes a region that is recognized by the proteasome and allows it to initiate degradation efficiently [ 56 ]. In this context, the proteasome has difficulty degrading well-folded proteins that lack an unstructured region; therefore, the proteasome needs the assistance of the p97-Ufd1-Npl4 complex [ 57 ]. It is assumed that p97 provides the initiation site for the proteasome, and thus the proteasome can efficiently degrade a large number of proteins in cells.
3. Ubiquitin Signal for the Proteasome: Linkage Type and Length
3.1. Ubiquitin Chain Type Selectivity for Proteasomal Degradation
It is widely known that the tetra-Lys48-linked chain is the primary signal in substrate degradation by the proteasome [ 58 ]. Curiously, neither the proteasome itself nor Rad23, Dsk2, or Ddi1 show strict selectivity for Lys48 chains in vitro [ 59 , 60 ]. Recent studies have suggested that various ubiquitin architectures can also target proteins for proteasomal degradation. Multiple mono-ubiquitylation can efficiently induce proteasomal degradation, at least in vitro [ 61 ]. Additionally, multiple short chains with Lys11, Lys48, and Lys63 linkages can efficiently induce proteasomal degradation [ 61 , 62 ]. Moreover, in mammalian cells, anaphase-promoting complex/cyclosome (APC/C) substrates modified with Lys11/Lys48 branched chains are degraded more efficiently than those with homogenous Lys48-linked chains [ 63 ]. In yeast, Lys29/Lys48 branched chains attached to ubiquitin fusion degradation substrates accelerate proteasomal degradation [ 64 ]. Lys63/Lys48 branched chains also trigger proteasomal degradation [ 65 ]. To clarify what type of ubiquitin signal is primarily recognized by the proteasome in vivo, we performed a quantitative proteomic analysis of the ubiquitin linkage-type selectivity of major ubiquitin-binding domain (UBD)-containing proteins and the proteasome in yeast [ 4 ]. Mass spectrometry-based quantification revealed that the proteasome mainly binds Lys29 and Lys48 chains (about 7% and 90%, respectively), suggesting that these chains are the primary signals in yeast cells. A comparative analysis of the ubiquitin linkage selectivity of 14 major UBD proteins in yeast revealed that the UBL–UBA proteins and all p97 cofactors showed strong preferences for Lys48 linkage, whereas UBD proteins related to endocytosis were associated with K63 linkage. We also found that Npl4 had strict selectivity for the Lys48-linked chains. Given that all upstream factors for the proteasome were highly selective for Lys48- and Lys29-linked chains in vivo, but only Npl4 had Lys48 chain selectivity in vitro, we propose that the p97-Ufd1-Npl4 complex rather than Rad23 and Dsk2 determines the Lys48-linkage selectivity for proteasomal degradation in cells. Notably, although the abundance of Lys11 linkage was estimated to be very low (comprising only 1.3% of the eight different linkages) in our experimental setting, a more recent study demonstrated that Lys11/Lys48-mixed ubiquitin chains are utilized for the proteasomal degradation of misfolded proteins in the cytoplasm [ 66 ]. In mammalian cells, mass spectrometry-based quantification revealed that the human proteasome contains relatively high levels of Lys11 and Lys63 linkages, probably derived from Lys11/Lys48 and Lys48/Lys63 branched chains [ 65 ], clearly suggesting that proteasome-targeting signals are more complex in higher eukaryotes.
3.2. Ubiquitin Chain Length as a Signal for Proteasomal Degradation
Ubiquitin chain length is also an important factor for ubiquitin signaling. Historically, it has been thought that the Lys48 chain is the primary signal for proteasomal degradation. An in vitro analysis revealed that four or more ubiquitin molecules on substrate proteins are sufficient to target proteins to the proteasome [ 58 ]. However, a recent study suggested that various chain lengths contribute to substrate degradation in vitro. A single-molecule kinetic analysis showed that the proteasome degrades cyclin B2 with multiple short chains [ 61 , 62 ]. The authors visualized the activity of the APC, a ubiquitin ligase that plays an important role in the cell cycle. The APC/C rapidly attached mono- to tri-ubiquitin molecules to cyclin B2 [ 61 , 62 ]. In addition, mono-ubiquitylated small disordered proteins (<150 amino acids) are sufficiently degraded by the proteasome [ 67 ]. Nuclear magnetic resonance studies demonstrated that Rpn10 and Rpn13 simultaneously bind to ubiquitin chains, with a preference for Rpn10 for distal ubiquitin and Rpn13 for proximal ubiquitin [ 68 ]. Cryo-electron microscopy analysis revealed that the distance between Rpn10 and Rpn13 is approximately 100 Å, which is the same length as a tetra-ubiquitin chain [ 69 ]. One possible scenario is that this distance determines the minimum length for a ubiquitin chain recognized by the proteasome. Despite the fundamental importance of each substrate’s ubiquitin chain length, there have been no methods to determine it, other than through estimation via gel mobility on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). To determine the length of ubiquitin chains in biological samples, we designed an approach using trypsin and a ubiquitin chain protector, named “ubiquitin chain protection from trypsinization (Ub-ProT)” [ 70 ]. In native conditions, trypsin preferentially cleaves at Arg74 of ubiquitin [ 71 ], but substrate-attached chains are protected from trypsinization in the presence of a ubiquitin chain protector such as trypsin resistant tandem ubiquitin-binding entity (TR-TUBE) [ 70 , 72 ]. The Ub-ProT method, using soluble fractions obtained from yeast, revealed that the substrate-attached ubiquitins mainly ranged from monomers to heptamers [ 70 ]. Interestingly, the maximal ubiquitin chain length hardly changed as a result of proteasome inhibition, suggesting that the mechanism for regulating the ubiquitin chain length lies upstream of the proteasome in cells. By contrast, in p97 and Npl4 mutants, the global ubiquitin chain length was elongated, suggesting that the recognition and segregation of ubiquitylated substrates by p97-Ufd1-Npl4 are the key steps for determining ubiquitin chain length in cells.
On the basis of these findings, we proposed a model for ubiquitin code in proteasomal degradation (
Figure 3
). In this model, the p97-Ufd1-Npl4 complex is the factor that is most upstream of the proteasome and is involved in recognizing Lys48-linked ubiquitin conjugates; in particular, Npl4 governs the Lys48 selectivity of proteasomal degradation. p97-dependent segregation may antagonize ubiquitylation and terminate ubiquitin chain elongation on the substrate complex. It can be hypothesized that Npl4 recognizes and segregates Lys48 chains (which are roughly heptamers in length) on the substrate. Rad23 and Dsk2 then capture the substrates and deliver them to the proteasome. Twomey et al. demonstrated that otu1, a p97-associated deubiquitylating enzyme, cleaves ubiquitin chains on the substrate and requires efficient substrate unfolding by p97. It remains unclear how deubiquitylated substrates are handed over to shuttle factors. Besides, the decrease in the segregation activity of mutant p97 results in the elongation of the ubiquitin chain on the substrates. It appears that substrates that remain in complexes can be transported to the proteasome and inhibit proteasome activity by competing with authentic ubiquitylated substrates.
Figure 3. A model of the major route for degradation of proteasomal substrates. Two- to seven-mer Lys48 chains attached on the substrate are recognized by Npl4, and the substrate is segregated by p97. Then, the segregated substrate is transferred to shuttle factors and delivered to the proteasome.
4. Intracellular Dynamics of the Proteasome
4.1. Discovery of Stress-Dependent Proteasome Nuclear Foci
The proteasome is localized in both the cytoplasm and the nucleus. In particular, in proliferating yeast and mammalian cells, the proteasome is highly enriched in the nucleus and is presumably involved in the degradation of nuclear proteins [ 73 , 74 , 75 ]. When nuclear proteasomes are eliminated in yeast by a chemically-induced dimerization system, ubiquitylated proteins show significant accumulation [ 76 ]. However, the biological importance of proteasomal degradation in the nucleus under basal conditions is not well characterized. Abnormal proteins, such as those that are misfolded, are presumably constantly produced and then degraded by the proteasome, not only in the cytoplasm but also in the nucleus. During our microscopic analysis of the proteasome, we unexpectedly observed that proteasomes rapidly formed multiple foci in the nucleus upon hyperosmotic stress [ 36 ]. These proteasome foci were transient structures that emerged within a minute after hyperosmotic stimulation and disappeared after a few hours. Cryo-electron tomographic analysis successfully captured the clustering of proteasomes in the nucleus upon osmotic stimulation. We investigated whether these proteasome foci consisted of droplets, as they contained no aggregates or scaffold proteins. Indeed, these foci had droplet-like properties: they consisted of small foci that fused into larger foci, their shape was almost spherical, and they dissolved following the addition of 1,6-hexanediol, an aliphatic alcohol that destabilizes liquid droplets. Proteasome foci did not co-localize with known nuclear structures, such as promyelocytic leukemia bodies or Cajal bodies, suggesting that the nuclear proteasome foci induced by hyperosmotic stress have distinct roles. Liquid–liquid phase separation (LLPS) has become a hot topic in the life sciences in recent years. Cellular structures formed through LLPS are called membrane-less organelles or biomolecular condensates. These include stress granules, cytosolic p-bodies, and nuclear speckles [ 77 ]. LLPS is a rapid, reversible, and widespread compartmentalization mechanism in cells. Distinct subcompartments facilitate the spatiotemporal regulation of biological reactions [ 77 ]. We found that proteasome foci mainly co-localized with Lys48-linked ubiquitin chains and did not form in cells that were treated with the E1 inhibitor. By contrast, the number and size of foci increased and their clearance was delayed in cells treated with a proteasome inhibitor or p97 inhibitor. Thus, ubiquitylated substrates are required for the formation of proteasome foci and proteasomal degradation is necessary for their clearance, suggesting that proteasome foci are the proteolytic sites of ubiquitylated proteins. Proteomics analysis revealed that the ubiquitylation level of several housekeeping proteins, including histones, HSP90 (HSP90AB1 and HSP90AA1), and ribosomal proteins, increased under hyperosmotic stress, suggesting that this stress has global effects on the cellular proteome. In cultured cells, about 75,000 ribosome subunit molecules are synthesized per minute, and orphan subunits that fail to be incorporated into ribosomes are degraded by the proteasome [ 78 , 79 , 80 ]. Electron microscopic analysis showed that the nucleolar dense fibrillar compartment, where pre-ribosomes are assembled, was disrupted under hyperosmotic stress. Hyperosmotic stress also inhibited ribosome assembly in the nucleus, suggesting that the assembly process is susceptible to this condition. Some ribosomal proteins (RPL15, RPL29) aggregated in the nucleoplasm upon hyperosmotic stress and merged with proteasome foci, and they subsequently disappeared within an hour. These findings suggest that orphan ribosomal subunits are one of the major types of substrates in proteasome foci under hyperosmotic stress.
4.2. Molecular Mechanism of the Formation of Proteasome Foci
We also revealed that some proteasome-interacting proteins, including p97, RAD23B, and the ubiquitin ligase UBE3A (also known as E6-AP), co-localized to proteasome foci. The knockout of UBE3A reduced the number of proteasome foci formed upon hyperosmotic stress, suggesting that UBE3A regulates the proteasome itself or the ubiquitylation of substrate proteins in the foci [ 81 ], but the underlying molecular mechanism remains unknown. On the other hand, the proteasome foci were not detected in RAD23B knockout cells. We first assumed that the ubiquitylated proteins form foci without RAD23B. However, neither proteasomes nor ubiquitin formed foci in RAD23B knockout or mutated in the UBA domain cells, suggesting that the ubiquitin-binding ability of RAD23B induces the phase separation of ubiquitylated proteins. Proteins that induce LLPS can be classified into two groups. One consists of denatured proteins with intrinsically disordered regions (IDRs) such as fused in sarcoma (FUS) or tar DNA binding protein-43 (TDP-43); these proteins phase-separate with RNA [ 82 , 83 ]. Others cause phase separation due to the multivalent interaction of molecules which use multiple domains like the Src homology 3 (SH3) domain and the proline-rich motif [ 84 ]. RAD23B has two UBA domains, so it can bind to two ubiquitin chains. Each UBA domain weakly interacts with a ubiquitin monomer, specifically in a 1:1 molecular ratio, but it is known that the avidity increases exponentially when ubiquitin forms a chain [ 85 ]. We observed the co-phase separation of RAD23B and Lys48 chains in vitro. RAD23B prefers ubiquitin chains with four or more ubiquitin molecules, and both UBA domains of RAD23B are required for droplet formation. Therefore, the LLPS of proteasomes, ubiquitin chains, and RAD23B is mediated through multivalent interactions between polyubiquitin and RAD23B.
Based on these findings, we proposed a model for the formation of proteasome foci (
Figure 4
). Hyperosmotic stress increases molecular crowding and accumulates ubiquitylated proteins such as ribosomal proteins. Consequently, RAD23B and ubiquitylated substrates form liquid droplets by LLPS, and proteasomes and their cofactors are recruited to the foci. We assume that the proteasome foci are the sites for the sequestration and efficient degradation of ubiquitylated proteins in the nucleus. Like RAD23B, UBQLN is also linked to LLPS, though it is a completely different mechanism. UBQLN2 is recruited to stress granules and undergoes LLPS without ubiquitin [
86
]. The LLPS is promoted by multivalent interactions across the IDR and the UBA domain of UBQLN2.
Figure 4. Hyperosmotic stress-induced proteasome foci in the nucleus. The multivalent interactions between polyubiquitin chains and the UBA of RAD23B drive the liquid–liquid phase separation (LLPS). Then, the proteasomes and p97 are recruited to the foci and degrade the ubiquitylated substrates.
Interestingly, ubiquitin binding disrupts the UBQLN2 LLPS, suggesting that ubiquitin and UBQLN2 interactions result in the concomitant extraction of the polyubiquitylated substrate from stress granules. Importantly, some ALS-linked UBQLN mutations promote UBQLN2 oligomerization and accelerate LLPS formation in vitro [
87
], implying that the solidification of UBQLN2 directly links to ALS’ pathology. It has been reported that autophagy, another proteolytic system, also utilizes ubiquitin chain-dependent phase separation. The ubiquitin-selective autophagy adapter p62 has a Phox and Bem1 (PB1) domain, a UBA domain, and an LC3-binding domain for oligomer formation. p62 collects ubiquitylated substrates upon proteasome inhibition and oxidative stress, forms a droplet structure, and facilitates autophagy. The formation of these droplets (called p62 bodies) requires polyubiquitin chains linked with eight or more ubiquitins, and the UBA domain in p62 is important for the formation of p62 bodies [
88
]. Thus, one of the biological roles of polyubiquitin chain formation may be to induce LLPS. Since more than 100 proteins with UBDs are encoded in the human genome and many have multiple UBDs, a distinct LLPS mechanism is likely used by each ubiquitin-dependent pathway.
5. Conclusions and Perspective
Emerging evidence, reviewed in this article, emphasizes the crucial steps of substrate extraction/segregation and transport that are mediated by p97 and shuttling factors for proteasomal degradation. However, further studies are needed to elucidate how these steps together impact the ubiquitylated substrate to achieve effective degradation. In addition, the spatiotemporal and elaborate regulation of proteasomes is important for cell responses to the intra- and extracellular environment, since the proteasome plays a fundamental role in protein homeostasis. Since a number of proteasome-containing structures are known [
89
,
90
,
91
,
92
], the discovering of the osmotic stress-inducing proteasome phase separation sheds light on the importance of proteasome dynamics in response to the cellular environment. As the intracellular density of biomolecules is very high, the compartmentation of proteasomes and substrates with the help of shuttling factors may facilitate efficient proteasomal degradation. We expect that research over the next decade on the molecular mechanisms of substrate delivery and proteasome dynamics will contribute to a comprehensive understanding of the ubiquitin–proteasome system.
Author Contributions
H.T. and Y.S. wrote the original draft; A.E. and Y.S. edited the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research was supported by AMED under Grant Numbers JP18gm1110003 (Y.S) and by MEXT/JSPS KAKENHI Grant Numbers JP18K19352 (Y.S.), JP20H03214 (H.T.), JP18K14913 (H.T.), JP26293018 (Y.S.), and JP18H05498 (Y.S.).
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Proteasomal ubiquitin receptors. ( a ) Domain architectures of intrinsic proteasomal ubiquitin receptors. Known ubiquitin and ubiquitin-like (UBL) domain-binding domains are indicated by thick-bordered boxes. The prefix “h” indicates the human protein; “y” indicates the yeast protein; “a” indicates the arabidopsis protein. VWA, von Willebrand factor A. UIM, ubiquitin-interacting motif. Pru, Pleckstrin-like receptor for ubiquitin. DEUBAD, deubiquitinase adaptor. ( b ) Domain architectures of extrinsic ubiquitin receptors. UBL, ubiquitin-like. UBA, ubiquitin associated. HDD, helical domain of Ddi1. RVP, predicted retroviral protease-like. ( c ) The interaction map for ubiquitin and ubiquitin receptors. Known interactions are indicated by arrows. USP, ubiquitin-specific protease.
Figure 3. A model of the major route for degradation of proteasomal substrates. Two- to seven-mer Lys48 chains attached on the substrate are recognized by Npl4, and the substrate is segregated by p97. Then, the segregated substrate is transferred to shuttle factors and delivered to the proteasome.
Figure 4. Hyperosmotic stress-induced proteasome foci in the nucleus. The multivalent interactions between polyubiquitin chains and the UBA of RAD23B drive the liquid–liquid phase separation (LLPS). Then, the proteasomes and p97 are recruited to the foci and degrade the ubiquitylated substrates.
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(PDF) A New Species of Minute Noblella (Anura:Strabomantidae) from Southern Peru: The Smallest Frog of the Andes
PDF | We describe a new species of Pristimantis from a cloud forest at 2450-2800 m in the Cordillera Oriental in southern Ecuador (Zamora Chinchipe).... | Find, read and cite all the research you need on ResearchGate
A New Species of Minute Noblella (Anura:Strabomantidae) from Southern Peru: The Smallest Frog of the Andes
February 2009
Copeia2009(1)
DOI: 10.1643/CH-07-270
Authors:
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Edgar Lehr
Illinois Wesleyan University
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Alessandro Catenazzi
Florida International University
Abstract and Figures
We describe a new species of Pristimantis from a cloud forest at 2450-2800 m in the Cordillera Oriental in southern Ecuador (Zamora Chinchipe). The new species has a maximum snout-vent length of 17.9 mm (average SVL of 21 males = 12.3 mm ± 1.2, and of 19 females = 15.9 mm ± 1.3). This new species is the second smallest frog from Ecuador and smallest Pristimantis. Morphologically and phylogenetically, the new species is similar to P. caeruleonotus and P. colodactylus. It is distinguished from them and its congeners by its size, tuberculation, a distinct color pattern consisting of tan blotches on dorsum, spots on a brown venter, minute brown spots on anterior and posterior surfaces of the thighs, and other morphological features. Determination of small body size in frogs is discussed and meristic data of 40 minute frogs are compiled.
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Lateral (A) and dorsal (B) views of head and ventral views of hand (C) and foot (D) of Noblella pygmaea (MUSM 26320). …
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Type locality (indicated by an arrow) of Noblella pygmaea in southern Peru. …
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Elevation profile (right) and estimated density (left; average number of frogs/100 m 2 + SE) of Noblella pygmaea and sympatric …
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Montane forest at the quadrat plot where one specimen of Noblella pygmaea (MUSM 26318) was collected, 250 m east of the type locality, on 1 August 2007. Photo by A. Catenazzi. …
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Selected Anurans with Maximum Male Snout-Vent Lengths below 17 mm, Arranged by Increasing Maximum SVL. Range is followed by mean, SD, and sample size, if data are available. …
Alessandro Catenazzi
A New Species of Minute Noblella (Anura: Strabomantidae)
from Southern Peru: The Smallest Frog of the Andes
Edgar Lehr
1
and Alessandro Catenazzi
2
We describe a new species of Noblella from the upper Cosn˜ipata Valley in southern Peru (Cusco Region). Specimens were
found in the leaf litter of a cloud forest between 3025 and 3190m elevation. The most distinctive character of the new
species isitsdiminutivesize(maximumSVL female12.4 mm,male11.1 mm).Withanaveragesnout–ventlengthof
11.4 mm ( n = 7) in adult specimens, the new species is the smallest Andean frog, and one of the smallest anurans in the
world. The new frog is rare (between 30 and 75 frogs/ ha) and found only in montane scrub and forest habitats near the
ecotone with the high-Andean puna grasslands. Although the amphibian fun gal infection ( Batrachochytrium
dendrobatidis ) has been recorded in southern Peru, no infections were detected in the new species.
Describimos una nueva especie de Noblella de la parte alta del Valle Cosn˜ipata en el sur de Peru´(Regio´n Cusco). Los
especı´menes fueron encontrados en la hojarasca del bosquenublado a elevaciones entre 3025 y 3190m. La
caracterı´stica ma´s destacada de la nueva especie es su taman˜o diminuto (longitud hocico–cloaca ma´xima 12.4 mm en
hembras y 11.1 mm en machos). Con una longitud promedio de 11.4mm ( n = 7) en individuos adultos, esta especie es la
ranita ma´ s pequen˜a de los Andes, y entre los anuros ma´s pequen˜os del mundo. Esta nueva ranita es rara (densidad entre
30 y 75 individuos/ha) y habita los matorrales y bosques nublados cerca del ecotono con los pajonales altoandinos
(puna).Lainfeccio´ ncausadaporelhongo Batrachochytrium dendrobatidis ha sido reportada en anuros del sur de Peru ´;
sin embargo no detectamos la presencia de este hongo en individuos de la nueva especie.
R ECENT genetic studies of neotropical frogs indicate
that amphibian diversity may be highly underesti-
mated (Fouquet et al., 2007). Many of the newly
described species belong either to Pristimantis or Phrynopus,
which are major components of the Andean anuran faunas.
Intensive fieldwork in Peru and revision of museum
specimens collected in Peru within the last decade resulted
in the discovery of 37 new species of Pristimantis(Duellman
and Pramuk, 1999; Lehr et al., 2006; Duellman and Lehr,
2007) and 17 new species of Phrynopus (Duellman, 2000;
Lehr et al., 2000; Lehr, 2001; Lehr et al., 2002a; Lehr and
Aguilar, 2002, 2003; Lehr et al., 2005; Lehr, 2006, 2007;
Chaparro et al., 2007; Duellman and Hedges, 2008).
Based on molecular genetic data, Hedges et al. (2008)
allocated species of Phrynopus to five genera: Bryophryne,
Lynchius ,Niceforonia ,Noblella ,Phrynopus , andPsychrophy-
nella . De la Riva et al. (2008a) resurrected Noblella and
recognized Phyllonastes as its junior synonym. All species in
the above mentioned genera have limited distributions
often not exceeding the type locality and belong to the
family Strabomantidae (Hedges et al., 2008), which contains
direct developing frogs with snout–vent lengths up to
56.4mm (Lehr et al., 2002b). Partly because of their
restricted distributions, most species are classified as criti-
cally endangered, endangered, or unknown due to data
deficiency (IUCN et al., 2006).
Long-term fieldwork in the Cosn ˜ipata Valley (Cusco
Region) in southern Peru was conducted by the junior
author between 1996 and 1999 to study amphibian diversity
and population density of terrestrial and leaf-litter frogs
alonganelevationaltransectbetween600and3600 m
(Catenazzi and Rodrı´guez, 2001). During July and August
2007, and February 2008, some localities along the transect
were resampled to assess the current condition and trends of
frog populations, in view of the recent declines of montane
neotropical amphibians (Young et al., 2001; Lips et al.,
2005). Among the specimens obtained during fieldwork is a
new species of leaf-litter Noblella which is distinguished
from all known Andean anurans by its minute size. The
purpose of this paper is to describe the new species and to
assess its population density and conservation status. The
relationship between miniaturization in frogs and cloud
forest leaf-litter as a potential habitat is discussed.
MATERIALS AND METHODS
Institutional abbreviations follow Leviton et al. (1985) with
the addition of MUSM for Museo de Historia Natural,
Universidad Nacional Mayor de San Marcos, Lima, Peru,
and MTD for Museum fu¨r Naturkunde Dresden, Dresden,
Germany. We captured frogs in 10 3 10 m
2
leaf-litter
quadrat plots (Jaeger and Inger, 1994) at the Wayqecha
Research Center and within the Manu National Park in
southeastern Peru, at the ecotone between the high-Andean
puna grasslands and the cloud forest. A team of four (2008),
five (in 2007), and two persons (in 1998 and 1999) searched
intensively for frogs within the quadrat plots by removing
leaf-litter and moss, lifting rocks and fallen logs, and
examining other favorable microhabitats (e.g., water-filled
epiphytic bromeliads) during the day. We sampled four
quadrat plots for every 100m of elevation between 2800
and 3400 m, for a total of 24 quadrat plots in 1998 and 1999
(wet season: 8–19 January 1998 and 29 January–6 March
1999), 24 plots in 2007 (dry season: 25 July–4 August) and
24 plots in 2008 (wet season: 19–26 February). The total
sampling effort was 90 person-hours during 1998 and 1999,
266 person-hours during 2007, and 114 person-hours during
2008. We collected skin swabs from each frog captured in
1
Staatliche Naturhistorische Sammlungen Dresden, Museum fu¨r Tierkunde, Ko¨nigsbru¨cker Landstrasse 159, D-01109 Dresden, Germany; E-
mail: [email protected]. Send reprint requests to this address.
2
Division of Integrative Biology, University of South Florida, 4202 East Fowler Avenue, SCA110 Tampa, Florida 33620. Present address:
Department of Integrative Biology, University of California at Berkeley, 3060 Valley Life Sciences Building # 3140, Berkeley, California
94720; E-mail: [email protected].
Submitted: 18 December 2007. Accepted: 24 September 2008. Associate Editor: D. Kizirian.
F 2009 by the American Society of Ichthyologists and Herpetologists DOI: 10.1643/CH-07-270
Copeia 2009, No. 1, 148–156
quadrat plots in 2007. Skins swabs were analyzed using PCR
for the presence of Batrachochytrium dendrobatidis.
Taxonomy follows Hedges et al. (2008) and the format for
the description follows that of Lynch and Duellman (1997),
except that the term dentigerous processes of vomers is used
instead of vomerine odontophores (Duellman et al., 2006).
Conditions of the tympanum follow Lynch and Duellman
(1997). Specimens were preserved in 10 % formalin and
stored in 70 % ethanol. Specimens were dissected to
determine the sex and maturity, and the otic region was
dissected in order to determine the condition of the
tympanic annulus. The following measurements were taken
with digital calipers under a microscope and rounded to the
nearest 0.1 mm: snout–vent length (SVL), tibia length (TL),
foot length (FL, distance from proximal margin of inner
metatarsal tubercle to tip of Toe IV), head length (HL, from
angle of jaw to tip of snout), head width (HW, at level of
angle of jaw), eye diameter (ED), tympanum diameter (TY),
interorbital distance (IOD), upper eyelid width (EW),
internarial distance (IND), eye–nostril distance (E–N,
straight line distance between anterior corner of orbit and
posterior margin of external nares). Comparative lengths of
Toes III and V were determined by adpressing both toes
against Toe IV; relative lengths of Fingers I and II were
determined by adpressing the fingers against each other.
Skin of Finger IV was removed to count number of
phalanges. Drawings were made by the senior author using
a stereomicroscope with drawing tube attachment. Photo-
graphs taken by A. Catenazzi were used for descriptions of
coloration in life. Photographs of all types have been
deposited at the Calphoto online database (http://calphotos.
berkeley.edu). Spelling of locality names follow standards of
the U.S. Board on Geographic Names (http://earth-info.nga.
mil/gns/html/index.html) and for localities not listed in this
database, according to Carta Nacional ‘‘Calca,’’ Hoja 27-s,
Instituto Geogra´fico Nacional, Lima.The elevation profile
was generated using SRTM 90 m digital elevation data.
Noblella pygmaea , new species
Figures 1, 2; Tables 1, 2
Holotype.— MUSM 26320, Peru, Cusco Region, Province of
Paucartambo, District of Cosn˜ipata, Wayqecha Research
Center, Quebraba Toqoryuoc, gravid female, 13 u 11 931.92 0S,
71 u35 928.97 0 W, 3100 mabove sealevel, 3August 2007, A.
Catenazzi, I. Chinipa, A. Machaca, W. Qertehuari, and R.
Santa Cruz.
Paratypes.— MUSM 24536, 26318, MTD 47286 (three adult
females), MUSM 24535, 26319, MTD 47287 (three adult
males), all from the type locality and its surroundings.
MUSM 26318, 250m east of the type locality, 13 u 11 929.36 0S,
71 u35 921.34 0 W, 3025m above sea level, 1 August 2007.
MUSM 26319, type locality, 3 August 2007. MTD 47286,
200meastofthetypelocality,13 u 11 9 30.12 0 S,
71 u35 922.56 0 W, 3060m above sea level, 4 August 2007.
MTD 47287, near the type locality, 13 u 11 931.92 0 S,
71 u35 928.97 0 W, 3135 mabove sealevel, 3August 2007. A.
Catenazzi, I. Chinipa, A. Machaca, W. Qertehuari, and R.
SantaCruz.MUSM24536,90 meast ofthetypelocality,
13 u11 933.1 0 S, 71 u35 926.1 0 W, 3062 m above sea level. MUSM
24535, 13 u 11 933.1 0 S, 71 u35 924.1’ 0 W, 3070m above sea level,
20 February 2008, A. Catenazzi, I. Chinipa, J. C. Jahuanchi,
and A. Machaca.
Diagnosis.— A new species of Noblella as defined by Heyer
(1977) and De la Riva et al. (2008a) that differs from the
currently eight known species in the genus (Hedges et al.,
2008) by its small size. With a SVL of 11.3–12.4mm in adult
Fig. 1. Noblella pygmaea (MUSM 26320, holotype, SVL12.4 mm) in
lateral (A), dorsal (B), and ventral (C) views. Photos by A. Catenazzi.
Lehr and Catenazzi—New minute Noblella149
females ( n 5 4) and a SVL of 10.3–11.1mm in adult males ( n
5 3), Noblella pygmaea is currently the smallest frog within
the genus and the smallest frog known to occur in the
Andes. Noblella pygmaea has three phalanges on Finger IV
and differs from N. carrascoicola , N. lochites , N. myrmecoides,
and N. ritarasquinae , which have two phalanges on Finger
IV. Noblella pygmaea differs from central Peruvian N.
duellmani by having a tympanum (absent in N. duellmani ),
Fig. 2. Lateral (A) and dorsal (B) views of head and ventral views of hand (C) and foot (D) of Noblella pygmaea (MUSM 26320).
Table 1. Selected Characters ( + 5 Character Present; — 5 Character Absent; ? 5 Character Status Unknown) and Character Conditions among
Peruvian Species of Bryophryne , Noblella , and Psychrophrynella Compared to N. pygmaea . Modified after Lehr (2006).
Characters and
source
N.
pygmaea ,
this paper
N. peruviana ,
Noble, 1921; De la
Riva et al., 2008a
P.
bagrecito ,
Lynch, 1986
P.
boettgeri ,
Lehr, 2006
B. bustamantei ,
Chaparro
et al., 2007
B. cophites ,
Lynch, 1975
B. nubilosus ,
Lehr and
Catenazzi, 2008
Maximum SVL
(mm)
12.41618.6 18.423.429.321.9
Tympanum ++ ++ Not apparent——
Dentigerous
processes of
vomers
—— —————
Dorsolateral folds + —— ++ — +
Vocal sac ++ + — + — +
Vocal slits ++ + — + ——
Nuptial pads————— +—
Finger I , II + — ++ +++
Tarsal tubercle— ++ ——— —
150 Copeia 2009, No. 1
and from northern Peruvian N. heyeri and N. lynchiand
southern Peruvian N. peruviana by lacking tarsal tubercles or
folds (inner surface of tarsus bearing one prominent tubercle
in N. heyeri , N. lynchi , and N. peruviana ;Table 1). Noblella
pygmaea differs from N. myrmecoides from Amazonian
lowlands in lacking circumferential grooves on digits
(present in N. myrmecoides ). Six other small species of
strabomantid frogs which lack circumferential grooves are
known to occur in southern Peru: Psychrophrynella bagrecito,
P. boettgeri ,P. usurpator , Bryophryne bustamantei , B. cophites ,
and B. nubilosus . Noblella pygmaea is readily distinguished
from these species by its minute size (Table 1). Furthermore
it lacks a tarsal fold which is present in both P. bagrecitoand
P. usurpator . Noblella pygmaea has a tympanum which is
absent in Bryophryne . Both Noblella pygmaea and P. boettgeri
have a tympanumand dorsolateral folds, but Noblella
pygmaea has vocal slits which are absent in P. boettgeri .
Description of holotype.— Head narrower than body, slightly
longer than wide; head width 31.5 % of SVL; head length
33.1 % of SVL; snout short, rounded in dorsal and lateral
views (Figs. 2A, 2B), eye diameter slightly smaller than eye–
nostril distance; nostrils not protuberant, situated close to
snout; canthus rostralis slightly curved in dorsal view,
rounded in profile; loreal region nearly vertical; lips
rounded; upper eyelid with small tubercles; width of upper
eyelid narrower than IOD (upper eyelid width 52.6 %of
IOD); supratympanic fold short, narrow; tympanic mem-
brane and tympanic annulus present, upper margin con-
cealed by supratympanic fold; tympanum diameter 63.6 %of
eye diameter; two enlarged, elongate postrictal ridges on
each side of head, upper ridge larger than lower. Choanae
small, round, widely separated from each other, slightly
concealed by palatal shelf of maxilla; dentigerous processes
of vomers absent; tongue long and narrow, about three
times as long as wide, not notched posteriorly, posterior
one-third free.
Skin on dorsum tubercular with tubercles more densely
arranged on posterior half of body; short, narrow dorsolat-
eral folds present from posterior margin of eye to mid of
body; skin on flanks tuberculate; skin on chest, belly, and
thighs areolate, other ventral surfaces smooth; discoidal fold
not evident, pectoral fold present; cloaca protuberant; large
tubercles absent in cloacal region. Outer surface of brachium
each with a row of small tubercles; palmar tubercles distinct,
outer palmar tubercle not bifid, approximately two times
the size of elongate, inner palmar tubercle; supernumerary
indistinct; subarticular tubercles prominent, ovoid in dorsal
view, rounded in lateral view, largest at base of fingers;
fingers with narrow lateral fringes; Finger IV has three
phalanges; Finger I shorter than Finger II; tips of digits
rounded, circumferential grooves absent (Fig. 2C).
Hind limbs moderate, tibia length 41.1 % of SVL; foot
length 40.3 % of SVL; upper and posterior surfaces of hind
limbs tubercular; heel with one minute, round tubercle;
outer surface of tarsus without tubercles; inner metatarsal
tubercle elevated, ovoid, about one and a half times conical,
rounded outer metatarsal tubercle; low plantar supernumer-
ary tubercles present; subarticular tubercles well defined,
ovoid in dorsal view, rounded in lateral view; toes with
narrow lateral fringes, basal webbing absent; toe tips slightly
pointed, slightly smaller than those on fingers, circumfer-
ential grooves absent; relative lengths of toes: 1 , 2 , 5 ,3
, 4 (Fig. 2D).
SVL 12.4; tibia length 5.1; foot length 5.0; head length
4.1; head width 3.9; eye diameter 1.1; tympanum diameter
0.7; interorbital distance 1.9; upper eyelid width 1.0;
internarial distance 1.5; eye–nostril distance 1.2.
In ethanol, dorsum mottled dark gray and dark brown on
tan background; broad pale gray dorsolateral stripe from
upper eyelid to insertion of thighs; narrow, slightly elevated
dark brown ridge middorsally from sacral region to cloaca;
flanks slightly darker than dorsum; anterior surface of thighs
colored as dorsum, posterior surface with narrow, pale gray
stripe from cloaca diagonally to inside of knee; dorsal and
lateral tubercles bearing pale gray tips; throat, chest, and
venter chocolate brown, thighs mottled tan and chocolate
brown; iris dark gray.
Color in life as above except throat, chest, belly, and
thighs reddish brown with minute gray spots; iris dark
brown with few gold spots, pupil with an orange ringlet.
Variation.— Males are smaller than females and have vocal
slits and a vocal sac, but lack nuptial pads. Otherwise, all
specimens are structurally like the holotype. Slight differ-
ences can be observed in coloration pattern (in life). One
male (MUSM 26319) has a mottled reddish brown and tan
dorsum with dark brown flecks and pale gray tubercles. Dark
brown flecks are present on the head, and the dorsolateral
band is tan. The flanks are mottled dark brown and pale
gray. The shanks and tarsus are dorsally pale greenish brown
with dark brown flecks. Throat, chest, and belly are mottled
chocolate brown and pale gray, whereas other ventral
surfaces are chocolate brown with pale gray spots. One
female (MTD 47286) has a pale brown dorsum with scattered
brown flecks and pale gray tubercles. The flanks are grayish
brown, and the chest and belly are mottled pale gray and
tan, whereas all other ventral surfaces are tan with minute
gray and orange spots. All specimens have a narrow, pale
gray stripe from the cloaca diagonally to inside of the knee
on the posterior surfaces of the thighs. Measurements of
female (MTD 47286, MUSM 26318, 24536) and male
paratypes (MUSM 26319, MTD 47287, MUSM 24535,
Table 2. Ranges (in mm) and Proportions of Noblella pygmaea;
Ranges Followed by Means and One Standard Deviation in Parentheses.
CharactersFemales ( n = 4)Males ( n =3)
SVL11.3–12.4 (11.9 6 0.5)10.3–11.1 (10.7 60.3)
TL4.7–5.1 (4.9 6 0.1)4.5–4.6 (4.6 60.0)
FL4.8–5.0 (4.9 6 0.1)4.3–4.6 (4.5 60.1)
HL3.7–4.1 (3.9 6 0.2)3.6–3.8 (3.9 60.1)
HW3.6–3.9 (3.7 6 0.1)3.5–3.7 (3.6 60.1)
ED1.1–1.2 (1.1 6 0.1)1.2 (1.2 60.0)
TY0.4–0.7 (0.5 6 0.1)0.5–0.6 (0.6 60.0)
IOD1.5–1.9 (1.7 6 0.2)1.5–1.8 (1.5 60.2)
EW0.8–1.0 (0.9 6 0.1)0.8–0.9 (0.8 60.0)
IND1.1–1.5 (1.3 6 0.2)1.1–1.2 (1.1 60.0)
E–N0.8–1.2 (1.0 6 0.2)0.7–0.9 (0.8 60.1)
TL/SVL 0.40–0.420.41–0.45
FL/SVL 0.39–0.420.41–0.45
HL/SVL 0.32–0.330.34–0.37
HW/SVL 0.30–0.320.33–0.34
HW/HL 0.30–0.320.33–0.34
E–N/ED 0.67–1.090.58–0.75
EW/IOD 0.53–0.560.44–0.75
TY/ED 0.33–0.640.42–0.50
Lehr and Catenazzi—New minute Noblella151
separated by slash, respectively): SVL 12.3, 11.6, 11.3/11.1,
10.6, 10.3; tibia length 4.9, 4.8, 4.7/4.5, 4.6, 4.6; foot length
4.8, 4.8, 4.8/4.5, 4.3, 4.6; head length 4.0, 3.7, 3.7/3.8, 3.9,
3.6; head width 3.7, 3.7, 3.6/3.7, 3.5, 3.5; eye diameter 1.1,
1.2, 1.2/1.2, 1.2, 1.2; tympanum diameter 0.4, 0.4, 0.5/0.6,
0.6, 0.5; interorbital distance 1.6, 1.5, 1.6/1.8, 1.2, 1.5; upper
eyelid width 0.9, 0.8, 0.9/0.8, 0.9, 0.8; internarial distance
1.1, 1.2, 1.2/1.2, 1.1, 1.1; eye–nostril distance 0.8, 1.1, 0.8/
0.9, 0.9, 0.7. See Table 2 for ranges and proportions of the
type series.
Distribution and ecology.— The new species is known from
two localities in the upper Cosn˜ipata Valley in southeastern
Peru, at elevations of 3025–3190m (Figs.3, 4). Type
specimens were collected from steep slopes of montane
forest draining into the Quebrada Toqoryuoc, which, along
with the Quebradas Toqohuayqo and Pillahuata, form the
Rı´o Cosn˜ipata. This forest is currently preserved by the
Amazon Conservation Association and is linked to the
Wayqecha Research Center by a series of trails. The second
locality is approximately 3km northwest of the type
locality, on the eastern ridge of Cerro Macho Cruz, along
the Ericson trail connecting Acanaco to Pillahuata within
the Manu National Park, at elevations of 3120–3190m. This
ridge separates the drainage basins of the Toqohuayqo and
Pillahuata streams. We found five individuals of this species
at Cerro Macho Cruz on 11 January 1998.
All type specimens were found in the cloud forest leaf
litter (Fig.5). Four of the six 10 3 10 m
2
quadrat plots where
frogs were collected in 2007 and 2008 had large cover of
Chusquea bamboos, accounting for the large arbustive cover
(between 50 and 80 % ). Overstory density averaging 98.1 6
0.3 % and leaf-litter depth averaging 12.0 6 0.4 cmin
quadrat plots with N. pygmaea in 2007 and 2008 did not
differ from overstory (t 5 1.15, df 5 58, P 5 0.25) and leaf-
litter depth (t 5 0.74, df 5 58, P 5 0.46) values from all
quadrat plots between 2800 and 3400 m.
The cloud forest grades into elfin forests and the high-
Andean puna grasslands at elevations between 3200 and
3500 m, depending on slope aspect, steepness, and distur-
bance regimes. The ecotone between the montane forest
and the puna grasslands at Toqoryuoc is located approxi-
mately200 mNWof,andapproximately120 m(in
elevation) above, the type locality. The ridge of Cerro
Macho Cruz has more xeric vegetation, with reduced tree
cover and a larger proportion of herbaceous plants. Two
quadrat plots where N. pygamaea were found represented
two habitat types found along this ridge: arbustive and
herbaceous vegetation in montane scrub along the edge of
the ridge, and elfin forest with abundant ground moss cover.
Conspicuous plant genera in the upper Cosn˜ipata valley
include Alnus , Begonia , Bomarea , Calceolaria , Clethra , Clusia,
several Ericaceae, Juglans , Miconia , Oxalis , Peperomia , Wein-
mannia ,Symplocos , bamboos (Chusquea ), terrestrial ferns
( Cyathea ), and epiphytic bromeliads ( Pitcairnea , Tillandsia;
Cano et al., 1995; Foster et al., 2007. Plantas llamativas de
Pillahuata, Plantas llamativas de Acjanaco. http://fm2.
fieldmuseum.org/plantguides/).
Skin swabs from all Noblella pygmaea captured in 2007
tested negative for Batrachochytrium dendrobatidis . Moreover,
skin swabs from all sympatric frogs captured in quadrat plots
between2800and3400 min2007testednegativefor B.
dendrobatidis .
Fig. 3. Type locality (indicated by an arrow) of Noblella pygmaeain
southern Peru.
Fig. 4. Elevation profile (right) and estimated density (left; average
numberoffrogs/100 m
2
+ SE) of Noblella pygmaea and sympatric
species of Bryophryne and Psychrophrynella between 2800 and
3400melevationintheupperCosn˜ ipataValley,basedon10 3
10 m
2
quadrat plots during the wet seasons of 1998, 1999, and 2008
and the dry season of 2007 ( n 572).
Fig. 5. Montane forest at the quadrat plot where one specimen of
Noblella pygmaea (MUSM26318)was collected,250 meast ofthe
type locality, on 1 August 2007. Photo by A. Catenazzi.
152 Copeia 2009, No. 1
Noblella pygmaea is a rare species with a known elevational
distribution between 3000 and 3200m (Fig.4). Based on our
quadrat plots from 1998, 2007, and 2008, N. pygmaea is the
second most common leaf-litter frog between 3000 and
3200 m,whereitwasfoundsyntopicallywith Bryophryne
nubilosus . The number of N. pygmaea in quadrat plots
averaged 0 (1998/99), 0.50 6 0.29 (2007) and 0.50 60.29
(2008) between 3000and3099 m ( n 5 4 plots/season) and
1.50 6 0.86 (1998/99), 0.75 6 0.48 (2007), and 0 (2008)
between3100and3199 m( n 5 4 plots/season). Anurans
foundinotherquadratplotsbetween2800and3400 m
include Bryophryne cophites , B. nubilosus , B. sp., Gastrotheca
excubitor , Oreobates lehri , Pristimantis pharangobates ,and
Psychrophrynella usurpator . Additional species are known to
occur between 2800 and 3400 m: Centrolene sp., Gastrotheca
ochoai , Telmatobius sp., ‘‘Hyla’’ antoniiochoai , andHyloscirtus
armatus (De la Riva and Chaparro, 2005; Catenazzi, pers.
obs.).
Frog calls were heard (not recorded) in 1998, 2007, and
2008 in quadrat plots that contained Noblella pygmaeaand
Bryophryne nubilosus . The holotype contains four unpig-
mented ovarian eggs (two in each ovary) that are indicative
of terrestrial deposition.
Etymology.— The specific name pygmaea is the feminized
form of the Latin noun pygmaeus meaning ‘‘dwarf’’ and
refers to the small size of this species.
DISCUSSION
The herpetofauna of the upper Cosn˜ipata Valley (Cusco
Region) was largely unknown before the construction of the
Paucartambo–Pilcopata road connecting Andean locations
to the Amazon lowlands. Duellman’s fieldwork in 1971 and
1975 resulted in the description of five new species of
Pristimantis (Duellman, 1978). Lynch (1975) described
Bryophryne cophites and placed Noblella peruviana under the
new combination Phrynopus peruvianus based on specimens
collected near Abra Acanaco ( 5 Acjanaco, Acanacu), close to
the type locality of N. pygmaea . De la Riva et al. (2008a) stated
that this population actually represents an undescribed
species of Psychrophrynella ,recentlynamedas P. usurpator
(De la Riva et al., 2008b). Lehr and Catenazzi (2008) described
B. nubilosus , which occurs syntopically with N. pygmaea .
Therefore, with this description and a forthcoming descrip-
tion of a new Bryophryne species, five species of strabomantid
frogs are known to occur in the leaf litter of the elfin and cloud
forests of the upper Cosn˜ipata Valley above 2800 m.
Miniaturization in anurans has evolved independently in
diverse lineages(Wells,2007; Table 3). Thesmallest frog is
Brachycephalus didactyla from Brazil: females reach a maxi-
mum snout–vent length of 10.2 mm (Izecksohn, 1971). The
term ‘‘smallest frog’’ is problematic (Estrada and Hedges,
1996). Accurate estimation of body sizes requires a large
series of specimens to cover variation in body size within a
population. Records of body sizes often rely on a low
number of individuals ( Eleutherodactylus iberia: Estrada and
Hedges, 1996: four specimens, this paper: seven specimens)
despite the availability of large series in some cases
(Izecksohn, 1971). Some reports may reflect sex-based
sampling bias (Biju et al., 2007).
Studies focussing on ecophysiological adaptations among
high-elevation anurans are scarce (Navas, 1996), and we are
not aware of any study trying to explain ecophysiological
aspects of miniaturization in anurans. There seems to be no
Table 3. Selected Anurans with Maximum Male Snout–Vent Lengths below 17 mm, Arranged by Increasing Maximum SVL. Range is followed by mean, SD, and samplesize, if data are available.
SpeciesMax male SVLRangeFemalesMalesCountryReferences
Brachycephalus didactylus 8.68.6–10.2 ( n 5 80)10.28.6BrazilIzecksohn, 1971
Eleutherodactylus iberia 10.09.6–10.5 ( n 5 4)10.5 ( n 5 1)9.6–10.0 (9.80 6 0.12, n 5 3)CubaEstrada and Hedges, 1996
Stumpffia tridactyla 1110–11?10–11MadagascarGlaw and Vences, 2007
Noblella pygmaea 11.110.3–12.4 ( n 5 7)11.3–12.4 (12.9 6 0.5, n 5 4)10.3–11.1 (10.7 6 0.3, n 5 3)PeruThis paper
Eleutherodactylus limbatus 11.79.8–11.8 ( n 5 9)11.1–11.8 (11.6 6 0.17, n 5 4)9.8–11.7 (10.5 6 0.36, n 5 5)CubaEstrada and Hedges, 1996
Stumpffia pygmaea 1210–1211 ( n 5 1)10–12MadagascarGlaw and Vences, 2007
Noblella myrmecoides ?12.0–13.6 ( n 5 3)12.0–13.6 ( n 5 3)unknownLynch, 1976
Brachycephalus ferruginus 12.511.6–14.5 ( n 5 13)13.0–14.5 (13.8 6 0.6, n 5 4)11.6–12.5 (12.2 6 0.3, n 5 9)BrazilAlves et al., 2006
Brachycephalus pombali 13.912.6–15.3 ( n 5 8)14.6–15.3 (15.0 6 0.3, n 5 4)12.6–13.9 (13.3 6 0.5, n 5 4)BrazilAlves et al., 2006
Nyctibatrachus minimus 14.010.0–14.9 ( n 5 16)14.9 ( n 5 1)10.0–14.0 (12.3 6 1.4, n 5 15)IndiaBijuetal., 2007
Noblella heyeri 14.112.9–15.913.1–15.912.9–14.1PeruLynch, 1986
Pristimantis trachyblepharis 15.812.1–19.2 ( n 5 39)15.8–19.2, (17.2, n 5 19)12.1–15.8, (13.8, n 5 20)EcuadorLynch and Duellman, 1980
Phrynopus bracki 16.213.2–19.817.5–19.813.2–16.2PeruHedges, 1990; this paper
Psychrophrynella bagrecito 16.313.8–18.614.4–18.613.8–16.3PeruLynch, 1986
Psychrophrynella iatamasi 16.4815.74–16.4815.74 ( n 5 1)16.48 ( n 5 1)BoliviaAguayo-Vedia and Harvey, 2001
Psychrophrynella boettgeri 16.811.3–18.4 ( n 5 23)14.0–18.4 (16.2 6 1.4, n 5 14)11.3–16.8 (14.1 6 1.6, n 5 9)PeruLehr, 2006
Lehr and Catenazzi—New minute Noblella153
relationship between body size and temperature (i.e.,
Bergmann’s rule) in amphibians (Feder et al., 1982; Adams
and Church, 2007, but see Ashton, 2002). Moreover, Navas
(2006) suggests that amphibians are able to shift their
physiology to adjust for activity at lower temperatures,
which implies that temperature is less likely to drive
patterns of distribution and evolution of body sizes in
amphibians at high elevations. The advantage of small body
size may be that it results in a better use of small patches of
suitable habitat and food resources (the ‘mosaic elements
model’ of Hutchinson and MacArthur, 1959). Cloud forest
leaf-litter provides a unique habitat for anurans, yet it is
often distributed in patches which alternate with other
types of habitats (elfin forests, montane scrub, grassland).
Strabomantid frogs do not need to migrate for reproduction
(they lay eggs in the leaf litter) and probably have very small
home ranges. Under these circumstances, the evolution of a
small body size could be beneficial to frogs that can exploit a
specific niche not occupied by larger species. Given the
extent of Andean cloud forests, we are certain that many
other new species of frogs will be discovered if habitats are
thoroughly sampled. Unfortunately, cloud forests are
threatened by habitat destruction, fragmentation, and
climate change. In addition to these threats, the amphibian
fungal infection Batrachochytrium dendrobatides has been
recorded in high elevation anurans in Cusco (Seimon et al.,
2007),isknownfromelevationsabove3400 minthe
Cosn˜ipata Valley (A. Catenazzi, pers. obs.), and is likely to
affect N. pygmaea in the future.
MATERIAL EXAMINED
Bryophryne cophites . Peru: Cusco, Paucartambo, Cosn˜ipata,
SslopeAbraAcanaco,14 kmNNEPaucartambo,3400 m,
KU 138884 (holotype); N slope Abra Acanaco, 3450 m, KU
138885–908, 138911–5 (all paratypes); Tres Cruces, MUSM
26313, 26315, 26266–67, 26283–84.
Bryophryne nubilosus . Peru: Cusco, Paucartambo, Cosn ˜i-
pata, 500m NE Esperanza, 2712m, MUSM 26310–11;
Quebrada Toqoruyoc,3097 m, MUSM26312, MTD47293;
3065 m, MTD 47294; Esperanza, 2800 m, MUSM 26316–17.
Psychrophrynella bagrecito . Peru: Cusco, Quispicanchis,
Marcapata: Rı´o Marcapata, below Marcapata, ca. 2740m,
KU 196512 (holotype), KU 196513–18, 196520–21, 196523–
25 (all paratypes); La Convencio´n: HaciendaHuyro between
Huayopata and Quillabamba, 1830 m, KU 196527–28.
Psychrophrynella usurpator . Peru: Cusco, Paucartambo,
Cosn˜ipata:NslopeAbraAcanaco,3450 m, KU138917;N
slope Abra Acanaco, 3450m, KU 138919–24, KU 138929–35;
Tres Cruces, KU 17325, KU173327–29; Esperanza, 3090 m,
MTD 46371–72; N slope Abra Acanaco, Paucartambo,
3400 m, MTD 45021–22.
ACKNOWLEDGMENTS
We are grateful to W. Duellman for his helpful comments
on an earlier version of the manuscript. Specimens were
loaned by J. Co´rdova (MUSM).AC was assisted in the field
by J. Carrillo, W. and F. Qertehuari, A. Machaca, I. Chinipa,
J. Jahuanchi, and R. Santa Cruz. AC thanks the staff of the
Amazon Conservation Association in Cusco and Wayqecha
for field and logistic support; the National Institute for
Natural Resources in Lima for research, collecting, and
export permits; and the administration of the Manu
National Park in Cusco for research permit and logistic
support. Fieldwork was funded by grants from the Amazon
Conservation Association, the Chicago Board of Trade
Endangered Species Fund, the Rufford Small Grants Foun-
dation, and the Fondation Matthey-Dupraz to AC. EL thanks
the Humboldt-Foundation for an alumni grant to conduct
research at the Natural History Museum and Biodiversity
Research Center, The University of Kansas.
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| https://www.researchgate.net/publication/47552649_A_New_Species_of_Minute_Noblella_AnuraStrabomantidae_from_Southern_Peru_The_Smallest_Frog_of_the_Andes?_sg%5B0%5D=started_experiment_milestone |
(PDF) The Role of Hypoxia-Inducible Factor-1 in Acetaminophen Hepatotoxicity
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The Role of Hypoxia-Inducible Factor-1 in Acetaminophen Hepatotoxicity
May 2011
Journal of Pharmacology and Experimental Therapeutics 338(2):492-502
DOI: 10.1124/jpet.111.180521
Authors:
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Abstract and Figures
Hypoxia-inducible factor-1α (HIF-1α) is a critical transcription factor that controls oxygen homeostasis in response to hypoxia, inflammation, and oxidative stress. HIF has been implicated in the pathogenesis of liver injury in which these events play a role, including acetaminophen (APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP overdose has been reported to activate HIF-1α in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1α signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1α contributes to APAP hepatotoxicity. Conditional HIF-1α deletion was generated in mice using an inducible Cre-lox system. Control (HIF-1α-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1α-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1α is involved in the early stage of APAP toxicity. In further studies, HIF-1α-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1α signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-1α-deficient animals had decreased hepatic neutrophil accumulation and plasma concentrations of interleukin-6, keratinocyte chemoattractant, and regulated upon activation normal T cell expressed and secreted compared with control mice, suggesting an altered inflammatory response. HIF-1α contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity.
Conditional HIF-1 ␣ deletion in mice . A, 5-week-old CRE- ERT2( ϩ / Ϫ )/HIF-1 ␣ flox/flox mice were treated with OIL or 200 g/g TAM …
Primer sequences …
Effect of HIF-1 ␣ deletion on APAP hepatotoxicity. Five-week-old …
Time course of APAP-induced liver injury in HIF1-deficient mice. HIF-1 fl/fl or HIF-1 / mice were treated with APAP (400 mg/kg) or SAL, and plasma and liver samples were taken 2, 6, and 24 h later. A, liver injury was assessed from plasma ALT activity; data represent means S.E.M. of n 3-8 animals per group. a indicates significantly different from SAL-treated mice; b indicates significantly different from APAP-treated HIF-1 fl/fl mice; c indicates significantly different from the same treatment at 2 h. B, livers were processed for histology and stained with hematoxylin and eosin. Sections are shown from mice with ALT values near the median. …
Mitochondrial Bax translocation. Mice were treated with SAL or 400 mg/kg APAP, and 6 h later liver samples were taken. A, quantifica- tion of Bax: Cox IV colocalization was performed as described under Materials and Methods . a indicates significantly different from SAL- treated mice. There were no significant differences between SAL-treated HIF-1 ␣ ϩ fl/ ϩ fl and HIF-1 ␣ ⌬ / ⌬ mice, so they were combined for statistical …
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John J LaPres
Author content
The Role of Hypoxia-Inducible Factor-1
␣
in Acetaminophen
Hepatotoxicity
Erica M. Sparkenbaugh, Yogesh Saini, Krista K. Greenwood, John J. LaPres,
James P. Luyendyk, Bryan L. Copple, Jane F. Maddox, Patricia E. Ganey,
and Robert A. Roth
Departments of Pharmacology and Toxicology (E.M.S., J.F.M., P.E.G., R.A.R.) and Biochemistry and Molecular Biology (Y.S.,
K.K.G., J.J.L.), and Center for Integrative Toxicology (E.M.S., Y.S., K.K.G., J.J.L., J.F.M., P.E.G., R.A.R.), Michigan State
University, East Lansing, Michigan; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas
Medical Center, Kansas City, Kansas (J.P.L., B.L.C.)
Received February 12, 2011; accepted May 12, 2011
ABSTRACT
Hypoxia-inducible factor-1
␣
(HIF-1
␣
) is a critical transcription
factor that controls oxygen homeostasis in response to hyp-
oxia, inflammation, and oxidative stress. HIF has been impli-
cated in the pathogenesis of liver injury in which these events
play a role, including acetaminophen (APAP) overdose, which is
the leading cause of acute liver failure in the United States.
APAP overdose has been reported to activate HIF-1
␣
in mouse
livers and isolated hepatocytes downstream of oxidative stress.
HIF-1
␣
signaling controls many factors that contribute to APAP
hepatotoxicity, including mitochondrial cell death, inflamma-
tion, and hemostasis. Therefore, we tested the hypothesis that
HIF-1
␣
contributes to APAP hepatotoxicity. Conditional HIF-1
␣
deletion was generated in mice using an inducible Cre-lox
system. Control (HIF-1
␣
-sufficient) mice developed severe liver
injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1
␣
-
deficient mice were protected from APAP hepatotoxicity at 6 h,
but developed severe liver injury by 24 h, suggesting that
HIF-1
␣
is involved in the early stage of APAP toxicity. In further
studies, HIF-1
␣
-deficient mice had attenuated thrombin gener-
ation and reduced plasminogen activator inhibitor-1 production
compared with control mice, indicating that HIF-1
␣
signaling
contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-
1
␣
-deficient animals had decreased hepatic neutrophil accu-
mulation and plasma concentrations of interleukin-6, keratino-
cyte chemoattractant, and regulated upon activation normal T
cell expressed and secreted compared with control mice, sug-
gesting an altered inflammatory response. HIF-1
␣
contributes
to hemostasis, sterile inflammation, and early hepatocellular
necrosis during the pathogenesis of APAP toxicity.
Introduction
Hypoxia-inducible factor (HIF) is the master regulator of
oxygen homeostasis. It regulates the expression of a large
battery of genes involved in angiogenesis, erythropoiesis,
glycolysis, inflammation, and cell death (Lee et al., 2007).
HIF comprises two constitutively expressed subunits:
HIF-1 ␣ and HIF-1  . HIF-1 ␣ is regulated primarily at the
level of protein stability: at normal oxygen tension, oxygen-
dependent proline hydroxylation of HIF-1 ␣ targets it for
rapid proteasomal degradation. In hypoxia, decreased pro-
line hydroxylation causes HIF-1 ␣ to accumulate and trans-
locate to the nucleus, where it binds to HIF-1  , forming the
transcriptionally competent HIF-1 that binds hypoxia re-
sponse elements in DNA. HIF-regulated genes include plas-
minogen activator inhibitor-1 (PAI-1), vascular endothelial
growth factor (VEGF), tumor necrosis factor ␣ (TNF ␣ ), inter-
leukin-1  (IL-1  ), and cell death proteins such as BNIP3 and
This research was supported by the National Institutes of Health National
Institute of Environmental Health Sciences [Grants R01-ES004139, R01-
ES12186]. E.M.S. was supported in part by the National Institutes of Health
National Institute of Environmental Health Sciences [Training Grant T32
ES007255].
Portions of this work were presented previously: Sparkenbaugh EM, Saini
Y, LaPres JJ, Maddox JF, Ganey PE, and Roth RA (2010) HIF-1 ␣ deletion
protects mice from acetaminophen hepatotoxicity and reduces activation of the
hemostatic system, at The Society of Toxicology Annual Meeting ; 2010 March
7–11; Salt Lake City, UT. Society of Toxicology, Reston, VA.
Article, publication date, and citation information can be found at
http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180521.
ABBREVIATIONS: HIF, hypoxia-inducible factor; ALT, alanine aminotransferase; APAP, N- acetyl- p -aminophenol; IL, interleukin; KC, keratinocyte
chemoattractant; PA, plasminogen activator; PAI-1, PA inhibitor-1; PMN, polymorphonuclear neutrophil; RANTES, regulated upon activation norma lT
cell expressed and secreted; TAM, tamoxifen; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; PCR, polymerase chain reaction ;
SAL, saline; OIL, corn oil; BB, blocking buffer; Cox IV, cytochrome c oxidase subunit IV; MIP, macrophage inflammatory protein; TAT, thrombin-
antithrombin; HPRT, hypoxanthine guanine phosphoribosyl transferase; BNIP3, BCL2/adenovirus E1B 19-kDa protein-interacting protein 3.
0022-3565/11/3382-492–502$25.00
T HE J OURNAL OF P HARMACOLOGY AND E XPERIMENTAL T HERAPEUTICS Vol. 338, No. 2
Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics 180521/3703925
JPET 338:492–502, 2011 Printed in U.S.A.
492
Nix (Murdoch et al., 2005; Lee et al., 2007). HIF-1 ␣ expres-
sion and activation are also regulated by oxidative stress
(Klimova and Chandel, 2008), inflammatory cytokines
(Walmsley et al., 2005a), and thrombin (Go ¨ rlach et al., 2001).
Because of the many factors that can modulate HIF induction
and the variety of downstream signaling targets, HIF has
been identified as a key regulator of a generalized stress
response (James et al., 2006).
HIF-1 ␣ has been implicated in hepatocyte death in models
of liver injury that have an inflammatory or oxidative stress
component, such as sepsis (Peyssonnaux et al., 2007), isch-
emia/reperfusion (Cursio et al., 2008), alcoholic liver disease
(Li et al., 2006), and fibrosis (Copple et al., 2009). Oxidative
stress and mitochondrial dysfunction play a key role in acet-
aminophen [ N -acetyl- p -aminophenol (APAP)]-induced liver
injury (James et al., 2003). APAP overdose is the leading
cause of drug-induced liver failure in the United States (Lee,
2007). At toxic doses, APAP is bioactivated by cytochrome
P450 enzymes to n -acetyl- p -benzoquinone imine, which is
reactive, depletes GSH, and binds covalently to intracellular
proteins, leading to mitochondrial dysfunction, production of
reactive oxygen species, and hepatocellular necrosis (Jollow
et al., 1973).
A report by James et al. (2006) indicated that APAP over-
dose causes nuclear accumulation of HIF-1 ␣ in mouse livers
as early as 1 h after treatment, which is before the onset of
liver hypoxia and hepatocellular injury. Furthermore, N-
acetyl cysteine, which inactivates n -acetyl- p -benzoquinone
imine (James et al., 2006) or cyclosprin A, which prevents
mitochondrial permeability transition, prevented HIF-1 ␣ ac-
cumulation (Chaudhuri et al., 2011). Taken together, these
data suggest that mitochondrial dysfunction and reactive
oxygen species are important contributors to early HIF-1 ␣
stabilization in APAP overdose.
In addition to cellular necrosis caused by oxidative stress
and mitochondrial dysfunction, APAP hepatotoxicity is asso-
ciated with disturbances to the hemostatic system in humans
(James et al., 2002) and experimental animals (Ganey et al.,
2007). APAP overdose caused tissue factor-dependent activa-
concentration of PAI-1, and fibrin deposition in liver (Ganey
et al., 2007). Inhibition of coagulation system activation
through genetic or pharmacologic methods attenuated
APAP-induced liver injury, suggesting a role for thrombin
and the coagulation system in the pathogenesis. During in-
jury progression, fibrin deposition can contribute to tissue
ischemia and hypoxia, which might enhance HIF-1 ␣ accumu-
lation above that caused by oxidative stress alone.
APAP hepatotoxicity is accompanied by a sterile inflam-
matory response (Williams et al., 2010), and concurrent in-
flammation can sensitize mice to APAP-induced liver injury
(Maddox et al., 2010). Mediators released from necrotic hepa-
tocytes activate Kupffer cells, recruit and activate polymor-
phonuclear neutrophils (PMNs), and consequently produce
cytokines that influence APAP-induced hepatocellular injury
(James et al., 2005; Cover et al., 2006). The role of PMNs in
APAP hepatotoxicity remains controversial, with evidence
both for and against a contribution of PMNs to injury pro-
gression (Jaeschke, 2008). HIF-1 ␣ plays a critical role in
PMN function; it influences phagocytosis, motility, invasive-
ness, and apoptosis (Cramer et al., 2003; Peyssonnaux et al.,
2005; Walmsley et al., 2005a,b). HIF-1 ␣ also contributes to
Therefore, HIF-1 ␣ might participate in the inflammatory
response that accompanies APAP-induced liver injury.
In addition to the many factors mentioned above that associ-
ate APAP-induced liver injury with hypoxia signaling, HIF-1 ␣
can contribute directly to the cell death of hepatocytes by up-
regulation of cell death genes. Nonetheless, it is currently un-
known whether HIF-1 ␣ is involved causally in APAP-induced
liver injury. To test the hypothesis that HIF-1 ␣ contributes to
the pathogenesis of APAP-induced liver injury, conditional
HIF-1 ␣ -deficient animals were generated, and the role of
HIF-1 ␣ in APAP-induced hepatotoxicity, disruption of hemosta-
sis, and inflammation was evaluated.
Materials and Methods
Materials. Unless otherwise stated, all reagents were purchased
from Sigma-Aldrich (St. Louis, MO).
Generation of Conditional HIF-1 ␣ -Deficient Animals. HIF-
1 ␣
flox/flox
mice (Ryan et al., 1998) were a gift from Randall Johnson
(University of California, San Diego, CA), and UBC-Cre-ERT2( ⫹ / ⫺ )
mice were purchased from The Jackson Laboratory (Bar Harbor, ME).
The Cre-ERT2 is regulated by the ubiquitin C promoter and is ex-
posed of Cre recombinase and a mutated estrogen receptor that is
selectively activated and targeted to the nucleus by ( Z )-1-( p -
dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene, trans- 2-[4-(1,2-
diphenyl-1-butenyl)phenoxy]- N , N -dimethylethylamine [tamoxifen
(TAM)] but not estrogen (Ruzankina et al., 2007). C57BL/6 HIF-1 ␣
flox/flox
and UBC-Cre-ERT2( ⫹ / ⫺ ) transgenic mice were mated to generate
UBC-Cre-ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice capable of conditional recom -
bination in the floxed HIF-1 ␣ gene when treated with TAM. Male
UBC-Cre-ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice (4 –5 weeks old) were treated
once a day for 5 days with 200 g/g body weight TAM in corn oil (OIL)
vehicle by oral gavage (Ruzankina et al., 2007). TAM-treated UBC-Cre-
ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice were HIF-1 ␣ -deficient (denoted as HIF-
1 ␣
⌬ / ⌬
), and OIL-treated animals were HIF-1 ␣ -sufficient (denoted as
software (National Institutes of Health, Bethesda, MD). Background
staining in livers from SAL-treated mice was set as the threshold,
were stained as described previously (Maddox et al., 2010), and PMN
accumulation was quantified by counting the average number of
Detection of Bax. Frozen liver sections (5 m) were fixed in 4%
paraformaldehyde for 30 min at room temperature. Fixed sections
were washed 3 ⫻ 7 min in phosphate-buffered saline (PBS) and
blocked in 10% donkey serum ⫹ 0.1% Triton X-100 (blocking buffer;
BB) for 1 h. Sections were incubated overnight at 4°C with the
following primary antibodies (and their dilutions): rabbit anti-Bax
(1:200) (Cell Signaling Technology, Danvers, MA) and goat anti-
cytochrome c oxidase subunit IV (Cox IV) (1:100) (Santa Cruz Bio-
technology, Inc., Santa Cruz, CA) diluted in BB. After incubation,
sections were washed 3 ⫻ 7 min in PBS, blocked in BB for 1 h, and
washed 3 ⫻ 7 min again. Sections were incubated with donkey
anti-rabbit Alexa Fluor 568 (1:1000) and donkey anti-goat Alexa
Fluor 488 (1:1000) (Invitrogen) in BB and washed, then mounted
fl/fl
] were treated with
OIL or 200 g/g TAM daily for 5 days. Twenty one days later, mice were
treated with APAP or SAL intraperitoneally. Plasma ALT activity was
measured 6 h after APAP administration. Data represent means ⫾ S.E.M. of
n ⫽ 3– 8 animals per group. a indicates significantly different from respec-
tive SAL-treated mice; b indicates significantly different from OIL-treated
mice; c indicates significantly different from HIF-1 ␣
⫹ fl/ ⫹ fl
mice.
Fig. 3. Time course of APAP-induced liver injury in HIF-
1 ␣ -deficient mice. HIF-1 ␣
⫹ fl/ ⫹ fl
or HIF-1 ␣
⌬ / ⌬
mice were
treated with APAP (400 mg/kg) or SAL, and plasma and
liver samples were taken 2, 6, and 24 h later. A, liver injury
was assessed from plasma ALT activity; data represent
means ⫾ S.E.M. of n ⫽ 3– 8 animals per group. a indicates
significantly different from SAL-treated mice; b indicates
significantly different from APAP-treated HIF-1 ␣
⫹ fl/ ⫹ fl
mice; c indicates significantly different from the same
treatment at 2 h. B, livers were processed for histology and
stained with hematoxylin and eosin. Sections are shown
from mice with ALT values near the median.
Role of HIF-1
␣
in Acetaminophen Hepatotoxicity 495
statistically with appropriate post hoc tests. P ⬍ 0.05 was the crite-
rion for significance.
Results
Effect of Conditional Deletion of HIF-1 ␣ Gene on
Liver HIF-1 ␣ Expression. Conditional HIF-1 ␣ knockout
mice were generated by mating HIF-1 ␣
flox/flox
mice (Ryan et
al., 1998) with transgenic mice that express the Cre-recom-
binase transgene (Ruzankina et al., 2007) under the control
of the ubiquitin C promoter, and the HIF-1 ␣ gene was inac-
tivated upon TAM treatment (Fig. 1A). Mice treated with
TAM (HIF-1 ␣
⌬ / ⌬
mice) displayed no obvious phenotypic dif -
ferences compared with control animals. There was signifi-
cantly less expression of HIF-1 ␣ mRNA in HIF-1 ␣
⌬ / ⌬
mice
compared with HIF-1 ␣
⫹ fl/ ⫹ fl
controls (Fig. 1B), demonstrat -
ing effective HIF-1 ␣ deletion. At 24 h, APAP overdose in-
creased expression of HIF-1 ␣ mRNA at 24 h by 437-fold in
HIF-1 ␣
⫹ fl/ ⫹ fl
. In HIF-1 ␣
⌬ / ⌬
mice, there was a modest in -
crease in HIF-1 ␣ mRNA expression (by 26-fold) at 24 h.
Expression of HIF-1 ␣ protein in livers was evaluated immu-
nohistochemically 2 h after SAL or APAP treatment. SAL-
treated HIF-1 ␣
⫹ fl/ ⫹ fl
mice had minimal staining, whereas
HIF-1 ␣ staining was not observed in HIF-1 ␣
⌬ / ⌬
mice (Fig.
1C). APAP overdose increased hepatocellular HIF-1 ␣ stain-
Fig. 4. Mitochondrial Bax translocation. Mice were treated with SAL or
400 mg/kg APAP, and 6 h later liver samples were taken. A, quantifica-
tion of Bax: Cox IV colocalization was performed as described under
Materials and Methods . a indicates significantly different from SAL-
treated mice. There were no significant differences between SAL-treated
HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice, so they were combined for statistical
purposes. B, representative ⫻ 60 confocal fluorescent micrographs of fro-
zen liver sections from two to three animals per group. DAPI,
4,6-diamidino-2-phenylindole.
Fig. 5. DNA fragmentation after APAP treatment . DNA fragmentation
was evaluated by the terminal deoxynucleotidyl transferase-mediated
dUTP nick-end labeling assay in HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice treated
with SAL or 400 mg/kg APAP 6 or 24 h earlier. Magnification: ⫻ 200.
TABLE 2
Hepatic BNIP3 mRNA expression after APAP overdose
HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice were treated with SAL or APAP then killed at 2, 6, or 24 h. Real-time PCR was used to analyze liver tissue for expression of BNIP3 mRNA.
For each sample, the copy number of BNIP3 was normalized to that of HPRT, then further normalized to SAL-treated HIF-1 ␣
⫹ fl/ ⫹ fl
mice. Data represent mean
BNIP3/HPRT/SAL ratio ⫾ S.E.M. of n ⫽ 3– 6 animals.
Mouse
Real-Time PCR (BNIP3/HPRT versus SAL in HIF-1 ␣
⫹ fl/ ⫹ fl
)
SAL APAP
2h 6h 2 4h 2h 6h 2 4h
HIF-1 ␣
⫹ fl/ ⫹ fl
1.0 ⫾ 0.02 1.0 ⫾ 0.02 1.0 ⫾ 0.1 0.72 ⫾ 0.13 0.33 ⫾ 0.04 0.4 ⫾ 0.7
a
HIF-1 ␣
⌬ / ⌬
0.78 ⫾ 0.1 0.77 ⫾ 0.1 1.2 ⫾ 0.24 2.1 ⫾ 0.5
a,b
0.77 ⫾ 0.26 0.32 ⫾ 0.1
a
a
Significantly different from SAL-treated mice of the same genotype.
b
Significantly different from corresponding HIF-1 ␣
⫹ fl/ ⫹ fl
mice.
496 Sparkenbaugh et al.
ing in HIF-1 ␣
⫹ fl/ ⫹ fl
mice; the staining seemed to be cytoplas -
mic in most cells, with some nuclear staining. This supports
previous evidence that APAP overdose caused HIF-1 ␣ accu-
mulation in mouse liver (James et al., 2006; Chaudhuri et al.,
2011). There was markedly less HIF-1 ␣ staining in HIF-
1 ␣
⌬ / ⌬
mice treated with APAP, confirming successful deletion
of HIF-1 ␣ .
HIF-1 ␣ Inactivation Protects from Early APAP Hep-
atotoxicity. To determine whether TAM treatment could af-
fect APAP hepatotoxicity, UBC-Cre-ERT2( ⫺ / ⫺ )/HIF-1 ␣
flox/flox
mice, which do not express a functional Cre recombinase and
cannot remove HIF-1 ␣ , were treated with OIL or TAM for 5
days, and 3 weeks later were treated with SAL or 400 mg/kg
APAP. Both OIL- and TAM-treated mice developed severe liver
injury 6 h after treatment, indicating that TAM alone did not
affect APAP hepatotoxicity (Fig. 2). In contrast, when UBC-Cre-
ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice, which are capable of TAM-
induced Cre recombination, underwent the same treatments
OIL-treated UBC-Cre-ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice (HIF-1 ␣ -
sufficient) developed severe liver injury 6 h after treatment, but
injury was essentially absent in TAM-treated UBC-Cre-
ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice (HIF-1 ␣ -deficient) (Fig. 2), indi -
cating that the acute liver injury depended on HIF-1 ␣ signaling.
All subsequent experiments were performed in UBC-Cre-
ERT2( ⫹ / ⫺ )/HIF-1 ␣
flox/flox
mice.
Time Course of APAP Hepatotoxicity. HIF-1 ␣
⫹ fl/ ⫹ fl
mice treated with APAP had significantly greater plasma
ALT activity at 2 h compared with SAL-treated animals. The
former developed severe liver injury by 6 h, which continued
to increase through 24 h (Fig. 3A). APAP-treated HIF-1 ␣
⌬ / ⌬
Fig. 6. Effect of HIF-1 ␣ deletion on throm-
bin production and fibrin deposition . SAL
or 400 mg/kg APAP was administered
to HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice, and
plasma and liver samples were taken 2, 6,
and 24 h later. A, plasma TAT dimer was
measured as a marker of thrombin gener-
ation. Frozen liver samples were stained
immunohistochemically for fibrin. B, quan-
tification of fibrin. a indicates significantly
different from SAL-treated mice; b indi-
creased the colocalization of Bax with Cox IV, a mitochon-
drial marker (Fig. 4). In contrast this effect was not ob-
served in APAP-treated HIF-1 ␣
⌬ / ⌬
mice. APAP overdose
caused DNA fragmentation in centrilobular hepatocytes in
HIF-1 ␣
⫹ fl/ ⫹ fl
mice at 6 and 24 h; this effect was attenuated
upon HIF-1 ␣ deletion (Fig. 5).
HIF-1 ␣ Deletion Attenuates Coagulation System Ac-
tivation. Thrombin-antithrombin (TAT) concentration reflects
the activation of thrombin in plasma. In HIF-1 ␣
⫹ fl/ ⫹ fl
mice,
plasma TAT concentration was significantly increased by APAP
overdose 2, 6, and 24 h after treatment, although it was some-
what less at 24 h. In HIF-1 ␣
⌬ / ⌬
mice, plasma TAT was elevated
2 h after APAP, returned to baseline at 6 h, then increased
significantly by 24 h to a concentration greater than the value
⫹ fl/ ⫹ fl
mice (Fig. 6 A). A consequence of thrombin ac-
tivation in liver is deposition of fibrin, which was assessed by
immunohistochemical staining. In HIF-1 ␣
⫹ fl/ ⫹ fl
mice, fibrin de -
position was detected at 6 h after overdose and increased sig-
nificantly by 24 h. In contrast, there was no fibrin deposition in
HIF-1 ␣
⌬ / ⌬
mice detected until 24 h after APAP (Fig. 6B). In
HIF-1 ␣
⫹ fl/ ⫹ fl
mice, fibrin deposition at 6 h seemed to be centri -
lobular and sinusoidal after APAP overdose (Fig. 6C).
The fibrinolytic system consists of plasminogen and the
plasminogen activators tPA and uPA, which cleave plasmin-
ogen to plasmin to dissolve fibrin clots. PAI-1 is the endoge-
nous inhibitor of PAs, and elevation of active PAI-1 in plasma
suggests inhibition of fibrinolysis. Hepatic PAI-1 mRNA was
measured 2, 6, and 24 h after treatment. In SAL-treated
mice, basal PAI-1 mRNA expression was small (Table 3). In
⫹ fl/ ⫹ fl
mice treated with APAP, hepatic PAI-1 mRNA
was elevated by more than 10-fold as early as 2 h after APAP
and remained so through 24 h. In HIF-1 ␣
⌬ / ⌬
mice, PAI-1
mRNA increased to the same level as HIF-1 ␣
⫹ fl/ ⫹ fl
mice 2 h
after APAP, then decreased to baseline at 6 h only to increase
again by 24 h. The circulating concentration of active PAI-1
was also evaluated at 6 and 24 h. In HIF-1 ␣
⫹ fl/ ⫹ fl
mice, APAP
overdose increased the appearance of active PAI-1 in plasma
at 6 h, and PAI-1 concentration increased further by 24 h
(Fig. 7). This increase in PAI-1 was attenuated in HIF-1 ␣
⌬ / ⌬
mice at 6 h but was similar to that seen in HIF-1 ␣
⫹ fl/ ⫹ fl
mice
by 24 h.
APAP. Plasma concentrations of cytokines were measured
6 h after APAP exposure. Neither HIF-1 ␣ deletion nor
APAP overdose affected the plasma concentrations of IL-
1  , IL-2, IL-4, TNF ␣ , MIP-1 ␣ , or VEGF at this time (Table 4).
APAP overdose increased plasma concentrations of IL-6,
RANTES, and KC in HIF-1 ␣
⫹ fl/ ⫹ fl
mice, and these increases
were significantly attenuated upon HIF-1 ␣ deletion (Table
4). Plasma concentrations of IL-6, KC, and RANTES were
evaluated 24 h after APAP treatment. APAP overdose in-
creased IL-6 (Fig. 8A) and KC (Fig. 8B) in both HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice at 24 h; however, there were no
changes in RANTES (data not shown). Intrahepatic con-
centrations of KC and RANTES were also determined.
Hepatic RANTES was not altered by APAP (Fig. 8C), but
hepatic KC was significantly increased at 6 and 24 h after
Fig. 7. Effect of HIF-1 ␣ deletion on PAI-1 production. APAP or SAL
(400 mg/kg) was administered to HIF-1 ␣
and HIF-1 ␣
⌬ / ⌬
mice, and
plasma samples were taken after 2, 6, or 24 h. Active PAI-1 protein
was measured in plasma, and data represent means ⫾ S.E.M. of n ⫽
3– 8 animals per group. a indicates significantly different from SAL-
treated mice; b indicates significantly different from APAP-treated
HIF-1 ␣
⫹ fl/ ⫹ fl
mice.
TABLE 4
Cytokine concentrations in plasma of APAP-treated HIF-1 ␣
⫹ fl/ ⫹ fl
and
HIF-1 ␣
⌬ / ⌬
mice
HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice were treated with SAL or APAP, and plasma was
bead array.
Cytokine
Plasma Cytokine
SAL APAP
HIF-1 ␣
⫹ fl/ ⫹ fl
HIF-1 ␣
⌬ / ⌬
HIF-1 ␣
⫹ fl/ ⫹ fl
HIF-1 ␣
⌬ / ⌬
pg/ml
Interferon- ␥ 15.9 ⫾ 1.0 17.3 ⫾ 1.4 17.4 ⫾ 1.5 17.6 ⫾ 0.5
IL-1  6.1 ⫾ 0.5 6.2 ⫾ 0.3 6.9 ⫾ 0.6 6.5 ⫾ 0.5
IL-2 4.0 ⫾ 0.4 3.8 ⫾ 0.2 5.8 ⫾ 0.9 4.4 ⫾ 0.3
IL-4 4.8 ⫾ 0.3 5.0 ⫾ 0.5 4.5 ⫾ 0.4 4.2 ⫾ 0.3
IL-6 23.5 ⫾ 3.0 27.8 ⫾ 3.7 231 ⫾ 45.1
a
38.2 ⫾ 5.6
b
IL-10 10.9 ⫾ 0.4 11.6 ⫾ 0.4 14.0 ⫾ 1.4 11.5 ⫾ 0.2
IL-12 (p70) 14.8 ⫾ 0.6 15.4 ⫾ 0.2 14.6 ⫾ 0.5 14.4 ⫾ 0.3
KC (mIL-8) 49.8 ⫾ 7.4 40.3 ⫾ 8.0 573 ⫾ 372
a
110 ⫾ 25.5
b
MIP-1 ␣ 11.5 ⫾ 0.5 12.1 ⫾ 0.3 12.4 ⫾ 0.7 12.0 ⫾ 0.3
RANTES 28.5 ⫾ 4.0 27.3 ⫾ 1.5 52.9 ⫾ 10.9
a
33.2 ⫾ 3.2
b
TNF ␣ 17.9 ⫾ 0.4 18.4 ⫾ 0.5 20.0 ⫾ 1.0 18.3 ⫾ 0.4
VEGF 19 ⫾ 0.4 20.5 ⫾ 0.6 19.1 ⫾ 0.6 19.5 ⫾ 0.6
a
Significantly different from SAL-treated HIF-1 ␣
⫹ fl/ ⫹ fl
mice.
b
Significantly different from APAP-treated HIF-1 ␣
⫹ fl/ ⫹ fl
mice.
498 Sparkenbaugh et al.
APAP overdose in HIF-1 ␣
⫹ fl/ ⫹ fl
1 ␣
⌬ / ⌬
mice (Fig. 8D). KC is a chemokine important for
PMN infiltration, so hepatic PMNs were quantified. There
were significantly fewer PMNs in the livers of HIF-1 ␣
⌬ / ⌬
mice 6 and 24 h after APAP administration compared with
HIF-1 ␣
⫹ fl/ ⫹ fl
mice (Fig. 9 ).
Discussion
HIF-1 ␣ deletion protected mice from early APAP-induced
liver injury, but it did not prevent the development of severe
liver injury 24 h after overdose (Fig. 3). The protection from
toxicity at 2 and 6 h was not caused by decreased bioactiva-
tion, because the depletion of GSH was similar in HIF-1 ␣
⫹ fl/ ⫹ fl
and HIF-1 ␣
⌬ / ⌬
mice. These data suggest that HIF-1 ␣ has
dual roles in the pathogenesis of APAP-induced liver injury.
HIF-1 ␣ seems to have a damaging role in early progression of
into the mitochondria (Fig. 4), hemostasis (Figs. 6 and 7),
and/or the inflammatory response (Table 4 and Figs. 8 and 9).
The loss of protection at 24 h suggests that HIF-1 ␣ has a
protective role at later times, or that its absence delays the
onset of liver injury. The former suggestion is consistent with
a recently published report indicating that hepatocytes ex-
posed to moderate hypoxia were protected from APAP-in-
duced cell death (Yan et al., 2010). The protective effect of
hypoxia was attributed to hypoxic preconditioning, because
HIF-1 ␣ can induce the transcription of protective factors,
such as heme oxygenase-1 or erythropoietin (Bernhardt et
al., 2007). Furthermore, Kato et al. (2011) found that the
HIF-1 ␣ -regulated gene VEGF is important in liver repair
from APAP overdose.
APAP overdose increased hepatic HIF-1 ␣ protein a t2hi n
HIF-1 ␣
⫹ fl/ ⫹ fl
mice (Fig. 1C), an effect that was attenuated in
HIF-1 ␣
⌬ / ⌬
mice. This is consistent with published reports
that APAP overdose caused nuclear accumulation of HIF-1 ␣
treatment, an effect that was maintained through 12 h
(James et al., 2006; Chaudhuri et al., 2011). HIF-1 ␣ accumu-
lation occurred before the development of hypoxia in the liver
(Chaudhuri et al., 2011), suggesting that the initial mecha-
nism by which HIF-1 ␣ is stabilized is independent of hyp-
oxia. However, the coagulation system is activated and fibrin
deposits appear in the liver beginning 2 h after administra-
tion of APAP (Ganey et al., 2007), and tissue hypoxia be-
comes apparent between 2 and 4 h (Chaudhuri et al., 2011);
accordingly, coagulation-dependent hypoxia could contribute to
prolonged stabilization of HIF-1 ␣ during the progression of liver
injury.
APAP overdose caused HIF-1 ␣ -dependent translocation
of Bax to the mitochondrial membrane (Fig. 4). APAP
overdose causes c-Jun NH
2
-terminal kinase-dependent
Bax insertion into the mitochondrial membrane beginning
1 h after treatment (Saito et al., 2010), and Bax( ⫺ / ⫺ ) mice
were protected from APAP hepatotoxicity at 6 h, but not
12 h (Bajt et al., 2008a). Bajt et al. hypothesized that Bax
contributes to early mitochondrial permeability transition
proteins that initiate DNA fragmentation and hepatocel-
lular necrosis, but continuous oxidative stress supplants
this mechanism to cause cell damage at later times. Our
observation that HIF-1 ␣
⌬ / ⌬
mice had reduced Bax translo -
cation (Fig. 4) at 6 h after APAP is consistent with this
hypothesis. In addition, APAP-induced DNA fragmenta-
tion was attenuated in HIF-1 ␣
⌬ / ⌬
mice compared with
HIF-1 ␣
⫹ fl/ ⫹ fl
animals (Fig. 5). These data suggest that
HIF-1 ␣ is necessary for early Bax translocation and DNA
Fig. 8. Hepatic and plasma concentration
of cytokines. Plasma concentrations of
IL-6 and KC were measured at 24 h, liver
lysates were prepared, and the concentra-
tions of KC and RANTES were deter-
mined 6 and 24 h after SAL or APAP.
Data represent means ⫾ S.E.M. of n ⫽
concentration at 24 h. B, plasma KC con-
centration at 24 h. C, hepatic RANTES
concentration. D, hepatic KC concentra-
tion. a indicates significantly different
from SAL-treated mice; b indicates signif-
icantly different from APAP-treated HIF-
1 ␣
⫹ fl/ ⫹ fl
mice; c indicates significantly dif -
ferent from the same treatment at 6 h.
Role of HIF-1
␣
in Acetaminophen Hepatotoxicity 499
fragmentation; however, other APAP-induced signaling
overcomes this protection by 24 h.
In addition to its role in cell death signaling, HIF-1 ␣ might
contribute to APAP-induced liver injury by modulating the
hemostatic system. APAP overdose activates the coagulation
system and results in sinusoidal fibrin deposition in mice
(Ganey et al., 2007), and it is associated with alterations in
plasma hemostatic factors in humans (James et al., 2002).
Furthermore, reduction in coagulation attenuated liver in-
al., 2007), similar to our current finding in HIF-1 ␣
⌬ / ⌬
mice
(Fig. 3). In the absence of HIF-1 ␣ expression, there was
significant attenuation of thrombin generation (Fig. 6A) and
fibrin deposition (Fig. 6B) at 6 h. By 24 h, thrombin genera-
tion in HIF-1 ␣
⌬ / ⌬
mice had exceeded that seen in HIF-1 ␣
⫹ fl/ ⫹ fl
mice at the same time, and there was significant sinusoidal
fibrin (Fig. 6B). This raises the possibility that the protection
afforded by HIF-1 ␣ deletion is mediated by its ability to delay
thrombin generation and fibrin deposition, thereby delaying
the development of liver injury. However, it is also possible
that in the absence of liver injury in HIF-1 ␣
⌬ / ⌬
mice at 2 and
6 h there is not a stimulus for activation of thrombin.
HIF-1 ␣ also plays a role in fibrinolysis through the regu-
lation of PAI-1 expression (Copple et al., 2009). In the present
study, hepatic PAI-1 mRNA and plasma protein were ele-
⫹ fl/ ⫹ fl
mice (Table 3), consistent with previous findings (Ganey et
al., 2007; Bajt et al., 2008b). In contrast, in HIF-1 ␣
⌬ / ⌬
mice
PAI-1 mRNA was elevated at 2 h, returned to baseline by 6 h,
then increased to the same level as HIF-1 ␣
⫹ fl/ ⫹ fl
mice by 24 h
(Table 3). The appearance of active PAI-1 in the plasma
followed a similar pattern (Fig. 7). This result raises the
possibility that during APAP overdose PAI-1 expression is a
consequence of hepatocellular death and hemostasis, rather
than caused by a direct regulatory role by HIF-1 ␣ ; indeed
other transcription factors such as egr-1 and HIF-2 ␣ contrib-
ute to PAI-1 expression (Copple et al., 2009). PAI-1( ⫺ / ⫺ )
mice had enhanced liver necrosis and increased mortality
after administration of 200 mg/kg APAP compared with con-
trol animals, suggesting a protective role for PAI-1; the en-
hanced liver injury in PAI-1( ⫺ / ⫺ ) mice was associated with
decreased expression of proliferating cell nuclear antigen and
Appropriate tissue repair is necessary for recovery from
liver injury (Mehendale, 2005), and the HIF-1 ␣ -regulated
gene VEGF has been identified as an important mediator of
tissue repair after APAP hepatotoxicity (Donahower et al.,
| https://www.researchgate.net/publication/51130715_The_Role_of_Hypoxia-Inducible_Factor-1_in_Acetaminophen_Hepatotoxicity |
Cajuns (OFFTOPIC from Which is more European ? Finno-ugric...) [Archive] - Eupedia Forum
The word Cajun means Canadian Indian Ca(Injun) (Ca-jun) Injun is Native Indian. The Cajun were Kicked out by the British from Nova Scotia or somewhere in the east coast and they went to Louisana which was French controlled. The Cajun had Black blood. Frenchie Fuqua was a famous black NFL football player who was proudly Cajun. The Acadians http://www.acadian-cajun.com/hisacad1.htm The Cajun http://en.wikipedia.org/wiki/Cajun
Cajuns (OFFTOPIC from Which is more European ? Finno-ugric...)
The word Cajun means Canadian Indian Ca(Injun) (Ca-jun) Injun is Native Indian. The Cajun were Kicked out by the British from Nova Scotia or somewhere in the east coast and they went to Louisana which was French controlled. The Cajun had Black blood. Frenchie Fuqua was a famous black NFL football player who was proudly Cajun. The Acadians http://www.acadian-cajun.com/hisacad1.htm The Cajun http://en.wikipedia.org/wiki/Cajun
A short history of Acadians and Cajuns http://www.medschool.lsuhsc.edu/genetics_center/louisiana/article_cajunhistory.htm Frenchie Fuqua: https://www.facebook.com/pages/Frenchy-Fuqua/392714482753
A short history of Acadians and Cajuns http://www.medschool.lsuhsc.edu/genetics_center/louisiana/article_cajunhistory.htm Frenchie Fuqua: https://www.facebook.com/pages/Frenchy-Fuqua/392714482753 Frenchie Fuqua? Fuqua is typically a Huguenot name, not a Cajun one, Anglicized slightly from the original French "Fuquett." I actually descend distantly from the Huguenot immigrant most white Fuquas descend from, whose name is often recorded in late genealogies as "Guillame Fouquet" or some such, but whose actual name seems to have been Gill Fuquett. Frenchie, as a black man, is presumably descended from slaves of this family. Maybe other parts of his family or simply his culture was Cajun? Mod note: Moving these posts to a new thread.
Cajun is short for Acadian; the original name of Nova Scotia and Nova Scotians. White French colonists. Nothing to do with American indians or blacks, sorry. I have Acadian (Cajun) French ancestry. How very interesting that someone here would make a thread about us. Although, this post; it is totally inaccurate. We are mostly descended from French colonists. I would say that many of us (Cajuns) are probably our own ethnic group by now; and it seems we are partially homogeneous most the time. We probably have slightly different genetics now, to modern French people; due to 300-400 years of genetic isolation and insular separation. I have always wanted geneticists to study us Cajuns like they do any kind of homogeneous population in Europe; such as the Basques, Poles, Finns, or Albanians, and see what they could uncover.
Frenchie, as a black man, is presumably descended from slaves of this family. Maybe other parts of his family or simply his culture was Cajun? I used to follow the NFL and Frenchie used to appear with a fancy feathered cap or hat. I thought he was amusing. Anyway Fuqua being Huguenot is French, no? Only they were Protestants and killed by the French Catholics in France and many fled to England. My knowledge of Frenchie is not deep but just cursory. I heard from an Englishman who said 'cockney' accent came from he Huguenots learning English. Cajun is short for Acadian; the original name of Nova Scotia and Nova Scotians. White French colonists. Nothing to do with American indians or blacks, sorry. My apologies if I am wrong. I just commented without thoroughly checking.
You have Huguenots identified correctly. Cockney probably has its roots in Southeastern English dialects more than anything, but with plenty of slang from all sorts of East End London groups added in, including, no doubt, some influence from the Huguenots who settled there.Speaking of Huguenots, I have heard of Americans actually having closet French Huguenot ancestry. I am mostly of the Acadian (Cajun) French variety. But I also have almost 100% English ancestry on my dad's paternal side; hailing from Georgia and originally from South Carolina. My Cajun French ancestry also means that my family has Catholic background. My dad is half Cajun French and half American English. On my dad's paternal side; they were Protestants. I have noticed while looking up my ancestral records; that there seem to be some suspicious surnames in my lineage, that I have noticed; that seem to mean nothing in English, Old Norse or Old English. And they often appear to be Anglicized French in origin. (ex. Burnett, Ballard, Britton, Gaston) I would not be surprised if some of these names were French Huguenot. The legendary American folk legend Davy Crockett (Croquet?) had French Huguenot ancestry. His paternal ancestors bearing the Croquet surname originated from French Belgium. (Wallonia) when it was still part of France; and had escaped to England and Ireland in the 15th century. By the 16th century they had fled to the United States with English American (Protestant) colonists. Crockett's ancestors always claimed to be Irish or Scottish but were actually French refugees who blended in with Scots-Irish and English colonists; to avoid persecution by the French Catholics under Louis. I always thought it was rather interesting to discover if people in the USA had secret Huguenot ancestry. Even though they may have initially believed it to be Irish, Scottish, English or Dutch. prior etc
@ Melancon: I think you may have some reading to do in regards to the genetic make-up of self-reported "European-Americans" in Louisiana. including some Cajuns, no doubt: See: Bryc and Durand et al: The genetic ancestry of African, Latino, and European Americans across the United States. http://biorxiv.org/content/early/2014/09/26/009340 Just download the PDF. Lots of information there, but you might be particularly interested in the graphic which shows the states which have the highest percentage of "European-Americans" who have more than 2% African ancestry, presumably unknown African ancestry to many of them. Louisiana and South Carolina are among the leaders in that regard. Louisiana also leads among eastern and central states in the number of "European-Americans" who have more than 2% Amerindian ancestry. http://1.bp.blogspot.com/-dViY-OVquN4/VBs9Txr7KjI/AAAAAAAAJzA/8S6V3ym95ng/s1600/ea.jpg It shouldn't be a total surprise, of course. That there was admixture between the French colonists of Louisiana, of all stripes, and both Amerindians and African slaves has long been known, as is the phenomenon in American society known as "passing". From the text: "Using a less stringent threshold of 1%, our estimates suggest that as many as 8% of individuals from Louisiana, and upwards of 3% of individuals from some states in the West and Southwest, carry Native American ancestry. (Figure S8)" " In particular, individuals with African ancestry are found at much higher frequencies in states in the South than in other parts of the US: about 5% of self-reported European Americans living in South Carolina and Louisiana have at least 2% African ancestry. Lowering the threshold to at least 1% African ancestry (potentially arising from one African genealogical ancestor within the last 11 generations), European Americans with African ancestry comprise as much as 12% of European Americans from Louisiana and South Carolina and about 1 in 10 individuals in other parts of the South (Figure S9)." "In particular,individuals with African ancestry are found at much higher frequencies in states in the South than in other parts of the US: about 5% of self-reported European Americans living in South Carolina and Louisiana have at least 2% African ancestry. Lowering the threshold to at least 1% African ancestry (potentially arising from one African genealogical ancestor within the last 11 generations), European Americans with African ancestry comprise as much as 12% of European Americans from Louisiana and South Carolina and about 1 in 10 individuals in other parts of the South (Figure S9). " You can find further data in the Data Supplement found here: http://biorxiv.org/content/biorxiv/suppl/2014/09/18/009340.DC1/009340-1.pdf
Obviously, there ARE many Cajuns who do have American indian or Black ancestry. Only we do not call them Cajuns here. We call them Creoles (Cajuns with Black ancestry) or Métis. (Acadians with Native American) It is not possible that I have anything other than white, because I am somewhat inbred (homogeneous) and some of my ancestors share surnames; both on my mother and father's side. (Acadian names such as Pitre, Fuselier, Vidrine, Manuel, Mélançon, Fontenot etc.) I also have English ancestry on my dad's paternal side. (I also have at least one Galician Spanish ancestor that I know of, but he was 7th or 8th generation. And knowing the history of Spain, it is more possible for me to have Arabic ancestry at some point, rather than Black or American indian. If I do, it's probably about 55+ generations back. But the chances of this are extremely low. Especially considering I have only one ancestor who was Northern Spanish.) My family came from above the Lafayette area (Opelousas, Louisiana) which is the main area of most Acadian French whites; and their initial settlement after deportation from Nova Scotia by the British. If you travel forward East to New Orleans, you will find many Acadian "Cajuns" of mixed ethnicity. That is why the Black and Native American indian ancestry is so high in Louisiana. A lot of the Acadian French whites that moved to New Orleans mixed with Black slaves and American indians. For us in Acadiana, it is actually a lot more rare. Nothing to do with me though, lol. I'm 100% white I guarantee you.
Melancon: Nothing to do with me though, lol. I'm 100% white I guarantee you. I couldn't care less. You really shouldn't assume that these kinds of categorizations matter to other people the way that they do to you. However, perhaps you should invest in a spit test from 23andme, if you haven't already done so, and provide us with a screen shot. I've been following the postings in the Community Forum there for years, and there's an awful lot of very surprised southerners, including Louisiana Cajuns, who have posted on there about their previously unknown African and Amerindian ancestry. Just saying. There's also no indication in the study that the only people from Louisiana who had Amerindian and African ancestry were "Creoles". Plus, the whole thrust of your postings about the Finns has not been whether an individual Finn like Kristina has East Asian ancestry, and how much, but that Finns have East Asian, non-European ancestry. Therefore, the topic is not whether you individually have escaped having any of the ancestry which you find so objectionable, but whether Cajuns have such ancestry. Indeed, some "exotic" ancestry does show up in Cajuns. After whole clusters of "Ashkenazi" type hereditary breast cancer showed up in the Cajun community, they tracked ancestry and found it all led back to an Ashkenazi family who had changed their names, claimed to be German, and had married into the Cajun community. Given the high levels of endogamy, it spread like wildfire. Just google it...you'll find all the papers. Just for health reasons, I'd check to see whether those surnames appear in your family tree, given how the Cajuns are apparently so inbred. The high prevalence of genetic diseases is a consequence of such high levels of inbreeding, as I'm sure you know. As to Cajuns in general: "Not all Cajuns descend solely from Acadian exiles who settled in south Louisiana in the 18th century, as many have intermarried with other groups. Their members now include people with ancestry of British, Spanish, German, Italian, Native American (http://en.wikipedia.org/wiki/Native_Americans_in_the_United_States), Métis (http://en.wikipedia.org/wiki/M%C3%A9tis) and French Creole (http://en.wikipedia.org/wiki/Louisiana_Creole_people) settlers. Historian Carl A. Brasseaux asserted that it was this process of intermarriage that created the Cajuns in the first place.[2] (http://en.wikipedia.org/wiki/Cajun#cite_note-Brasseaux-2) Non-Acadian French Creoles (http://en.wikipedia.org/wiki/Louisiana_Creole_people) in rural areas were absorbed into Cajun communities. Some Cajun parishes, such as Evangeline (http://en.wikipedia.org/wiki/Evangeline_Parish) and Avoyelles (http://en.wikipedia.org/wiki/Avoyelles_Parish), possess relatively few inhabitants of Acadian origin. Their populations descend in many cases from settlers who migrated to the region from Quebec (http://en.wikipedia.org/wiki/Quebec), Mobile (http://en.wikipedia.org/wiki/Mobile,_Alabama), or directly from France (http://en.wikipedia.org/wiki/France). Theirs is regarded as the purest dialect of French spoken within Acadiana. Regardless, it is generally acknowledged that Acadian influences have prevailed in most sections of south Louisiana. Many Cajuns also have ancestors who were not French. Many of the original settlers in French Acadia were English (http://en.wikipedia.org/wiki/English_people), Irish (http://en.wikipedia.org/wiki/Irish_people), German (http://en.wikipedia.org/wiki/German_people), Greek (http://en.wikipedia.org/wiki/Greek_people), Spanish (http://en.wikipedia.org/wiki/Spanish_people) Canary Islanders (http://en.wikipedia.org/wiki/Isle%C3%B1os), and Italian (http://en.wikipedia.org/wiki/Italian_people) colonists who began to settle in Louisiana before and after the Louisiana Purchase (http://en.wikipedia.org/wiki/Louisiana_Purchase), particularly on the German Coast (http://en.wikipedia.org/wiki/German_Coast) along the Mississippi River (http://en.wikipedia.org/wiki/Mississippi_River) north of New Orleans (http://en.wikipedia.org/wiki/New_Orleans). People of Latin American (http://en.wikipedia.org/wiki/Latin_American) origin, a number of early Filipino (http://en.wikipedia.org/wiki/Filipino_people) settlers (notably in Saint Malo, Louisiana (http://en.wikipedia.org/wiki/Saint_Malo_%28Louisiana%29)), known as "Manilamen (http://en.wikipedia.org/wiki/Manilamen)," from the annual cross-Pacific (http://en.wikipedia.org/wiki/Pacific_Ocean) Galleon (http://en.wikipedia.org/wiki/Galleon) or Manila Galleon (http://en.wikipedia.org/wiki/Manila_Galleon) trade with neighboring Acapulco, Mexico (http://en.wikipedia.org/wiki/Acapulco,_Mexico), descendants of African American (http://en.wikipedia.org/wiki/African_American) slaves, and some Cuban Americans (http://en.wikipedia.org/wiki/Cuban_American) have also settled along the Gulf Coast (http://en.wikipedia.org/wiki/Gulf_of_Mexico) and, in some cases, intermarried into Cajun families. Anglo-American (http://en.wikipedia.org/wiki/Anglo) settlers in the region often were assimilated into Cajun communities, especially those who arrived before the English language became predominant in southern Louisiana." As you can see, French Creoles are an entity distinct from the Cajuns, but part of the Cajun jambalaya, one might say. :) It might be interesting for you to check it all out. You never know what could be hiding in that wood pile.
No offense; but you're totally ignorant and uninformed on the matter. I think it is better for you to dismiss yourself from me and my affairs. Maciamo has also told me that 23andme is not particularly accurate for genetics either. And that it is better to research your whole genome through a program like Dodecad or Eurogenes. I am suggesting that many white people who have had their genome covered with 23andme or FTDNA and discovered Black or American indian genetics are not always particularly accurate. And the science of genealogy is not always accurate either, any way; more or less. And it is always updating itself. Why not take your own advice; and upload your own genome with a screenshot? Let's see how Italian you truly are. Some Cajun parishes, such as Evangeline (http://en.wikipedia.org/wiki/Evangeline_Parish) and Avoyelles (http://en.wikipedia.org/wiki/Avoyelles_Parish), possess relatively few inhabitants of Acadian origin. This is not true. These two parishes actually make up a large portion of French people. I have family from there. It is a 45 minute drive into these two Parishes. (Counties). Some notable French families: Lafleur, Brignac, Chataignier, Porche, Meche, Prudhomme, Manuel, Babin, Carmouche, Andrepont. I can go on and on. Their members now include people with ancestry of British, Spanish, German, Italian, Native American (http://en.wikipedia.org/wiki/Native_Americans_in_the_United_States), Métis (http://en.wikipedia.org/wiki/M%C3%A9tis) and French Creole (http://en.wikipedia.org/wiki/Louisiana_Creole_people) settlers. Historian Carl A. Brasseaux asserted that it was this process of intermarriage that created the Cajuns in the first place.[2] (http://en.wikipedia.org/wiki/Cajun#cite_note-Brasseaux-2)Yeah. SOME not ALL. What is the percentage of Cajun French people having these ancestries? I would argue less than 5% of the whole 100%. That would suggest it is extremely rare. I am at least 70% French and I know this and can prove it by my genealogical records. But it is a very long list and is quite exhaustive.
Melancon, you are not arguing with me; you are arguing with science. The study which found African and Amerindian ancestry in so many Louisianians was based on whole genome comparisons of thousands of people...allele comparisons. Do you understand? You are also arguing with Louisiana historians and Acadian and Cajun genetic genealogists. Are you at all aware of that fact? Have you read the relevant historians? Have you subscribed to the Acadian list at rootsweb? In that regard, you might be interested in this article tracking Acadian ancestry. The admixture with "sauvage" women occurred in some families within a few generations of being on North American soil, and continued in Louisiana, where some African ancestry was also added in some families. There are well documented such cases. All of this might have contributed to the disrepute in which Cajuns used to be held in Louisiana. America has an unfortunate history in this regard with many groups. Of course, we're talking about traces remaining in current descendents. However, given how endogamous Cajuns are, you would think that what is present in a couple of families winds up being present in all of them, as was borne out with the tracking of the breast cancer gene. http://dna-explained.com/category/acadians/ Must I also repeat once again that this is not about you individually at all? It is about Louisiana people and Cajuns, in particular, just as the thrust of your argument on the other thread was about Finns in general, and not individual Finns, some of whom, I'm sure, show no or only trace amounts of East Asian. What is so difficult to understand here? You're perfectly free to ignore or deny science and history, of course. There are plenty of people who still insist that the earth was created 6,000 years ago in the face of all scientific evidence to the contrary. I'm sure there's also some hold-outs who believe that the sun revolves around the earth because they "see" it "move" across the sky. I feel it's my duty to point out, however, that such people are not accorded very much "respect", shall we say, among educated people. I also regret to inform you that I'm going to report your prior post. You can't say I didn't warn you. Adults have to be able to discuss these issues without resorting to personal attacks. Not that you care, I'm sure, but you're also now on my Ignore list, so don't expect any further responses.
Melancon, you are not arguing with me; you are arguing with science. The study which found African and Amerindian ancestry in so many Louisianians was based on whole genome comparisons of thousands of people...allele comparisons. Do you understand? You are also arguing with Louisiana historians and Acadian and Cajun genetic genealogists. Are you at all aware of that fact? Have you read the relevant historians? Have you subscribed to the Acadian list at rootsweb? In that regard, you might be interested in this article tracking Acadian ancestry. The admixture with "sauvage" women occurred in some families within a few generations of being on North American soil, and continued in Louisiana, where some African ancestry was also added in some families. There are well documented such cases. All of this might have contributed to the disrepute in which Cajuns used to be held in Louisiana. America has an unfortunate history in this regard with many groups. Of course, we're talking about traces remaining in current descendents. However, given how endogamous Cajuns are, you would think that what is present in a couple of families winds up being present in all of them, as was borne out with the tracking of the breast cancer gene. http://dna-explained.com/category/acadians/ Must I also repeat once again that this is not about you individually at all? It is about Louisiana people and Cajuns, in particular, just as the thrust of your argument on the other thread was about Finns in general, and not individual Finns, some of whom, I'm sure, show no or only trace amounts of East Asian. What is so difficult to understand here? You're perfectly free to ignore or deny science and history, of course. There are plenty of people who still insist that the earth was created 6,000 years ago in the face of all scientific evidence to the contrary. I'm sure there's also some hold-outs who believe that the sun revolves around the earth because they "see" it "move" across the sky. I feel it's my duty to point out, however, that such people are not accorded very much "respect", shall we say, among educated people. I also regret to inform you that I'm going to report your prior post. You can't say I didn't warn you. Adults have to be able to discuss these issues without resorting to personal attacks. Not that you care, I'm sure, but you're also now on my Ignore list, so don't expect any further responses.I am glad that I am on your ignore list. Because as I stated before; none of those sources have any real accuracy or merit and most of the time, are often outdated. And can be explained in a different way. All you have ever presented to me was passive-aggressive baseless accusations and assumptions; and hypocritical self-projection. I live in Louisiana and I believe I know our genetic heritage more than any other group of people; thank you. And I have also not disagreed with you. I have actually agreed with you on some points, if you read my posts. There is no such thing as ignorance towards your "sources"...You have simply misinterpreted them; Not I. I have simply gave you explanation for them, and you have simply ignored them completely or passed them off as opinion. I have made explanations for why American Indian and Black DNA is seen in Acadians at a high frequency. It doesn't mean they are true Acadians though. Because these people are no longer Cajuns anyway. You have the definition of a Cajun twisted to include Mixed-race ethnicity like Creoles and Metis. Cajuns are white Acadian French colonist descendents.
Actually, the original Acadian population of Nova Scotia included a lot of Micmac ancestry, mostly on the maternal side, because of the scarcity of women in the colony in the early days. And the Cajun population now includes a lot of non-Acadian ancestry. Given the former flexibility with surnames shown by Francophones in North America in the past, I'm dubious about any Cajun who claims to know who all his ancestors are. Many Cajun surnames are not found in France.Yeah right; yet another exaggeration; and false information regarding my ethnic origins, to get under my skin. BTW most of the Micmac ancestry has been discredited and European mtDna has been found in certain female individuals who were thought to be Micmac. Micmac and other American indian ancestry is actually extremely rare. I can see why a lot of newcomers have recently come to the board, have commented negatively and have a disdain for you and Angela. All you guys do is make baseless assumptions, bully, stalk and harass. Mind your own business and get a life hein? :) Oh, by the way ... Hein is "eh" in French.
Actually, the original Acadian population of Nova Scotia included a lot of Micmac ancestry, mostly on the maternal side, because of the scarcity of women in the colony in the early days. And the Cajun population now includes a lot of non-Acadian ancestry. Given the former flexibility with surnames shown by Francophones in North America in the past, I'm dubious about any Cajun who claims to know who all his ancestors are. Many Cajun surnames are not found in France.Please stop harassing and spreading disinformation. I've kept my thoughts from you for way too long and I think you are an arrogant, narcissistic, haughty sanctimony. I really do not appreciate your passive-aggressive taunting and will begin to report your messages to Moderators if you continue your passive-aggression. The easiest thing for me to do would be to put you on ignore and not associate myself with any of comments posts or responses from you, of any kind. I have no idea who you are or why you continue to patronize me or attempt to insult my intelligence or correct me; but I am tired of it. I don't have to listen to your ignorant drivelry; because for what I know; you don't have a PhD and your so far what you have presented to me; seems to suggest that you are a mostly incredulous member. I have a hard time believing why you are seen on this website with such High Status and awards; because most of the comments I have seen from you are mostly logical foxholes; thus your credibility has no importance or value to me.
I used to have a Cajun person on 23andme, their results were similar to a French person except they had 5% Native American. It probably was indigenous Canadian and acquired before migration to the US south.
Many French trappers who came to Canada could not get French girls so they mated with native aboriginal women. From a Portuguese Canadian I was told that the French government finally rounded up French prostitutes and shipped they over to Canada so that is why the Canadian French girls are very good-looking. I don't know how true this is but in summer in Toronto they are a lot of pretty Frech girls from Quebec selling flowers in the streets of Toronto. I asked a few of them and I was told they were from Quebec.
thats retarded.
Many French trappers who came to Canada could not get French girls so they mated with native aboriginal women. From a Portuguese Canadian I was told that the French government finally rounded up French prostitutes and shipped they over to Canada so that is why the Canadian French girls are very good-looking. I don't know how true this is but in summer in Toronto they are a lot of pretty Frech girls from Quebec selling flowers in the streets of Toronto. I asked a few of them and I was told they were from Quebec. A joke often repeated by English speaking Quebecers is that a pure laine Quebecer is a Francophone who's half Irish and half Algonquin. Les Pepsis hate that joke because it's sometimes quite close to the truth.
thats retarded.
I decided to check if there is any truth to what I was told.
The title "King's Daughters" was meant to imply state patronage, not royal or noble parentage. Most of these women were commoners of humble birth. As a fille du roi, a woman received the King’s support in several ways. The King paid one hundred livres (http://en.wikipedia.org/wiki/New_France_livre) to the French East India Company (http://en.wikipedia.org/wiki/French_East_India_Company) for the woman’s crossing, as well as furnishing a trousseau (http://en.wikipedia.org/wiki/Hope_chest).[8] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199273-74-8) The Crown paid a dowry for each woman; this was originally supposed to be four hundred livres, but as the Treasury could not spare such an expense, many were paid in kind.[9] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199275-9) As was the case for most emigrants who went from France to New France, 80% of the filles du roi were from the Paris, Normandy and Western regions.[10] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199254-10) The Hôpital-Général de Paris (http://en.wikipedia.org/wiki/General_Hospital_of_Paris) and the St-Sulpice parish were big contributors of women for the new colony.[11] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199257-58-11) As such, most of the filles du roi were from urban areas.[12] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992108-12) A few women came from other European countries, including Germany, England, and Portugal.[13] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELanctot195222.2C_103.2C_115.2C_117.2C126-13) Those who were chosen to be among the filles du roi and allowed to emigrate to New France were held to scrupulous standards, which were based on their "moral calibre" and whether they were physically fit enough to survive the hard work demanded by life as a colonist. The colonial officials sent several of the filles du roi back to France because they were judged below the standards set out by the King and the Intendant of New France.[14] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELanctot1952212-14)
Almost half of the filles du roi were from the Paris area, 16% from Normandy and 13% from western France. Many were orphans with very meager personal possessions, and their level of literacy was relatively low.[15] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-15) Socially, the young women came from different social backgrounds, but were all very poor. They might have been from an elite family that had lost its fortune, or from a large family with children to "spare."[16] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199251-16) Officials usually matched women of higher birth with officers or gentlemen living in the colony,[17] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry199268-17) sometimes in the hopes that the nobles would marry the young women and be encouraged to stay in Canada rather than return to France.
Integration into New French society
Year
Arrivals[18] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-indies-18)
1663
36
1664
1
1665
80-100
1666
0
1667
109
1668
80
1669
149
1670
c. 165
1672
0
1673
60
Total
832-852
The women disembarked in Quebec City (http://en.wikipedia.org/wiki/Quebec_City), Trois-Rivières (http://en.wikipedia.org/wiki/Trois-Rivi%C3%A8res), and Montreal (http://en.wikipedia.org/wiki/Montreal). After their arrival, their time to find husbands varied greatly. For some, it was as short as a few months, while others took two or three years before finding an appropriate husband.[19] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992131-19) For the process of choosing a husband, and the marriage, most couples would officially get engaged in church, with their priest and witnesses present.[20] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992145-20) Then, some couples went in front of the notary, to sign a marriage contract.[21] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992146-21) Marriages were celebrated by the priest, usually in the woman’s parish of residence.[22] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992140-22) While the marriage banns (http://en.wikipedia.org/wiki/Banns) customarily were to be published three times before a wedding could take place, the colony’s need for women to marry quickly led to few filles du roi having marriage banns announced.[23] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992149-23) It is known that 737 of these filles du roi were married in New France.[24] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-24)
The marriage contracts represented a protection for the women, both in terms of financial security if anything were to happen to them or their husband, and in terms of having the liberty to annul the promise of marriage if the man they had chosen proved incompatible.[25] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992150-25) A substantial number of the filles du roi who arrived in New France between 1669 and 1671 cancelled marriage contracts; perhaps the dowry they had received made them disinclined to stick with a fiancé they found themselves dissatisfied with.[26] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELandry1992152-26)
An early problem in recruitment was the women's adjustment to the new agricultural life. As Saint Marie de L'Incarnation (http://en.wikipedia.org/wiki/Marie_of_the_Incarnation_%28Ursuline%29) wrote, the filles du roi were mostly town girls, and only a few knew how to do manual farm work. This problem remained, but in later years, more rural girls were recruited.[citation needed (http://en.wikipedia.org/wiki/Wikipedia:Citation_needed)]
There were approximately 300 recruits who did not marry in New France. Some had changes of heart before embarking from the ports of Normandy and never left, some died during the journey, some returned to France to marry, and a few never did marry.[citation needed (http://en.wikipedia.org/wiki/Wikipedia:Citation_needed)]
Integration in Ville-Marie Prior to the King's Daughters, the women who immigrated to Ville-Marie, otherwise known as Montreal (http://en.wikipedia.org/wiki/Montreal), had been recruited by the Société Notre-Dame de Montréal (http://en.wikipedia.org/wiki/Soci%C3%A9t%C3%A9_Notre-Dame_de_Montr%C3%A9al) founded in 1641 in Paris.[27] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTEBeaudoinS.C3.A9vigny19968-27) Amongst these women were Jeanne Mance (http://en.wikipedia.org/wiki/Jeanne_Mance) and Marguerite Bourgeoys.[28] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTEBeaudoinS.C3.A9vigny199612-28) When the first filles du roi arrived in Montreal, they were taken in by Bourgeoys.[29] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTEBeaudoinS.C3.A9vigny199660-29) Initially, there were no comfortable lodgings to receive them, but in 1668 Bourgeoys procured a large farmhouse in which to house them: the Maison Saint-Gabriel (http://en.wikipedia.org/wiki/Maison_Saint-Gabriel).[30] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTEBeaudoinS.C3.A9vigny199661-30)
End of recruitment; growth of the settlement By the end of 1671, Talon suggested that it would not be necessary to sponsor the passage of girls for the next year, and the king accepted his advice.[18] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-indies-18) The migration briefly resumed in 1673, when the king sent 60 more girls at the request of Buade de Frontenac (http://en.wikipedia.org/wiki/Louis_de_Buade_de_Frontenac), the new governor, but that was the last of the Crown's sponsorship.[18] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-indies-18) Of the approximately 835 marriages of immigrants in the colony during this period, 774 included a fille du roi.[31] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-peupl-31) By 1672, the population of New France had risen to 6,700, from 3,200 in 1663.[31] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-peupl-31)
Rumours and legends http://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/The_Arrival_of_the_French_Girls_at_Quebec%2C_1667_-_C.W._Jefferys.jpg/220px-The_Arrival_of_the_French_Girls_at_Quebec%2C_1667_-_C.W._Jefferys.jpg (http://en.wikipedia.org/wiki/File:The_Arrival_of_the_French_Girls_at_Quebec,_16 67_-_C.W._Jefferys.jpg) The Arrival of the French Girls at Quebec, 1667. Watercolour by Charles William Jefferys (http://en.wikipedia.org/wiki/Charles_William_Jefferys)
The idea that the filles du roi were prostitutes has been an insidious rumour ever since the inception of the program in the 17th century. It seems to have arisen from a couple of misconceptions, both contemporary and modern, about immigration to French colonies in the New World. The first of these, which took root long before the first fille du roi emigrated, was that Canada was a penal colony. While there were two campaigns in the mid-16th century that involved the immigration of French criminals to Canada in exchange for their records being expunged, they were both short-lived. These programs resulted in little more than setting a precedent for viewing Canada as a place where those "of questionable morality" could be sent for one reason or another.[32] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELanctot195220-32)
The popularisation of the idea that the filles du roi in particular were prostitutes can be traced to an account by Baron La Hontan of his time in New France;[33] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-LofC-33) several earlier sources made the same assertion, including Saint-Amant (http://en.wikipedia.org/wiki/Saint-Amant), Tallement des Réaux (http://en.wikipedia.org/wiki/Tallement_des_R%C3%A9aux), and Paul LeJeune. In his account, La Hontan refers to the filles du roi as being "of middling virtue", and wrote that they had emigrated in the hopes of religious absolution.[34] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELanctot1952159-34) As early as 1738 Claude Le Beau countered his portrayal in an account of his own journey to New France, as did Pierre François Xavier de Charlevoix (http://en.wikipedia.org/wiki/Pierre_Fran%C3%A7ois_Xavier_de_Charlevoix) in his 1744 work.[35] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-FOOTNOTELanctot195225.2C33.2C192.2C195-35)
Out of nearly 800 filles du roi, only one, Catherine Guichelin, was charged with prostitution (http://en.wikipedia.org/wiki/Prostitution) while living in Canada, after she was abandoned by her husband.[33] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-LofC-33) She appeared before the Sovereign Council of New France (http://en.wikipedia.org/wiki/Sovereign_Council_of_New_France) under the charge of carrying out "a scandalous life and prostitution" on 19 August 1675. Her two children were 'adopted' by friends, and she was banished from Quebec City. She was reported to have turned to prostitution after her husband, Nicholas Buteau, abandoned the family and returned to France. She later gave birth to many children out of wedlock. Guichelin had at least two marriage contracts cancelled. She also wed twice more after returning to Sorel, Quebec (http://en.wikipedia.org/wiki/Sorel,_Quebec), then Montreal, Quebec (http://en.wikipedia.org/wiki/Montreal,_Quebec).[36] (http://en.wikipedia.org/wiki/King%27s_Daughters#cite_note-36)
http://en.wikipedia.org/wiki/King%27s_Daughters
In the 1660s the French government sent about 850 young women (single or widowed) called King's Daughters (http://en.wikipedia.org/wiki/King%27s_Daughters) ("filles du roi"). They quickly found husbands among the predominantly male settlers, as well as a new life for themselves. They came mostly from poor families in the Paris area, Normandy and the central-western regions of France. A handful were ex-prostitutes, but only one is known to have practiced that trade in Canada.[2] (http://en.wikipedia.org/wiki/History_of_Canadian_women#cite_note-2) As farm wives with very good nutrition and high birth rates they played a major role in establishing family life and enabling rapid demographic growth. They had about 30% more children than comparable women who remained in France. Landry says, "Canadians had an exceptional diet for their time. This was due to the natural abundance of meat, fish, and pure water; the good food conservation conditions during the winter; and an adequate wheat supply in most years."[3] (http://en.wikipedia.org/wiki/History_of_Canadian_women#cite_note-3)[4] (http://en.wikipedia.org/wiki/History_of_Canadian_women#cite_note-4) The American politician Hillary Clinton (http://en.wikipedia.org/wiki/Hillary_Clinton) is a descendant of one of them.[citation needed (http://en.wikipedia.org/wiki/Wikipedia:Citation_needed)]
Besides household duties, some women participated in the fur trade (http://en.wikipedia.org/wiki/North_American_fur_trade), the major source of cash in New France (http://en.wikipedia.org/wiki/New_France). They worked at home alongside their husbands or fathers as merchants, clerks and provisioners. Some were widowed, and took over their husbands' roles. A handful were active entrepreneurs in their own right.[5] (http://en.wikipedia.org/wiki/History_of_Canadian_women#cite_note-5)
In the early 19th century down to the 1950s upper-class Anglos (http://en.wikipedia.org/wiki/English_language) dominated high society in Montreal, and their women constructed and managed their identity and social position through central events in the social life, such as the coming out of debutantes. The elite young women were trained in intelligent philanthropy and civic responsibility, especially through the Junior Leagues. They seldom connected with the reform impulses of the middle class women, and for and were paternalistic in their views of the needs of working-class women.[6] (http://en.wikipedia.org/wiki/History_of_Canadian_women#cite_note-6)
http://en.wikipedia.org/wiki/History_of_Canadian_women
The Fur trade http://en.wikipedia.org/wiki/North_American_fur_trade http://www.ameriquefrancaise.org/en/article-363/French-Canadian_Trappers_of_the_American_Plains_and_Rocki es.html http://www.thecanadianencyclopedia.ca/en/article/fur-trade/
| https://www.eupedia.com/forum/archive/index.php/t-30618.html?s=845f44f3e31a4e9c7a3bb290bf7f9903 |
Questions about the KCA | Reasonable Faith
Dr. William Craig answers weekly Questions and Answers on Christian Doctrine and apologetics. Read question Questions about the KCA here.
#806 Questions about the KCA
Q
Dear Dr. Craig,
I am currently reading your book reasonable faith (theologisch) in the endeavour of trying to understand whether the christian faith is true or not.
I wanted to ask for clarification about your conclusion of the Kalam cosmological argument, that the first cause must be:Time- & SpacelessImmensely powerfulAnd personal
What definition of time- and spaceless are you using? It is unclear for me whether you mean independent of space time in general or simply independent of our space time.
I wanted to ask for clarification about your use of the term unimaginably powerful (unvorstellbar mächtig). Do you mean to suggest that the cause is omnipotent, or do you conclude that the cause must be sufficiently powerful to create the universe?
Lastly you conclude the personal trait from the previous traits. It appears to me that many more options with these traits are possible (e.g. meta space time or energy itself).
Furthermore, I wanted to clarify why you see the possibility of a space and timeless mind. As far as i know, no such thing was demonstrated to exist.
I also wanted to ask for clarification of how causation would work with no space time.
Thank you very much in advance,
Cyril
Germany
Dr. craig’s response
A
I’m delighted to have a question from Germany, Cyril, and especially from someone who is investigating the truth of the Christian faith! I hope that I can be of help and encouragement to you in your quest.
What definition of “timeless” and “spaceless” am I using? I mean “having neither temporal location nor extension” and “having neither spatial location nor extension,” where something has a temporal and spatial location iff it exists at a moment of time and at a place in space, and something has a temporal and spatial extension iff it persists in time and is extended in space. These definitions are intended to be completely general.
I deliberately used the expression “unimaginably powerful” rather than “omnipotent” because we cannot infer from the First Cause’s creation of the universe that it is literally omnipotent in the philosophical sense; but in order to create the entire universe without a material cause it must be unimaginably powerful, if not omnipotent.
Ask for the personal traits of the First Cause, I’d recommend that you look again at the three arguments I give for the personhood of the Creator. My arguments are: (1) the cause of the origin of the universe must be either an abstract object or an unembodied mind, and abstract objects are not causes; (2) only a personal cause can explain the origin of a temporal effect with a beginning from an eternal cause; (3) there are two types of causal explanation, personal and scientific, and there cannot be a scientific explanation of a first physical state of the universe. As I reflect on these arguments, I think that they are quite compelling. The alternatives you mention (meta-spacetime or energy itself) are excluded by the philosophical and scientific arguments for an absolute beginning of the universe, including all matter and energy and time itself. So the question comes back to the arguments in support of the second premise of the KCA, that the universe began to exist.
The above three arguments just are arguments for the existence of an unembodied Mind which is the Creator of the universe. In fact we have confirmation of the existence of such a cosmic Mind in other theistic arguments, such as the argument from the fine-tuning of the universe, the argument from the applicability of mathematics to physical phenomena, and the moral argument from the objectivity of moral values and duties. This Mind must exist timelessly and spacelessly, since time and space began to exist. No incoherence has been demonstrated in the existence of such a Mind.
Finally, as for the truth of the causal principle, the key point is that it is not just a physical principle like a law of nature that applies only within our universe. Rather it is a metaphysical principle: being comes only from being. This metaphysical principle, as old as Parmenides, requires that anything that begins to exist has a cause.
Notice that causal priority does not entail temporal priority. In my view God’s causing the universe to come into being is simultaneous with the universe’s coming into being.
| https://www.reasonablefaith.org/question-answer/P570/questions-about-the-kca |
BATES v. SOUTHGATE | 308 Mass. 170 | Mass. | Judgment | Law | CaseMine
Get free access to the complete judgment in BATES v. SOUTHGATE on CaseMine.
BATES v. SOUTHGATE
308 Mass. 170 31 N.E.2d 551
Case Information
CITATION CODES
308 Mass. 170 31 N.E.2d 551
ATTORNEY(S)
L. Wheeler, Jr., (H.A. Reynolds with him,) for the defendants.
E.O. Proctor, for the plaintiff.
JUDGES
QUA, J.
ACTS
No Acts
Important Paras
As a matter of principle it is necessary to weigh the advantages of certainty in contractual relations against the harm and injustice that result from fraud. In obedience to the demands of a larger public policy the law long ago abandoned the position that a contract must be held sacred regardless of the fraud of one of the parties in procuring it. No one advocates a return to outworn conceptions. The same public policy that in general sanctions the avoidance of a promise obtained by deceit strikes down all attempts to circumvent that policy by means of contractual devices. In the realm of fact it is entirely possible for a party knowingly to agree that no representations have been made to him, while at the same time believing and relying upon representations which in fact have been made and in fact are false but for which he would not have made the agreement. To deny this possibility is to ignore the frequent instances in everyday experience where parties accept, often without critical examination, and act upon agreements containing somewhere within their four corners exculpatory clauses in one form or another, but where they do so, nevertheless, in reliance upon the honesty of supposed friends, the plausible and disarming statements of salesmen, or the customary course of business. To refuse relief would result in opening the door to a multitude of frauds and in thwarting the general policy of the law. Go to
The case of Granlund v. Saraf, 263 Mass. 76 , was a suit in equity by the buyer for rescission of his purchase of a retail business induced by fraudulent representations as to the amount of the gross receipts. By a document forming part of the transaction the defendants had attempted to provide that if after six months from the date of sale the plaintiffs should find that one of the defendants had made any misrepresentation, that defendant would take the store back and refund the money, but only on certain specified conditions. The court said, "It is a fundamental principle of law, as it is of morals, public policy and fair dealing, that a party cannot contract against liability for his own fraud. Fraud which enters into the making of the contract cannot be excluded from the reach of the law by any form of phrase inserted in the contract itself. Parties cannot by written words prevent the law from inquiring into and granting relief for fraud in the substance of the contract. Butler v. Prussian, 252 Mass. 265, 268 . Many contracts have been refused enforcement whereby a party has striven to shield himself from the results of his fraudulent practices upon the other party. Such contracts, if given validity, would overcome the salutary maxim which pervades the common law, that fraud vitiates every transaction at the election of the injured party" (page 79). And again: "Attempts under the form of contract to secure total or partial immunity from liability for fraud are all under the ban of the law. The extent of the relief granted to the injured party, in order to be adequate and complete, cannot not be constricted by act of the parties. The nature of fraud and the grounds upon which the law denounces it are such that it cannot be made the subject of preliminary or contemporaneous alleviating contract" (page 80). Relief was granted to the plaintiffs without observance of the conditions upon which rescission was to be limited by the terms of the contract. Nevertheless the court distinguished Colonial Development Corp. v. Bragdon "and similar decisions where parties, freely and without fraud or imposition, have made a written contract to the effect that all representations touching the subject matter of the contract are therein set forth; in such cases it has been held that the terms of the formal contract cannot be varied or contradicted by proof that there were other antecedent representations fraudulent in nature" (pages 80-81). Go to
Colonial Development Corp. v. Bragdon, 219 Mass. 170 , was an action of contract to recover the purchase price of land sold, with a cross action for deceit. The contract contained this clause: "No agent of this company has authority . . . to make any reference, representation or agreement not contained in this contract and none not contained herein shall be binding upon the seller, or in any wise effect [ sic ] the validity of this contract or form any part hereof, but all statements made have been merged and set forth herein" (page 173). It was held that because of this provision previous false and fraudulent representations by the plaintiff's authorized agents as to the condition of the land, inducing the defendant to sign the contract, were neither a defence nor the basis of a cross action. The court said: "It is a fundamental principle of law that contracts in writing voluntarily executed with full knowledge of their contents by rational beings acting on their own judgment must be enforced"; and also: "The defendant relies on the proposition that fraud vitiates every contract. But there is a distinction between a fraud which is antecedent to a contract, and fraud which enters into the making of the contract. The present case belongs to the former class" (page 174). The only cases cited are Cannon v. Burrell, hereinbefore discussed, and McCoy v. Metropolitan Life Ins. Co. 133 Mass. 82 . The latter case, decided in 1882, merely held that the application for an insurance policy was part of the contract of insurance and that misrepresentations contained in it material to the risk were a defence to an action on the policy. The case of Colonial Development Corp. v. Bragdon has been frequently regarded as the leading authority for a distinction supposed to exist in this Commonwealth between "antecedent" fraud and "fraud which enters into the making of the contract." Neither kind of fraud is defined in the opinion, and no reason is given why a contract should be voidable if procured by fraud perpetrated at one time or in one manner and valid if procured by fraud perpetrated at another time or in another manner. Go to
For the reasons set forth we conclude that the distinction stated in Colonial Development Corp. v. Bragdon, 219 Mass. 170, 174 , and repeated in the later cases hereinbefore mentioned, between "fraud which is antecedent to a contract" and "fraud which enters into the making of the contract" cannot be maintained, and that contracts or clauses attempting to protect a party against the consequences of his own fraud are against public policy and void where fraud inducing the contract is shown, whether that fraud was "antecedent" to the contract or "entered into the making" of it. In the words of Granlund v. Saraf, 263 Mass. 76, at page 80 , "Attempts under the form of contract to secure total or partial immunity from liability for fraud are all under the ban of the law." Go to
There is, closely related to the cases we have here discussed, another class of cases wherein the parties have contracted that goods are bought "as is," thus purporting to cast upon the buyer by agreement all risk as to the condition of the goods. It would seem that if parties could bind themselves by contract against the effect of "antecedent" fraud an agreement of the kind described ought to be as effective to that end as an agreement that no representations have been made. Yet the issue of fraud has been held to be open in these cases. Reinherz v. American Piano Co. 254 Mass. 411, 421, 422, 423 . Connelly v. Fellsway Motor Mart, Inc. 270 Mass. 386, 390, 391 . New England Foundation Co. Inc. v. Elliott Watrous, Inc. 306 Mass. 177, 182 . Go to
Five months after the decision in Florimond Realty Co. Inc. v. Waye, last above discussed, further significant language was used. Connelly v. Fellsway Motor Mart, Inc. 270 Mass. 386 , was an action at law for deceit by which the plaintiff was induced to buy an automobile from the defendant by a false representation made before the execution of the contract that the automobile was a new one. The contract provided that it embodied "all the terms and conditions of sale," that the automobile was sold "as is, where is, and as shown. No guarantee as to year of car." The court said that the evidence did not warrant a finding of "fraud which entered into the making of the contract as distinguished from fraud which was antecedent thereto" (page 388). Thereupon, treating the representation as "antecedent," the court discussed briefly Colonial Development Corp. v. Bragdon and cases following it. The court then referred to the parol evidence rule by which "all previous or contemporaneous oral discussion or written memoranda are assumed to be rejected or merged in" a written contract, and said, "It is this principle which has been held applicable in the group of cases already cited and illustrated by Colonial Development Corp. v. Bragdon, supra, although in them there were also express agreements relating to representations. These cases constitute no exception to the general rule that fraud vitiates every contract at the election of the injured party. It does not authorize parties to attempt to provide by written contract that there shall be no liability for fraud" (page 390). It was held, at least for the purposes of an action of tort, that "the false representations were not merged in the written agreement" (page 391), and a verdict for the plaintiff was allowed to stand. Thus the court, in substance, stated that Colonial Development Corp. v. Bragdon was merely an illustration of the parol evidence rule and not the pronouncement of a distinct principle. Go to
8 B.U. Law Rev. 57. 10 Id. 446. 6 Brooklyn Law Rev. 450, 451. 32 Ill. Law Rev. 944. 75 Univ. of Pa. Law Rev. 281. See 25 Col. Law Rev. 231; 20 Cornell Law Quarterly, 91; 32 Mich. Law Rev. 1004. Compare, however, 22 Cornell Law Quarterly, 103. Go to
This decision deals with fraud and its consequences. Nothing we have said limits or alters the effect of the parol evidence rule. That rule does not stand in the way of rescission for fraud. Weeks v. Currier, 172 Mass. 53, 55 . Busiere v. Reilly, 189 Mass. 518, 520 . Harris v. Delco Products, Inc. 305 Mass. 362, 364 . Go to
Upon this evidence the jury could find, if they were not bound to find, that at the time of the telephone conversations both parties expected a confirmation slip to be delivered later as the embodiment of the bargain and regarded the slip, after its delivery and acceptance, as expressing the final terms of the contract between them. The slip stated the names of seller and buyer, the subject matter of the sale, the price, and the terms of payment as "cash transaction." It contained all the essential elements of a contract. Even though previous oral conversations would be enough in themselves to establish an oral contract the parties may, nevertheless, by mutual understanding postpone the culmination of their negotiations into a contract to the later preparation and delivery of a written instrument. It is immaterial that the plaintiff did not sign the "confirmation slip." Thomas v. Barnes, 156 Mass. 581, 583, 584 . Glackin v. Bennett, 226 Mass. 316, 320 . Gould v. Converse, 246 Mass. 185, 188 . Greaney v. McCormick, 273 Mass. 250, 253 . Williston on Contracts (Rev. Ed.) § 90A. Go to
On the question of fraud there was evidence that before the plaintiff bought the stock one of the defendant partners stated to the plaintiff, as an inducement to buy, that the gypsum company had received an order for forty thousand tons of gypsum to be delivered in New York at $2.66 a ton, upon which the company would derive a profit of about $1 a ton, and that the plaintiff relied upon this statement in agreeing to buy, in accepting the "confirmation slip," and in paying for the stock. There was no evidence that the defendants by any statement on their part withdrew or corrected the alleged representation, and the evidence that the plaintiff in fact still continued to rely upon it and was induced by it to accept the confirmation slip as the contract between the parties was before the jury for their consideration. The defendants denied having made any such representation, but admitted that the company had not received such an order and that they knew it had not. When taken in connection with other evidence in the case, which need not be stated, as to the history and prospects of the gypsum company, there can be no doubt that a representation as to an order for forty thousand tons at the price stated could be found to have been material as an inducement to buy the stock, and that upon the evidence just recited the verdict for the plaintiff can be sustained, unless as matter of law the provisions of the "confirmation slip" constitute a defence. Gurney v. Tenney, 197 Mass. 457, 465 . Schleifer v. Worcester North Savings Institution, 306 Mass. 226, 228 . Indeed, there has been no argument to the contrary. Go to
The case of Florimond Realty Co. Inc. v. Waye, 268 Mass. 475 , was a suit for specific performance of a contract to purchase land. The salesman employed by the plaintiff had made false representations as to the character of the land. The contract contained a provision that all terms and representations were "embraced" in the contract and that "No representations, promises or agreements except as herein contained shall be binding on the parties hereto" (page 478). In holding that a court of equity would not grant specific performance of a contract thus tainted, the court said that the terms of the contract could not be invoked to prevent the court from examining all the circumstances in order to ascertain whether it would be conformable to good conscience to grant that relief. "No one can escape the equitable consequences of his fraudulent statements inducing a contract by inserting therein a clause of this nature. The principle on which Colonial Development Corp. v. Bragdon, 219 Mass. 170 , and similar cases (see Sullivan v. Roche, 257 Mass. 166, 171 , for collection of them,) rest, to the effect that a written contract freely and intelligently made, without misrepresentation as to its contents or execution, untainted by fraud as to its substance, providing that all inducing representations are therein set forth, is binding upon the parties, is confined within narrow limits, is not to be enlarged, and does not extend to specific performance on facts like those here disclosed" (pages 479-480). The court then calls attention to a number of cases to which reference is hereinafter made, which either in their tendency or by express statement are opposed to the doctrine of Colonial Development Corp. v. Bragdon. Go to
Noack v. Standard Stores, Inc. 281 Mass. 53 , was also an action of tort for deceit. The plaintiff had been induced to buy stock from the defendant by fraudulent representations that the stock would be just like money in a bank or lent on a mortgage and that she could get her money back from the company any time she wanted it, and by other false statements. The contracts of purchase provided that, "No condition, agreements or representations, written or verbal, other than those printed herein, shall be binding" (page 55). The court held that the representations made "were false representations respecting the identity of the property which the plaintiff was told she was purchasing. It is plain that this was a deliberate fraud respecting the contract itself, and entitles the plaintiff to the relief she seeks, notwithstanding the recital in the contract relied on by the defendant" (page 56). The opinion quotes from Butler v. Prussian, 252 Mass. 265 , hereinbefore mentioned, and cites Colonial Development Corp. v. Bragdon and its companion case, Sullivan v. Roche, only to say that they "are distinguishable in their facts" (page 57). It is inconceivable that the court which in Connelly v. Fellsway Motor Mart, Inc. and in Noack v. Standard Stores, Inc. allowed the injured party to recover in an action of deceit for fraud would have held valid against him the contract of sale and purchase obtained through the same fraud. Go to
The distinction announced in Colonial Development Corp. v. Bragdon has met with a generally unfavorable reception in the courts of other jurisdictions and by commentators. As far as we have been able to ascertain that case has been cited eight times in reported decisions outside this Commonwealth, and the distinction was finally approved only once. Professor Williston says that it is "not to be supported." Williston on Contracts (Rev. Ed.) § 811A, § 811. (See also Wigmore on Evidence [3d ed.] § 2439.) It is inconsistent with Am. Law Inst. Restatement: Contracts, § 573, and Am. Law Inst. Restatement: Agency, § 260 (2) (see comments b and c). It is opposed to the great weight of authority. It is difficult to reconcile with our own decision in Reagan v. Union Mutual Life Ins. Co. 189 Mass. 555 . And see Kilkus v. Shakman, 254 Mass. 274, 279 . Go to
Nothing herein said affects any evidential value of exculpatory clauses or agreements as tending to show that no extraneous representations were in fact made, or if made that they were not relied upon. Go to
The plaintiff did business as an "investment broker" in Salem. The defendants as partners carried on a brokerage business in Boston under the name of Southgate and Company. In this action of contract the plaintiff seeks to recover the purchase price paid by him to the defendants for five hundred shares of stock in Victoria Gypsum Company which he bought from them and later tendered back to them for the purpose of rescission after he learned, as he contends, that he had been induced to make the purchase by a fraudulent representation on their part. The defendants rely upon a "confirmation slip," sent by the defendants to the plaintiff, at the bottom of which was printed the following: "It is agreed between broker [defendants] and customer [plaintiff]: 1. That in making this transaction, we make no representation other than to identify the security and state the price. 2. That in this transaction we are acting solely as principals and not as agents." Below this appeared the printed signature "Southgate Co." The only point raised by the exceptions is whether the evidence justified submission of the case to the jury. Go to
At the beginning the question arises and has been argued whether the "confirmation slip" ever became part of the contract of purchase and sale of the stock. The evidence on this point came from the testimony of the plaintiff himself. He testified to a series of telephone talks on May 6, 1937, between himself and a member of the firm of Southgate and Company wherein the parties came to terms upon the sale and purchase of five hundred shares of the gypsum stock at $12 a share. On the following day the plaintiff received the "confirmation slip" from the defendants. The plaintiff testified that he used confirmation slips in his own business; that he could have refused to pay for the stock, if he did not want to take it on the terms stated in the slip; that there "wasn't the slightest question" but that he could have cancelled the order on May 6 before he received the "confirmation slip"; that he was content to pay for the stock and to take delivery on the terms set forth in the slip, and that he did so; that he expected his own customers to go through with their deals on the terms of his confirmation slips or "call the deal off"; that he did not expect to do anything different as a customer of Southgate and Company than he would expect of his own customers; that on May 19, after he had received the confirmation slip but, as the jury could find, before he knew that the representation was false, he "elected to go through, well knowing that the terms were that Southgate was making no representation with respect to this transaction other than to identify the security and state the price." Go to
In Butler v. Prussian, 252 Mass. 265 , the defendant sold to the plaintiff an automobile truck under a written contract of conditional sale which contained this language: "Said car is leased as is and no reference, representation, contract, agreement, promise, undertaking or understanding whatever not contained therein shall be binding upon the lessor, or in any wise affect the validity of this contract or form any part thereof, but all statements made have been merced [ sic ] and set forth herein. I further agree that there are no collateral agreements nor understandings whatsoever modifying or affecting the terms of the within lease or my liabilities thereunder, and that there are no set-offs, counter-claims nor defenses thereto" (pages 267-268). When the truck had been shown to the plaintiff it contained a new motor and other new operating parts. Shortly thereafter old machinery was substituted, and the contract described by number and model the substituted parts. The court said: "Fraud which enters into the making of the contract, as distinguished from that which is antecedent to it, cannot be excluded from the reach of the law by any form of phrase inserted in the contract itself. Parties may stipulate by their contract that the statements inducing its execution are all included in its recitals and that no agent has authority to make any representations not therein contained. But they cannot by written words prevent the law from inquiry into, and granting redress for, fraud which enters into the very substance of the contract itself. This distinction was pointed out in Colonial Development Corp. v. Bragdon, 219 Mass. 170, 174 " (page 268). After citing later cases hereinbefore discussed, the opinion adds: "While we do not depart from those decisions, we do not incline to extend them" (page 269). The court then held that there had been "a plain fraud as to the essence of the contract. There is no rule of law which prevents recovery for that wrong" (page 269). It is not easy to perceive a decisive distinction between the representation as to the character of the truck to be sold, implied by exhibiting the new machinery in Butler v. Prussian and the representation as to the character of the land to be sold made by word of mouth in Colonial Development Corp. v. Bragdon, nor is it easy to see how from a legal point of view one went "to the essence of the contract" more than the other. Go to
In the case before us the parties dealt directly with each other. No representations were made through an agent. Frequently a principal provides his agents with a form of contract containing clauses designed to limit the authority of his agents to make alterations in the form furnished or to make agreements or representations not contained in the form itself. Such a clause appears in Colonial Development Corp. v. Bragdon and in some of the other cases hereinbefore discussed. This decision does not touch upon the effect of such clauses as notice to a person dealing with the agent of limitations upon the agent's authority, or in the absence of fraud in procuring assent to such clauses, as limiting by contract the authority of the agent. But whatever effect such clauses may normally have as a protection to the principal it would seem that they should not enable him to enforce for his own benefit a contract procured through the actual fraudulent misrepresentation of his agent, whether that fraud is "antecedent" to the contract or "enters into the making" of it. If the principal insists upon the contract he must take it with the defect which his agent has implanted in it. Rackemann v. Riverbank Improvement Co. 167 Mass. 1, 3, 4 . Tremont Trust Co. v. Noyes, 246 Mass. 197, 207, 208 . Quincy Trust Co. v. Woodbury, 299 Mass. 565, 568 . Williston on Contracts (Rev. Ed.) § 811A (page 2283). Am. Law Inst. Restatement: Agency, §§ 260 (2), 298, 308. Go to
Inasmuch as in this case there was evidence for the jury that, notwithstanding the terms of the "confirmation slip," the sale of the stock was induced by a fraudulent representation of the defendants, the verdict of the jury must stand. Go to
Fraud. Contract,Validity, What constitutes. Sale,Validity, What constitutes contract of sale, "Confirmation slip."
Evidence warranted a finding that a "confirmation slip," sent by a seller of corporate stock to and accepted by the buyer following conversations between the parties, embodied their final contract of sale; and it was immaterial that the buyer did not sign the slip. A provision of a contract attempting to protect a party against the consequences of his own fraud inducing the contract is against public policy and is void; it is immaterial whether the fraud was "antecedent" to the contract or "entered into the making" of it. The fact, that a "confirmation slip" embodying a contract of sale by a broker of shares of stock of a corporation stated an agreement that "in making the transaction" the seller made no representation other than to identify the security and to state the price, was no defence to an action of contract by the buyer against the seller for recovery of the price paid, brought after rescission of the contract because of material fraudulent representations relating to the business of the corporation which were made personally by the seller to the buyer and which induced the sale.
QUA, J.
The plaintiff did business as an "investment broker" in Salem. The defendants as partners carried on a brokerage business in Boston under the name of Southgate and Company. In this action of contract the plaintiff seeks to recover the purchase price paid by him to the defendants for five hundred shares of stock in Victoria Gypsum Company which he bought from them and latertendered back to them for the purpose of rescission after he learned, as he contends, that he had been induced to make the purchase by a fraudulent representation on their part. The defendants rely upon a "confirmation slip," sent by the defendants to the plaintiff, at the bottom of which was printed the following: "It is agreed between broker [defendants] and customer [plaintiff]: 1. That in making this transaction, we make no representation other than to identify the security and state the price. 2. That in this transaction we are acting solely as principals and not as agents." Below this appeared the printed signature "Southgate Co." The only point raised by the exceptions is whether the evidence justified submission of the case to the jury.
At the beginning the question arises and has been argued whether the "confirmation slip" ever became part of the contract of purchase and sale of the stock. The evidence on this point came from the testimony of the plaintiff himself. He testified to a series of telephone talks on May 6, 1937, between himself and a member of the firm of Southgate and Company wherein the parties came to terms upon the sale and purchase of five hundred shares of the gypsum stock at $12 a share. On the following day the plaintiff received the "confirmation slip" from the defendants. The plaintiff testified that he used confirmation slips in his own business; that he could have refused to pay for the stock, if he did not want to take it on the terms stated in the slip; that there "wasn't the slightest question" but that he could have cancelled the order on May 6 before he received the "confirmation slip"; that he was content to pay for the stock and to take delivery on the terms set forth in the slip, and that he did so; that he expected his own customers to go through with their deals on the terms of his confirmation slips or "call the deal off"; that he did not expect to do anything different as a customer of Southgate and Company than he would expect of his own customers; that on May 19, after he had received the confirmation slip but, as the jury could find, before he knew that the representation was false, he"elected to go through, well knowing that the terms were that Southgate was making no representation with respect to this transaction other than to identify the security and state the price."
Upon this evidence the jury could find, if they were not bound to find, that at the time of the telephone conversations both parties expected a confirmation slip to be delivered later as the embodiment of the bargain and regarded the slip, after its delivery and acceptance, as expressing the final terms of the contract between them. The slip stated the names of seller and buyer, the subject matter of the sale, the price, and the terms of payment as "cash transaction." It contained all the essential elements of a contract. Even though previous oral conversations would be enough in themselves to establish an oral contract the parties may, nevertheless, by mutual understanding postpone the culmination of their negotiations into a contract to the later preparation and delivery of a written instrument.It is immaterial that the plaintiff did not sign the "confirmation slip." Thomasv. Barnes,156 Mass. 581, 583, 584. Glackinv. Bennett,226 Mass. 316, 320. Gouldv. Converse,246 Mass. 185, 188. Greaneyv. McCormick,273 Mass. 250, 253. Williston on Contracts (Rev. Ed.) § 90A.
Dolenv. Chase,237 Mass. 218, 220. Kilroyv. Schimmel,243 Mass. 262, 267. Gouldv. Converse,246 Mass. 185, 188. Longv. Agricultural Ins. Co.257 Mass. 240, 243. Geo. W. Wilcox, Inc.v. Shell Eastern Petroleum Products, Inc.283 Mass. 383, 387. See Ehrlichv. United Smelling Aluminum Co.252 Mass. 12, 15; Breskyv. Rosenberg,256 Mass. 66, 74-75; Peerless Petticoat Co.v. Colpak-Van Costume Co.273 Mass. 289, 292; McNultyv. Whitney,273 Mass. 494, 501; Dugganv. Mathew Cummings Co.277 Mass. 445; Rosenfieldv. United States Trust Co.290 Mass. 210, 217. Compare Bodellv. Sawyer,294 Mass. 534, 540.
On the question of fraud there was evidence that before the plaintiff bought the stock one of the defendant partners stated to the plaintiff, as an inducement to buy, that the gypsum company had received an order for forty thousand tons of gypsum to be delivered in New York at $2.66 a ton, upon which the company would derive a profit of about $1 a ton, and that the plaintiff relied upon this statement in agreeing to buy, in accepting the "confirmation slip," and in paying for the stock. There was noevidence that the defendants by any statement on their part withdrew or corrected the alleged representation, and the evidence that the plaintiff in fact still continued to rely upon it and was induced by it to accept the confirmation slip as the contract between the parties was before the jury for their consideration. The defendants denied having made any such representation, but admitted that the company had not received such an order and that they knew it had not. When taken in connection with other evidence in the case, which need not be stated, as to the history and prospects of the gypsum company, there can be no doubt that a representation as to an order for forty thousand tons at the price stated could be found to have been material as an inducement to buy the stock, and that upon the evidence just recited the verdict for the plaintiff can be sustained, unless as matter of law the provisions of the "confirmation slip" constitute a defence. Gurneyv. Tenney,197 Mass. 457, 465. Schleiferv. Worcester North Savings Institution,306 Mass. 226, 228. Indeed, there has been no argument to the contrary.
The defendants point to the "confirmation slip" and urge that therein the parties have contracted that no representation, and so of course no fraudulent representation, has been made; that the plaintiff is bound by the contract and has in effect agreed to take the stock at all events, whether he has been defrauded or not. The plaintiff may urge in reply that the jury could find that in real fact there was a fraudulent representation; that he was induced by it to purchase the stock; that even if the "confirmation slip" became the embodiment of the contract or a part of the contract, he was induced to accept the slip by the same fraud by which he was induced to purchase; and that if it is the policy of the law to refuse to honor a contract procured by fraud, that policy extends to all contracts and to all parts of contracts, as much to provisions inserted by the opposite party for the purpose of escaping the consequences of his own wrong as to any other part.
In Cannonv. Burrell,193 Mass. 534, 536, this courtrefused to recognize an attempted rescission by a buyer of goods who had signed an order wherein it was stated that separate agreements with salesmen were not binding, and that the sale was "made under inducements and representations herein expressed and no others." The defendant there contended that the plaintiff's salesman had represented that "he [the salesman] would give him [the defendant] exclusive sale of said goods in Rockland and vicinity" (page 535). It will be noted that the alleged representation was promissory in character and not an express representation of existing fact, although there was evidence from which possibly an inference might have been drawn that the salesman did not intend literally to keep his promise. The court cites no Massachusetts case dealing with the effect of actual fraudulent representations upon a contract containing a clause that no representations have been made. The decision seems to have been grounded principally upon lack of authority of the salesman to vary the terms of the order (see page 536).
Colonial Development Corp.v. Bragdon,219 Mass. 170, was an action of contract to recover the purchase price of land sold, with a cross action for deceit. The contract contained this clause: "No agent of this company has authority . . . to make any reference, representation or agreement not contained in this contract and none not contained herein shall be binding upon the seller, or in any wise effect [ sic] the validity of this contract or form any part hereof, but all statements made have been merged and set forth herein" (page 173). It was held that because of this provision previous false and fraudulent representations by the plaintiff's authorized agents as to the condition of the land, inducing the defendant to sign the contract, were neither a defence nor the basis of a cross action. The court said: "It is a fundamental principle of law that contracts in writing voluntarily executed with full knowledge of their contents by rational beings acting on their own judgment must be enforced"; and also: "The defendant relies on the proposition that fraud vitiates every contract. But there is a distinction between a fraud whichis antecedent to a contract, and fraud which enters into the making of the contract. The present case belongs to the former class" (page 174). The only cases cited are Cannonv. Burrell,hereinbefore discussed, and McCoyv. Metropolitan Life Ins. Co.133 Mass. 82. The latter case, decided in 1882, merely held that the application for an insurance policy was part of the contract of insurance and that misrepresentations contained in it material to the risk were a defence to an action on the policy. The case of Colonial Development Corp.v. Bragdonhas been frequently regarded as the leading authority for a distinction supposed to exist in this Commonwealth between "antecedent" fraud and "fraud which enters into the making of the contract." Neither kind of fraud is defined in the opinion, and no reason is given why a contract should be voidable if procured by fraud perpetrated at one time or in one manner and valid if procured by fraud perpetrated at another time or in another manner.
Colonial Development Corp.v. Bragdonhas been followed in O'Mearav. Smyth,243 Mass. 188, and in Sullivanv. Roche,257 Mass. 166, 171(this being the last case in which the supposed distinction has been made the precise ground of the decision). It has been cited with apparent approval in International Textbook Co.v. Martin,221 Mass. 1, 7, Eastern Advertising Co.v. E.L. Patch Co.235 Mass. 580, Bossv. Greater Boston Mortgage Corp.251 Mass. 455, and Eastern Advertising Co.v. Shapiro,263 Mass. 228, 232, although it would seem that the actual decisions in these cases could well have been rested, in so far as in truth they were not, upon the so called parol evidence rule. See Glackinv. Bennett,226 Mass. 316, 319, 320. The Colonial Development Corp.case was accepted but distinguished in Brownv. Grow,249 Mass. 495, 500, and, (without citing) in Reinherzv. American Piano Co.254 Mass. 411, 421, 422(where it is said that the words barring proof of fraudulent representations "must be explicit, have no folds, and be understood and intended by the parties unequivocally to effect such result"), and in Hashemv. Massachusetts Security Corp.255 Mass. 29, 31.
In Butlerv. Prussian,252 Mass. 265, the defendant sold to the plaintiff an automobile truck under a written contract of conditional sale which contained this language: "Said car is leased as is and no reference, representation, contract, agreement, promise, undertaking or understanding whatever not contained therein shall be binding upon the lessor, or in any wise affect the validity of this contract or form any part thereof, but all statements made have been merced [ sic] and set forth herein. I further agree that there are no collateral agreements nor understandings whatsoever modifying or affecting the terms of the within lease or my liabilities thereunder, and that there are no set-offs, counter-claims nor defenses thereto" (pages 267-268). When the truck had been shown to the plaintiff it contained a new motor and other new operating parts. Shortly thereafter old machinery was substituted, and the contract described by number and model the substituted parts. The court said: "Fraud which enters into the making of the contract, as distinguished from that which is antecedent to it, cannot be excluded from the reach of the law by any form of phrase inserted in the contract itself. Parties may stipulate by their contract that the statements inducing its execution are all included in its recitals and that no agent has authority to make any representations not therein contained. But they cannot by written words prevent the law from inquiry into, and granting redress for, fraud which enters into the very substance of the contract itself. This distinction was pointed out in Colonial Development Corp.v. Bragdon,219 Mass. 170, 174" (page 268). After citing later cases hereinbefore discussed, the opinion adds: "While we do not depart from those decisions, we do not incline to extend them" (page 269). The court then held that there had been "a plain fraud as to the essence of the contract. There is no rule of law which prevents recovery for that wrong" (page 269). It is not easy to perceive a decisive distinction between the representation as to the character of the truck to be sold, implied by exhibiting the new machinery in Butlerv. Prussianand the representation as to the character of the land to be soldmade by word of mouth in Colonial Development Corp.v. Bragdon,nor is it easy to see how from a legal point of view one went "to the essence of the contract" more than the other.
The case of Granlundv. Saraf,263 Mass. 76, was a suit in equity by the buyer for rescission of his purchase of a retail business induced by fraudulent representations as to the amount of the gross receipts. By a document forming part of the transaction the defendants had attempted to provide that if after six months from the date of sale the plaintiffs should find that one of the defendants had made any misrepresentation, that defendant would take the store back and refund the money, but only on certain specified conditions. The court said, "It is a fundamental principle of law, as it is of morals, public policy and fair dealing, that a party cannot contract against liability for his own fraud. Fraud which enters into the making of the contract cannot be excluded from the reach of the law by any form of phrase inserted in the contract itself. Parties cannot by written words prevent the law from inquiring into and granting relief for fraud in the substance of the contract. Butlerv. Prussian,252 Mass. 265, 268. Many contracts have been refused enforcement whereby a party has striven to shield himself from the results of his fraudulent practices upon the other party. Such contracts, if given validity, would overcome the salutary maxim which pervades the common law, that fraud vitiates every transaction at the election of the injured party" (page 79). And again: "Attempts under the form of contract to secure total or partial immunity from liability for fraud are all under the ban of the law. The extent of the relief granted to the injured party, in order to be adequate and complete, cannot not be constricted by act of the parties. The nature of fraud and the grounds upon which the law denounces it are such that it cannot be made the subject of preliminary or contemporaneous alleviating contract" (page 80). Relief was granted to the plaintiffs without observance of the conditions upon which rescission was to be limited by the terms of the contract. Nevertheless the court distinguished Colonial Development Corp.v. Bragdon"and similar decisions where parties, freely and without fraud or imposition, have made a written contract to the effect that all representations touching the subject matter of the contract are therein set forth; in such cases it has been held that the terms of the formal contract cannot be varied or contradicted by proof that there were other antecedent representations fraudulent in nature" (pages 80-81).
The case of Florimond Realty Co. Inc.v. Waye,268 Mass. 475, was a suit for specific performance of a contract to purchase land. The salesman employed by the plaintiff had made false representations as to the character of the land. The contract contained a provision that all terms and representations were "embraced" in the contract and that "No representations, promises or agreements except as herein contained shall be binding on the parties hereto" (page 478). In holding that a court of equity would not grant specific performance of a contract thus tainted, the court said that the terms of the contract could not be invoked to prevent the court from examining all the circumstances in order to ascertain whether it would be conformable to good conscience to grant that relief. "No one can escape the equitable consequences of his fraudulent statements inducing a contract by inserting therein a clause of this nature. The principle on which Colonial Development Corp.v. Bragdon,219 Mass. 170, and similar cases (see Sullivanv. Roche,257 Mass. 166, 171, for collection of them,) rest, to the effect that a written contract freely and intelligently made, without misrepresentation as to its contents or execution, untainted by fraud as to its substance, providing that all inducing representations are therein set forth, is binding upon the parties, is confined within narrow limits, is not to be enlarged, and does not extend to specific performance on facts like those here disclosed" (pages 479-480). The court then calls attention to a number of cases to which reference is hereinafter made, which either in their tendency or by express statement are opposed to the doctrine of Colonial Development Corp.v. Bragdon.
Five months after the decision in Florimond Realty Co. Inc.v. Waye,last above discussed, further significant language was used. Connellyv. Fellsway Motor Mart, Inc.270 Mass. 386, was an action at law for deceit by which the plaintiff was induced to buy an automobile from the defendant by a false representation made before the execution of the contract that the automobile was a new one. The contract provided that it embodied "all the terms and conditions of sale," that the automobile was sold "as is, where is, and as shown. No guarantee as to year of car." The court said that the evidence did not warrant a finding of "fraud which entered into the making of the contract as distinguished from fraud which was antecedent thereto" (page 388). Thereupon, treating the representation as "antecedent," the court discussed briefly Colonial Development Corp.v. Bragdonand cases following it. The court then referred to the parol evidence rule by which "all previous or contemporaneous oral discussion or written memoranda are assumed to be rejected or merged in" a written contract, and said, "It is this principle which has been held applicable in the group of cases already cited and illustrated by Colonial Development Corp.v. Bragdon, supra,although in them there were also express agreements relating to representations. These cases constitute no exception to the general rule that fraud vitiates every contract at the election of the injured party. It does not authorize parties to attempt to provide by written contract that there shall be no liability for fraud" (page 390). It was held, at least for the purposes of an action of tort, that "the false representations were not merged in the written agreement" (page 391), and a verdict for the plaintiff was allowed to stand. Thus the court, in substance, stated that Colonial Development Corp.v. Bragdonwas merely an illustration of the parol evidence rule and not the pronouncement of a distinct principle.
Noackv. Standard Stores, Inc.281 Mass. 53, was also an action of tort for deceit. The plaintiff had been induced to buy stock from the defendant by fraudulent representations that the stock would be just like money in a bank or lent on a mortgage and that she could get her money back from the company any time she wanted it, and by otherfalse statements. The contracts of purchase provided that, "No condition, agreements or representations, written or verbal, other than those printed herein, shall be binding" (page 55). The court held that the representations made "were false representations respecting the identity of the property which the plaintiff was told she was purchasing. It is plain that this was a deliberate fraud respecting the contract itself, and entitles the plaintiff to the relief she seeks, notwithstanding the recital in the contract relied on by the defendant" (page 56). The opinion quotes from Butlerv. Prussian,252 Mass. 265, hereinbefore mentioned, and cites Colonial Development Corp.v. Bragdonand its companion case, Sullivanv. Roche,only to say that they "are distinguishable in their facts" (page 57). It is inconceivable that the court which in Connellyv. Fellsway Motor Mart, Inc.and in Noackv. Standard Stores, Inc.allowed the injured party to recover in an action of deceit for fraud would have held valid against him the contract of sale and purchase obtained through the same fraud.
There is, closely related to the cases we have here discussed, another class of cases wherein the parties have contracted that goods are bought "as is," thus purporting to cast upon the buyer by agreement all risk as to the condition of the goods. It would seem that if parties could bind themselves by contract against the effect of "antecedent" fraud an agreement of the kind described ought to be as effective to that end as an agreement that no representations have been made. Yet the issue of fraud has been held to be open in these cases. Reinherzv. American Piano Co.254 Mass. 411, 421, 422, 423. Connellyv. Fellsway Motor Mart, Inc.270 Mass. 386, 390, 391. New England Foundation Co. Inc.v. Elliott Watrous, Inc.306 Mass. 177, 182.
We have reviewed the decisions of this court at unusual length because, although it cannot be said that Colonial Development Corp.v. Bragdonhas been expressly overruled, it is impossible to avoid the impression that the later decisions, several of them written by the same eminent chief justice who wrote the opinion in that case, have discloseda reluctance to apply the distinction there announced between "fraud which is antecedent to a contract, and fraud which enters into the making of the contract," and in some of these cases language has been used, reaching as it would seem beyond the immediate necessity of the case, and exceedingly difficult to reconcile with the existence of such a distinction. Some of the actual decisions are likewise difficult to reconcile with it. At least we may say that we are not now precluded by settled authority from reconsideration of the matter.
The distinction announced in Colonial Development Corp.v. Bragdonhas met with a generally unfavorable reception in the courts of other jurisdictions and by commentators.As far as we have been able to ascertain that case has been cited eight times in reported decisions outside this Commonwealth, and the distinction was finally approved only once.Professor Williston says that it is "not to be supported." Williston on Contracts (Rev. Ed.) § 811A, § 811. (See also Wigmore on Evidence [3d ed.] § 2439.) It is inconsistent with Am. Law Inst. Restatement: Contracts, § 573, and Am. Law Inst. Restatement: Agency, § 260 (2) (see comments b and c). It is opposed to the great weight of authority.It isdifficult to reconcile with our own decision in Reaganv. Union Mutual Life Ins. Co.189 Mass. 555. And see Kilkusv. Shakman,254 Mass. 274, 279.
8 B.U. Law Rev. 57. 10 Id. 446. 6 Brooklyn Law Rev. 450, 451. 32 Ill. Law Rev. 944. 75 Univ. of Pa. Law Rev. 281. See 25 Col. Law Rev. 231; 20 Cornell Law Quarterly, 91; 32 Mich. Law Rev. 1004. Compare, however, 22 Cornell Law Quarterly, 103.
Advance-Rumely Thresher Co. Inc.v. Jacobs,51 Idaho, 160, 167-169. Angerosav. White Co.248 App. Div. (N.Y.) 425, affirmed,275 N.Y. 524. Sharkeyv. Burlingame Co.131 Or. 185, 203-207. Land Finance Corp.v. Sherwin Electric Co.102 Vt. 73, 79-80. Bayliesv. Vanden Boom,40 Wyo. 411, 429-433. Jonesv. Bankers Trust Co.235 Fed. 649; S.C.239 Fed. 770, (at first approved, but upon rehearing disapproved). Arnoldv. National Aniline Chemical Co. Inc.20 F.2d 364, 369-370(an instructive discussion). Barnebeyv. Barron G. Collier, Inc.65 F.2d 864, 867(approved).
As a matter of principle it is necessary to weigh the advantages of certainty in contractual relations against the harm and injustice that result from fraud. In obedience to the demands of a larger public policy the law long ago abandoned the position that a contract must be held sacred regardless of the fraud of one of the parties in procuring it. No one advocates a return to outworn conceptions. The same public policy that in general sanctions the avoidance of a promise obtained by deceit strikes down all attempts to circumvent that policy by means of contractual devices. In the realm of fact it is entirely possible for a party knowingly to agree that no representations have been made to him, while at the same time believing and relying upon representations which in fact have been made and in fact are false but for which he would not have made the agreement. To deny this possibility is to ignore the frequent instances in everyday experience where parties accept, often without critical examination, and act upon agreements containing somewhere within their four corners exculpatory clauses in one form or another, but where they do so, nevertheless, in reliance upon the honesty of supposed friends, the plausible and disarming statements of salesmen, or the customary course of business. To refuse relief would result in opening the door to a multitude of frauds and in thwarting the general policy of the law.
For the reasons set forth we conclude that the distinction stated in Colonial Development Corp.v. Bragdon,219 Mass. 170, 174, and repeated in the later cases hereinbefore mentioned, between "fraud which is antecedent to a contract" and "fraud which enters into the making of the contract" cannot be maintained, and that contracts or clauses attempting to protect a party against the consequences of his own fraud are against public policy and void where fraud inducing the contract is shown, whether that fraud was "antecedent" to the contract or "entered into the making" of it. In the words of Granlundv. Saraf,263 Mass. 76, at page 80, "Attempts under the form of contract to secure total or partial immunity from liability for fraud are all under the ban of the law."
This decision deals with fraud and its consequences. Nothing we have said limits or alters the effect of the parol evidence rule. That rule does not stand in the way of rescission for fraud. Weeksv. Currier,172 Mass. 53, 55. Busierev. Reilly,189 Mass. 518, 520. Harrisv. Delco Products, Inc.305 Mass. 362, 364.
In the case before us the parties dealt directly with each other. No representations were made through an agent. Frequently a principal provides his agents with a form of contract containing clauses designed to limit the authority of his agents to make alterations in the form furnished or to make agreements or representations not contained in the form itself. Such a clause appears in Colonial Development Corp.v. Bragdonand in some of the other cases hereinbefore discussed. This decision does not touch upon the effect of such clauses as notice to a person dealing with the agent of limitations upon the agent's authority, or in the absence of fraud in procuring assent to such clauses, as limiting by contract the authority of the agent. But whatever effect such clauses may normally have as a protection to the principal it would seem that they should not enable him to enforce for his own benefit a contract procured through the actual fraudulent misrepresentation of his agent, whether that fraud is "antecedent" to the contract or "enters into the making" of it. If the principal insists upon the contract he must take it with the defect which his agent has implanted in it. Rackemannv. Riverbank Improvement Co.167 Mass. 1, 3, 4. Tremont Trust Co.v. Noyes,246 Mass. 197, 207, 208. Quincy Trust Co.v. Woodbury,299 Mass. 565, 568. Williston on Contracts (Rev. Ed.) § 811A (page 2283). Am. Law Inst. Restatement: Agency, §§ 260 (2), 298, 308.
Nothing herein said affects any evidential value of exculpatory clauses or agreements as tending to show that no extraneous representations were in fact made, or if made that they were not relied upon.
Inasmuch as in this case there was evidence for the jury that, notwithstanding the terms of the "confirmation slip," the sale of the stock was induced by a fraudulent representation of the defendants, the verdict of the jury must stand.
Exceptions overruled.
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Browsing Department of Biology by Title
Browsing Department of Biology by Title
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Vietnam: A Television History; Legacies; Interview with Muoi Van Nguyen, 1983
Vietnam: A Television History; Legacies; Interview with Muoi Van Nguyen, 1983
Part of The Vietnam Collection
.
07/20/1983
Muoi Van Nguyen was a former Vietnamese army officer and a refugee in Thailand who in the late 1970s was able to move to the United States. He describes the conditions in the refugee campplenty of food but danger presented by surrounding villagersand compares life as an army officer in Vietnam to his life in America. He talks about his jobs in America but hopes to return to his home country.
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Series
Vietnam: A Television History
Program
Legacies
Program Number
113
Title
Interview with Muoi Van Nguyen, 1983
Series Description
This 13 part series covers the history of Vietnam from France's colonial control, through the 1945 revolution, to the 1975 U.S. evacuation from Saigon and the years beyond. The series' objective approach permits viewers to form their own conclusions about the war.
101--Roots of a War--Despite cordial relations between American intelligence officers and Communist leader Ho Chi Minh in the turbulent closing months of World War II, French and British hostility to the Vietnamese revolution laid the groundwork for a new war.
102--The First Vietnam War (1946-1954)--The French generals expected to defeat Ho's rag-tag Vietminh guerrillas easily, but after eight years of fighting and $2.5 billion in U.S. aid, the French lost a crucial battle at Dienbienphu--and with it, their Asian empire.
103--America's Mandarin (1954-1963)--To stop the spread of communism in Southeast Asia, America replaced France in South Vietnam--supporting autocratic President Ngo Dinyh Diem until his own generals turned against him in a coup that brought political chaos to Saigon.
104--LBJ Goes to War (1964-1965)--With Ho Chi Minh determined to reunite Vietnam, Lyndon Baines Johnson determined to prevent it, and South Vietnam on the verge of collapse, the stage was set for massive escalation of the undeclared Vietnam War.
105--America Takes Charge (1965-1967)--In two years, the Johnson Administration's troop build-up dispatched 1.5 million Americans to Vietnam to fight a war they found baffling, tedious, exciting, deadly and unforgettable.
106--America's Enemy (1954-1967)--The Vietnam War as seen from different perspectives: by Vietcong guerrillas and sympathizers; by North Vietnamese leaders; by rank and file; and by American held prisoner in Hanoi.
107--Tet (1968)--The massive enemy offensive at the Lunar New Year decimated the Vietcong and failed to topple the Saigon government, but led to the beginning of America's military withdrawal.
108--Vietnamizing the War (1968-1973)--President Nixon's program of troop pull-outs, stepped-up bombing and huge arms shipments to Saigon changed the war, and left GI's wondering which of them would be the last to die in Vietnam.
109--Cambodia and Laos--Despite technical neutrality, both of Vietnam's smaller neighbors were drawn into the war, suffered massive bombing, and in the case of Cambodia, endured a post-war holocaust of nightmare proportions.
110--Peace is at Hand (1968-1973)--While American and Vietnamese continued to clash in battle, diplomats in Paris argued about making peace, after more than four years reaching an accord that proved to be a preface to further bloodshed.
111--Homefront USA--Americans at home divide over a distant war, clashing in the streets as demonstrations lead to bloodshed, bitterness and increasing doubts about the outcome.
112--The End of the Tunnel (1973-1975)--Through troubled years of controversy and violence, U.S. casualties mounted, victory remained elusive and American opinion moved from general approval to general dissatisfaction with the Vietnam war.
113--Legacies--Vietnam is in the Soviet orbit, poorer than ever, at war on two fronts; America's legacy includes more than one half million Asian refugees, one half million Vietnam veterans and some questions that won't go away.
Series release date: 9/1983
Program Description
Vietnam is in the Soviet orbit, poorer than ever, at war on two fronts; America's legacy includes more than one half million Asian refugees, one half million Vietnam veterans and some questions that won't go away.
Duration
00:12:12
Asset Type
Raw audio
Media Type
Audio
Subjects
Vietnam War, 1961-1975--Personal narratives, Vietnamese
Vietnam (Republic)
Assimilation (Sociology)
Vietnam--History--1945-1975
Identity
Vietnam (Democratic Republic)
Refugee camps
Villages
Rape
Vietnam War, 1961-1975--Influence
Theft
Vietnam--Politics and government
Immigrants
Refugees--Vietnam
Genres
Documentary
Topics
War and Conflict
Creators
Ellison, Richard (Series Producer)
Contributors
Muoi Van Nguyen (Interviewee)
Publication Information
WGBH Educational Foundation
Rights Summary
No materials may be re-used without references to appearance releases and WGBH/UMass Boston contract. 2) It is the liability of a production to investigate and re-clear all rights before re-use in any project. Rights Holder: WGBH Educational Foundation
Citation
Chicago :
“Vietnam: A Television History; Legacies; Interview with Muoi Van Nguyen, 1983,”
07/20/1983,
GBH Archives,
accessed June 28, 2023,
http://openvault.wgbh.org/catalog/A_45992393338B48B2BE2C6EB0536F1907 .
MLA :
“Vietnam: A Television History; Legacies; Interview with Muoi Van Nguyen, 1983.”
07/20/1983.
GBH Archives.
Web. June 28, 2023.
<
http://openvault.wgbh.org/catalog/A_45992393338B48B2BE2C6EB0536F1907 >.
APA :
Vietnam: A Television History; Legacies; Interview with Muoi Van Nguyen, 1983.
Boston, MA: GBH Archives.
Retrieved from
http://openvault.wgbh.org/catalog/A_45992393338B48B2BE2C6EB0536F1907
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Experimental determination of phonon thermal conductivity and Lorenz ratio of single crystal metals: Al, Cu, and Zn | Journal of Applied Physics | AIP Publishing
We use a magnetothermal resistance method to measure lattice thermal conductivity of pure single crystal metals over the intermediate temperature range of 5–60
Experimental determination of phonon thermal conductivity and Lorenz ratio of single crystal metals: Al, Cu, and Zn
Mengliang Yao
;
Mengliang Yao
1
Department of Physics, Boston College
, Chestnut Hill, Massachusetts 02467,
USA
Mona Zebarjadi
We use a magnetothermal resistance method to measure lattice thermal conductivity of pure single crystal metals over the intermediate temperature range of 5–60 K. Large transverse magnetic fields are applied to suppress electronic thermal conduction. The total thermal conductivity and the electrical conductivity are measured as functions of applied magnetic field. The lattice thermal conductivity is then extracted by extrapolating the thermal conductivity versus electrical conductivity curve at zero electrical conductivity. We used this method to experimentally measure the lattice thermal conductivity and Lorenz number in single crystal Al (100), Cu (100), and Zn (001) in the intermediate temperature range. Our results show that the measured phonon thermal conductivity versus temperature plot has a peak around
Θ D / 10
, and the Lorenz number is found to deviate from the Sommerfeld value in the intermediate temperature range.
Topics
Thermal transport
,
Electrical conductivity
,
Electrical resistivity
,
Magnetic ordering
,
Phonons
,
Debye temperature
,
Superfluids
,
Wiedemann-Franz law
,
Thermodynamic states and processes
I. INTRODUCTION
Thermal transport in metals is complex due to the coexistence of electron and phonon conduction and the strong interaction between them. The total thermal conductivity (
κ tot
) has two components: The electronic part (
κ e
κ ph
). The total thermal conductivity is the sum of these two components
κ tot = κ e + κ ph
. In high purity metals, such as single crystal metals, the electrons dominate thermal conduction due to their high density and the fact that the Fermi velocity of electrons is much greater than the speed of sound, i.e., the speed of phonons.
1
As a result, it is challenging to directly measure the phonon thermal conductivity of metals.
Because of the rarity of high magnetic fields ( H ≥ 10 kOe ) coupled with low-temperature measurements at that time, starting in the late 1950s, researchers measured the electrical resistivity of a series of dilute alloys at liquid He temperatures and extrapolated back to the conditions of a zero-impurity content in order to approximate the electronic thermal conductivity contributions in pure metals. 2Determining κ eis made possible by applying the Wiedemann-Franz law where κ e / σ ∝ T . 5–7However, this practice is both time consuming and laborious due to the number of samples and measurements needed rather than measuring only one single crystal.
Another possible way [magnetothermal resistance (MTR)] to probe the phonon thermal conductivity is by applying a large transverse magnetic field to a single specimen. By applying a sufficiently high magnetic field, the MTR method allows an indirect measure of the lattice thermal conductivity, provided that this value is field independent. This technique has already been successfully applied to semiconductors
3
and semimetals.
4
Since carrier mobility is relatively large in semiconductors and semimetals, the magnetic field available in a modern laboratory (
∼ 100 kOe
) is often large enough to saturate the magnetothermal resistance and isolate the phonon thermal conductivity. Making use of extrapolation, the electronic thermal conduction is virtually eliminated given that the lattice thermal conduction is field independent; the total thermal conductivity measured under large magnetic field is equal to the lattice thermal conductivity. This strategy is extended to the intermediate temperature regime (
T < 100 K
) because at higher temperatures (
T > 100 K
), extremely large magnetic fields (
≫ 100 kOe
) are required to suppress the electronic component of thermal conductivity for metals. Such larger magnetic fields are not only impractical but can also effect the lattice thermal conduction via electron-phonon interaction. This work focuses on single crystal metals in the low-temperature regime where metals have both a low electrical resistivity and large mobility values. At low temperatures, the thermal conduction of metals can be strongly affected by the magnetic fields available in the laboratory.
8
Only a few results have been reported on the phonon thermal conductivity and Lorenz ratio of single crystal metals. 5–7,18–21,25These limited data are due to the fact that the experimental setup is not easy to realize in the laboratory, controlling a large field and temperature simultaneously. Also, there are restrictions on the materials that can be explored by the magnetothermal resistance method, because a material requires a sufficiently high mobility at low temperature so that electronic saturation can be achieved. This applies to metals and some small band gap semiconductors. Similar to our observations, for example Wagner et al. 30measured the Lorenz ratio of single crystal W in the liquid He temperature regime and noted a variation in the Wiedemann-Franz ratio from the Sommerfeld value. This behavior was predicted by Bennett and Rice 31by theoretical calculation in the low temperature limit. The MTR method was also successfully applied to a series of single crystal metals at liquid He temperature regime, such as Al, 33Zn, 34Pb, 35Sn 36as noted in the literature; however, no such results have been reported in the intermediate temperature (e.g., 5–60 K) regime due to the experimental restrictions.
The advent of the Physical Properties Measurement System (PPMS) from Quantum Design makes the experimental measurement possible and reliable with the Thermal Transport Option (TTO). The aim of this paper is to present experimental techniques for determining phonon thermal conductivity and Lorenz ratio of single crystal metals at low temperatures. These results not only provide the basis for a comparison between experimental and future theoretical material calculations but also make the separation of
κ e
and
κ ph
possible in the thermoelectric materials where the knowledge of each component of thermal conductivity is critical. The MTR method can determine if a thermoelectric material is phonon or electron dominant. For metals, such first-principles calculations have been recently reported for single crystal Ni, Ag, and Au but only at a higher temperature regime than our experimental data.
27,28
In order to consider a magnetic field sufficient to suppress the electronic component of the total thermal conductivity, we require a sufficient large deflection angle γ , which is defined as the deviation of an electron away from its previous linear motion under the influence of the applied magnetic field between collisions 8
γ = ω c τ = μ B = σ 0 B n e ,
(1)
where,
ω c
is the cyclotron frequency,
τ
is the relaxation time,
μ
is the mobility,
B
is the magnetic induction strength,
σ 0
is the zero field electrical conductivity,
n
is the carrier concentration, and
e
is the elementary charge. If
γ ≫ 1
, then the field is said to be a classically large magnetic field.
9
In practice, even when
γ ∼ 1
, a significant suppression of electronic conduction can be observed.
8–12
The magnetic field corresponding to
γ ∼ 1
is used here as the threshold field where
B th ≡ 1 / γ
. As the temperature decreases, the threshold field decreases due to the decline of sample electrical resistivity and nearly constant carrier concentration. We estimate that the
γ
values for Al, Cu, and Zn at 100 kOe and 100 K are 0.05, 0.15, and 0.11, while the corresponding values at 50 K under the same applied field are 0.34, 1.01, and 0.39. Therefore, we observed that when the temperature is below 100 K, the suppression of electronic thermal conductivity becomes noticeable and is enhanced as the temperature decreases. The region
T < 100 K
corresponds to the area of highest mobility for Al, Cu, and Zn.
After obtaining the phonon thermal conductivity κ phfrom MTR, one is able to calculate the zero field Lorenz ratio (or Lorenz number) which is defined as 22,23,26
L ≡ κ e σ 0 T = κ 0 − κ ph σ 0 T
(2)
and characterizes the transport properties of electrons. It is widely used to estimate the electronic contribution to the total thermal conductivity from the electrical resistivity measurements, 13–16where κ eis the zero field electronic thermal conductivity, σ 0is the zero field electrical conductivity, κ 0is the zero field total thermal conductivity, and Tis the absolute temperature. The Sommerfeld value
L 0 = π 2 3 k B e 2 = 2.443 × 10 − 8 V 2 / K 2
(3)
is derived from a consideration of the Wiedemann-Franz law in metals by using Sommerfeld expansion and neglecting the thermoelectric term.
1
In deriving the constant Lorenz ratio, it is assumed that all scattering is elastic, including the electron-phonon scattering at high temperatures and the impurity scattering at low temperatures, and the same relaxation time is used for both electrical and thermal conductivities.
2
However, in the intermediate temperature range, the above two conditions may fail and the Lorenz ratio can significantly deviate from
L 0
. In order to fully describe the temperature dependence of the Lorenz number, we introduce separate relaxation time considerations for the electronic thermal conductivity and electrical conductivity. By introducing different relaxation times for electrical transport and electronic thermal transport without electron-phonon Umklapp processes, the temperature dependence of the dimensionless Lorenz ratio of free electrons in zero field
L ̃ ≡ L / L 0 = κ 0 − κ ph L 0 σ 0 T
can be described using the following formula:
2
L ̃ = β + T Θ D 5 J 5 Θ D T β + T Θ D 5 J 5 Θ D T 1 + 3 α 2 π 2 Θ D T 2 − 1 2 π 2 J 7 Θ D / T J 5 Θ D / T ,
(4)
where βdescribes the purity of the sample, αis the ratio between Fermi wave vector k Fand Debye wave vector q D , J nis defined as
J n Θ T ≡ ∫ 0 Θ / T x n e x e x − 1 2 d x
(5)
and Θ Dis the Debye temperature which can be estimated from the electrical resistivity through Bloch's T 5law 2,24
ρ T = ρ imp + α el − ph T Θ R 5 J 5 Θ R T ,
(6)
where ρ impis the residual electrical resistivity, α el − phis the electron-phonon coupling constant, and Θ Ris the resistivity Debye temperature.
II. EXPERIMENTAL DETAILS
Samples were commercially obtained single crystal metals: Cu (100) 99.99% from MTI Co., while Al (100) 99.999% and Zn (001) 99.999% from Goodfellow Cambridge Ltd. Samples were cut into typical dimensions of 1 × 2 × 10 mm 3, and Ag contacts were sputtered onto the surface to provide low resistance solder contacts for a standard 4-probe resistance measurement. Sample dimensions allow resistivity measurements to be made with current and voltage along the same axis. This is referred to as the xx-configuration. The 4-probe resistivity or Hall measurements with I and V in orthogonal directions are referred to as the yx-configuration. Reduced sample resistivity at low temperatures makes it impossible to measure in the yx-configuration.
Thermal conductivity measurements were performed using the thermal transport option (TTO) of the PPMS, where the heat flow in the sample is perpendicular to the applied magnetic field (i.e., transverse orientation). The thermal conductivity measurements were performed by sweeping temperature across the range of 60 K to 5 K and in a fixed magnetic field varying from 0 to 90 kOe. Resistivity data were obtained using a LR-700 AC resistance bridge from Linear Research Inc. by fixing temperature and slowly sweeping the applied magnetic field. In order to determine
Θ D
, sample heat capacity was measured using a standard adiabatic technique from 2–300 K in zero magnetic field. Our propagated measurement error was calculated from a consideration of standard deviation and determined to be 8% for
κ ph
and 14% for the Lorenz ratio.
III. ANALYSIS OF MAGNETO-TRANSPORT MEASUREMENTS
Residual resistance ratios (RRR), defined by ρ 300 K / ρ 2 K , indicating a rough index of the sample purity and the resistivity Debye temperatures Θ R , fitted using Eq.(6), are summarized in TableI. The Debye temperatures Θ Dfrom our adiabatic heat capacity measurements (data not shown) of the same samples confirm the consistency with Θ R .
TABLE I.
Summary of magnetoresistance measurements.
Specimen . RRR . Θ R / K . Θ D / K . Field direction . Crystal structure . Al (100) 200 415 395 (100) fcc Cu (100) 100 337 323 (100) fcc Zn (001) 800 221 233 (001) hex
Specimen . RRR . Θ R / K . Θ D / K . Field direction . Crystal structure . Al (100) 200 415 395 (100) fcc Cu (100) 100 337 323 (100) fcc Zn (001) 800 221 233 (001) hex
Generally, transport measurements made in zero or low magnetic fields are considered as scalar quantities. However, as magnetic field effects increase, these quantities must be treated as tensor quantities. These transport coefficient tensors exhibit non-zero off diagonal elements due to Hall effects of the applied field. Because the electrical transport coefficients are tensors, the electrical conductivity,
σ x x ,
is not in general equal to the inverse of its corresponding electrical resistivity component, i.e.,
σ x x ≠ 1 / ρ x x
, except in zero field. Electrical conductivity
σ x x
can be derived from magnetoresistance
ρ x x / ρ 0
using Eqs.
(7)
and
(8)
. These formulae require a fitting of the magnetoresistance data in order to derive the two fitting parameters to calculate the electrical conductivity,
σ x x
, where the formulae are derived for a transverse magnetoresistance of a square Fermi surface with constant relaxation time
8
ρ x x ρ 0 = 4 c π 1 − 2 γ π tanh π 2 γ + 1 1 + γ 2 4 c π + 1 4 c π 1 − 2 γ π tanh π 2 γ + 1 1 + γ 2 2 + 8 γ c π 2 1 − sech π 2 γ − γ 1 + γ 2 2 ,
(7)
σ x x = 4 c π 1 − 2 γ π tanh π 2 γ + 1 1 + γ 2 4 c π + 1 ρ 0 ,
(8)
where γand care the two dimensionless fitting parameters.
In order to extract κ phfrom κ tot , the functional form of both κ x x Band σ x x B , the following formulae are required, which are derived for isotropic single band materials:
σ B = σ 0 1 + μ d 2 B 2 ,
(9)
κ tot B = κ ph + κ 0 1 + μ t 2 B 2 ,
(10)
where σ 0and κ 0are the measurements in zero field, and μ dand μ tare drift and thermal mobility values, respectively. Combining(9)and(10)together
κ tot σ = κ ph + κ 0 − κ ph 1 + λ 2 σ 0 σ − 1 ,
(11)
where λ = μ t / μ dis considered as a fitting parameter. κ tot σrepresents the relationship between σand κ tot . If λ = 1 , then κ totand σare linearly related, which is observed at high temperatures. 3However, in the low temperature regime, λ ≠ 1and a non-linear relationship is observed between κ totand σ .
Figure
1
shows the temperature dependent behavior of the total thermal conductivity and electrical resistivity under various applied magnetic fields for Al (001), Cu (001), and Zn (100) single crystal metals. As mentioned previously, the threshold field,
B th
, decreases as the temperature is reduced. Therefore, when applying the maximum field of 90 kOe, we observe a significant suppression of the electronic transport below 60 K. Furthermore, we note the temperature dependent electrical resistivity of Zn in the field has minima unlike the behavior of the Al and Cu samples in the same temperature region. This behavior is due to the fact that Zn is a compensated metal,
8
which results in a large magnetoresistance phenomenon at low temperatures.
FIG. 1.
Thermal conductivity 1(a), 1(c), 1(e) and electrical resistivity 1(b), 1(d), 1(f) are plotted against temperature between 5 and 60 K (for Al and Cu) or 40 K (for Zn) in different magnetic fields. The inset for 1(a), 1(c), and 1(f) illustrates the magnetic field effect between 0 and 90 kOe on thermal conductivity for Al and Cu, electrical resistivity for Zn, as a function of temperature. To compare our results to the previous thermal conductivity data measured in zero field, Mendelssohn and Rosenberg 32(solid black stars), we include these data in Figs. 1(a), 1(c), and 1(e).
FIG. 1.
Thermal conductivity 1(a), 1(c), 1(e) and electrical resistivity 1(b), 1(d), 1(f) are plotted against temperature between 5 and 60 K (for Al and Cu) or 40 K (for Zn) in different magnetic fields. The inset for 1(a), 1(c), and 1(f) illustrates the magnetic field effect between 0 and 90 kOe on thermal conductivity for Al and Cu, electrical resistivity for Zn, as a function of temperature. To compare our results to the previous thermal conductivity data measured in zero field, Mendelssohn and Rosenberg 32(solid black stars), we include these data in Figs. 1(a), 1(c), and 1(e).
In order to extract
κ ph
from
κ tot
, one needs to plot the measured thermal conductivity vs. the calculated electrical conductivity, see Eqs.
(7)
,
(8)
, and
(11)
. Figure
2
shows
κ tot ∼ σ
curves at constant temperature (5 K and 40 K) for each metal from which we can extrapolate
κ ph
. The data points (with error bars) in the central plots for Figs.
2(a)–2(f)
show the effects of the lowest magnetic fields at the upper right side of the curve. The values for
κ tot
and
σ
decrease in magnitude as the applied magnetic field increases. At high temperature, e.g.,
T > 100 K
, we expect the
κ tot ∼ σ
curves to have a linear relationship, since
λ = 1
. As the temperature decreases, one expects
κ tot ∼ σ
curve to deviate from a linear relationship, because the electrical resistivity and thermal conductivity have differing responses to the applied field. We find evidence for this behavior in the
κ tot ∼ σ
curves in Fig.
2
. These differing responses result from the different relaxation times for
σ
and
κ
in the field. Figure
2
confirms this expected behavior, as noted by comparing the linearity of the curves at 5 K and 40 K. The intercepts of the curves in Figs.
2(a)–2(f)
represent the value of
κ ph
, which is assumed to be field independent and is a condition of our analysis. In the upper left inset of Figs.
2(a-i)
,
2(c-i)
, and
2(e-i)
for 5 K, we demonstrate the fit of magnetoresistance according to Eq.
(7)
. The upper left inset at 40 K, Figs.
2(b-i)
,
2(d-i)
, and
2(f-i)
show the derived field dependence of electrical conductivity from the magnetoresistance fit to theory. These curves confirm the validity of Eq.
(7)
as a fit of magnetoresistance data to theory (red fit line). The field dependence of total thermal conductivity is taken directly from our thermal transport measurements and is shown in the lower right inset of Figs.
2(b-ii)
,
2(d-ii)
, and
2(f-ii)
for the 40 K data. The bottom right inset of Figs.
2(a-ii)
,
2(c-ii)
, and
2(e-ii)
at 5 K shows an expanded region of
κ tot ∼ σ
curves from 50 kOe to 90 kOe. These curves extrapolate the sample behavior to the intercepts corresponding to the high field limit and confirm a high correlation between theory and measurement.
FIG. 2.
Total thermal conductivity is plotted against electrical conductivity at 5 K and 40 K with a fit to Eq.(11). The top left inset in 5 K figure shows the magnetoresistance curve vs. the field along with a fit (Eq.(7)). The bottom right inset to Figs. 2(a-ii), 2(c-ii), and 2(e-ii) shows the expanded region of the curve at high fields. Both insets for the data at 40 K Figs. 2(b), 2(d), and 2(f) show the field behavior of electrical and thermal conductivities along with their fit to theory (Eqs.(9)and(10)).
FIG. 2.
Total thermal conductivity is plotted against electrical conductivity at 5 K and 40 K with a fit to Eq.(11). The top left inset in 5 K figure shows the magnetoresistance curve vs. the field along with a fit (Eq.(7)). The bottom right inset to Figs. 2(a-ii), 2(c-ii), and 2(e-ii) shows the expanded region of the curve at high fields. Both insets for the data at 40 K Figs. 2(b), 2(d), and 2(f) show the field behavior of electrical and thermal conductivities along with their fit to theory (Eqs.(9)and(10)).
Close modal
Figure
3
shows the temperature-dependent phonon thermal conductivity and dimensionless Lorenz ratio for Al, Cu, and Zn. Also, Fig.
3
demonstrates how large the phonon thermal conductivity
κ ph
is in comparison to the total thermal conductivity
κ tot
. In Figs.
3(a)
,
3(c)
, and
3(e)
,
κ ph
and
κ tot 90 kOe
curves are plotted vs. temperature; they demonstrate the effective suppression of thermal conductivity with magnetic field (90 kOe). We observe the
κ e
suppression is greatest at low temperature as expected because the threshold field,
B th
, is minimum at low temperatures. The difference between the two curves is smallest at the lowest temperature, confirming that the classically large magnetic field is reached for low temperatures. It is noted that at higher temperatures, e.g., 60 K, a proportionately larger magnetic field is necessary to suppress the electron contribution to thermal conduction. The insets to Figs.
3(a)
,
3(c)
, and
3(e)
show the phonon contribution of thermal conductivity to the total thermal transport. The calculations demonstrate the ratio
κ ph / κ tot 0 kOe
increases by up to 50% in the experimental temperature range investigated for these electron dominated metals (discussed further in Sec.
IV
). Because the primary carriers of thermal transport in these metals are electrons, both the electronic and total thermal conductivity should have a similar temperature dependence. This behavior is illustrated in the insets to Figs.
3(b)
,
3(d)
, and
3(f)
. The dimensionless Lorenz ratio is shown in Figs.
3(b)
,
3(d)
, and
3(f)
and indicates a deviation from unity as the temperature increases. Berman and MacDonald have shown the deviation from the Sommerfeld value in 1950s, although they calculated their Lorenz ratio from the total thermal conductivity
κ tot
rather than the electronic thermal conductivity
κ e
.
29
The direct cause of this deviation is the inelastic scattering between electrons and phonons and a difference in the relaxation time required for thermal transport and electrical processes during the electron-phonon scattering. The relaxation time for the thermal transport process is shorter than the one for the electrical process. The behavior of the temperature dependent dimensionless Lorenz ratio for metals is well described by Eq.
(4)
, as shown by our fit to theory. Following the trend of the fitting function (Eq.
(4)
), we expect the recovery of the W-F law and the Sommerfeld value
L 0
to be restored at room temperature.
FIG. 3.
Phonon thermal conductivity (Figs. 3(a), 3(c), and 3(e)) and dimensionless Lorenz ratio (Figs. 3(b), 3(d), and 3(f)) are plotted against temperature for Al, Cu, and Zn single crystals. Figures 3(a), 3(c), and 3(e) also show a comparison between κ phand κ tot 90 kOe ; the insets to them show the ratio κ ph / κ tot 0 kOeat the same temperature range. The insets to Figs. 3(b), 3(d), and 3(f) illustrate the comparison between κ tot 0 k O eand κ e 0 k O e . We compare our data in Fig. 3(d) with Berman and MacDonald 29(open stars), which is derived from total thermal conductivity without applying a magnetic field.
FIG. 3.
Phonon thermal conductivity (Figs. 3(a), 3(c), and 3(e)) and dimensionless Lorenz ratio (Figs. 3(b), 3(d), and 3(f)) are plotted against temperature for Al, Cu, and Zn single crystals. Figures 3(a), 3(c), and 3(e) also show a comparison between κ phand κ tot 90 kOe ; the insets to them show the ratio κ ph / κ tot 0 kOeat the same temperature range. The insets to Figs. 3(b), 3(d), and 3(f) illustrate the comparison between κ tot 0 k O eand κ e 0 k O e . We compare our data in Fig. 3(d) with Berman and MacDonald 29(open stars), which is derived from total thermal conductivity without applying a magnetic field.
IV. DISCUSSION
The theoretical fit to data in Figs.
2
and
3
using Eqs.
(7)
,
(9)
,
(10)
, and
(4)
accurately describes the dynamic transport response between magnetoresistance, electrical conductivity, and total thermal conductivity. The high correlation between the theoretical fit of Eq.
(4)
to data for the Lorenz ratio indicates the validity of the formula, as well as the different scattering relaxation times in the thermal and electrical processes. It is important to note that when comparing the extrapolation of
κ ph
for 5 K and 40 K in Fig.
2
for all samples to the fit to Eq.
(11)
, error is considerably less at the lower temperature than at the higher temperature. The extrapolation at higher temperature may overestimate
κ ph
due to the fitting parameters of Eq.
(11)
and can result in a slightly larger ratio of
κ ph / κ tot
. In order to reduce overestimating the ratio of
κ ph / κ tot
, this would require an improved theory of electron dominant metals and different functional form of
κ tot σ
not currently available.
Another method to reduce an overestimation of the ratio of
κ ph / κ tot
is to use samples with the lowest possible impurity concentration or highest residual resistivity ratio (RRR). Impurities and dislocations can significantly increase electron scattering in thermal conductivity particularly when considering single crystal metals which are electron dominant. The RRR values of our single crystal metals are given in Table
I
and are on the order of 100; our Zn sample has the highest RRR value, and its
κ ph
ratio is also the lowest at low temperatures. As a result, samples with lower impurity and higher RRR values can be considered to reduce the overestimation of
κ ph
ratio.
2,17,18,25
Figure
4
shows
κ ph
vs.
T
and illustrates how the different scattering mechanisms in Al, Cu, and Zn single crystals change across the temperature spectrum of 5 K–60 K. From phonon transport theory at low temperatures (
T ≪ Θ D
), the phonons scatter with electrons resulting in
κ ph
with a temperature dependence of
T 2
, and at even lower temperatures,
κ ph
exhibits a
T 3
law behavior following from the heat capacity of phonons. In the high temperature regime (
T ≫ Θ D
), the Umklapp process dominates the scattering, with a
T − 1
dependence. The change in the power law behavior as a function of
T
, as shown in all three curves in Fig.
4
, indicates the change in the scattering process. This change results in a peak in the
κ ph ∼ T
curve, which usually occurs around 10% of the Debye temperature
1,2
and is demonstrated in all three curves.
FIG. 4.
View large Download slide
Phonon thermal conductivity of Al, Cu, and Zn is plotted against temperature in a log-logscale. Two dashed lines are a guide to the eye, showing different T power law values across the temperature range.
FIG. 4.
Phonon thermal conductivity of Al, Cu, and Zn is plotted against temperature in a log-logscale. Two dashed lines are a guide to the eye, showing different T power law values across the temperature range.
A requirement of the technique employed here is high sample mobility (e.g ., > 10 3 cm 2 V − 1 s − 1 ) so that a large magnetic field (∼100 kOe) can suppress the electronic transport. Furthermore, the samples should have a high electrical conductivity; otherwise, the relative change of electrical conduction with the field will be too small for comparison and all the points in the κ tot ∼ σplot will collapse, making the extrapolation of σ = 0unreliable.
In the past, due to the limited availability of large magnetic fields and convenient methods to measure thermal conductivity while applying magnetic fields, very few single crystal metals were explored in transverse field to extract the phonon thermal conductivity or the Lorenz ratio. Some metals, such as Al,
18
Cu,
6,19,20,25
Zn,
21
Au,
18
Ag,
18
have results for their Lorenz ratio utilizing
κ tot
instead of
κ e
. However, the method employed there lacks the functionality of estimating
κ e
from
σ
The method described here can be applied to semiconductor single crystals, such as Bi 2Te 3and Bi 2Se 3, which are widely used in thermoelectric applications. A determination of κ efor TE materials is helpful when attempting to reduce κ totin order to improve efficiency. In both of these semiconductors, the phonon contribution to κ totis comparable with the electronic counterpart, or may even be dominant across the temperature spectrum. In metals, the Lorenz ratio drops quickly in the intermediate temperature range, as seen in Fig.3. If the Sommerfeld value is used to estimate κ e , then the real electronic thermal conductivity can be overestimated. The advantage of employing our experimental method on semiconductors is the ability of making Hall measurements on samples to obtain ρ y x . Measuring both ρ x xand ρ y xleads to a greater precision in deriving σ rather than fitting from Eq.(7).
V. CONCLUSIONS
The phonon thermal conductivity and Lorenz ratio of several single crystal metals (Al, Cu, and Zn) are extracted from the total thermal conductivity through magnetothermal resistance (MTR) measurements. We find the phonon thermal conductivity has a peak around Θ D / 10 , while the Lorenz ratio deviates from the Sommerfeld value in the intermediate temperature range. This technique could prove helpful in evaluating other materials, particularly semiconductors, used in thermoelectric applications, where the suppression of κ totcan lead to enhanced thermoelectric efficiency ( ZT).
ACKNOWLEDGMENTS
This work was supported by Solid State Solar–Thermal Energy Conversion Center (S3TEC), an Energy Frontier Research Center funded by the U. S. Department of Energy, Office of Science, and Office of Basic Energy Science under Award No. DE-SC0001299. C.P.O. would like to thank Millie Dresselhaus, R. D. Farrell, S.J., C. Noyes, and Bryan Paulsen, S.J. for helpful comments on the manuscript, and acknowledges financial support from the Trustees of Boston College. M.Y. is grateful to D. Broido and M. Graf for helpful discussions and comments on the manuscript. The work at the University of Virginia is supported by the Air Force Young Investigator Award, Grant No. FA9550-14-1-0316.
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Plants | Free Full-Text | Assessing the Impact of Geographical Distribution and Genetic Diversity on Metabolic Profiles of a Medicinal Plant, Embelia ribes Burm. f.
The extensive use of Embelia ribes Burm. f. (Embelia) in tribal medicine proclaimed global attention as a promising candidate in complementary and alternative medicine. The knowledge of chemical blends is a prerequisite for the selection of raw materials for herbal medicine formulations; however, the influence of geographical distance and genetic diversity on the metabolome of Embelia fruits is unknown. Therefore, we collected Embelia fruits from four locations across the Western Ghats of India and analyzed the metabolic profile and genotypic diversity of Embelia fruits by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inter simple sequence repeats (ISSR), respectively. LC-MS/MS analysis yielded 583 compounds; however, the trimmed data resulted in 149 compounds. Further, MS/MS analysis identified 36 compounds, among which we reported 30 compounds for the first time from Embelia. These compounds belong to 11 compound classes that suggest location-specific chemical blends of Embelia fruits. Multivariate analysis showed 94% compound diversity across the accessions. ISSR analysis suggests 95% polymorphism across the accessions. A significant positive correlation (80%) between metabolomics and genotypic data matrices validates the genotype& rsquo;s influence in tuning Embelia& rsquo;s metabolic profiles. We conclude that the chemical profiles of Embelia are location-specific, which can be explored for the selection of herbal trade sustainably.
Assessing the Impact of Geographical Distribution and Genetic Diversity on Metabolic Profiles of a Medicinal Plant, Embelia ribes Burm. f.
by Shubhangi Raskar , Vishwabandhu Purkar , Milind Sardesai and Sirsha Mitra *
Department of Botany, Savitribai Phule Pune University, Pune 411007, India
Author to whom correspondence should be addressed.
Plants 2022 , 11 (21), 2861; https://doi.org/10.3390/plants11212861
Received: 15 September 2022 / Revised: 8 October 2022 / Accepted: 20 October 2022 / Published: 27 October 2022
(This article belongs to the Special Issue Phytochemical and Nutritional Analyses of Medicinal and Aromatic Plants (MAP) )
Abstract
The extensive use of
Embelia ribes
Burm. f. (Embelia) in tribal medicine proclaimed global attention as a promising candidate in complementary and alternative medicine. The knowledge of chemical blends is a prerequisite for the selection of raw materials for herbal medicine formulations; however, the influence of geographical distance and genetic diversity on the metabolome of Embelia fruits is unknown. Therefore, we collected Embelia fruits from four locations across the Western Ghats of India and analyzed the metabolic profile and genotypic diversity of Embelia fruits by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inter simple sequence repeats (ISSR), respectively. LC-MS/MS analysis yielded 583 compounds; however, the trimmed data resulted in 149 compounds. Further, MS/MS analysis identified 36 compounds, among which we reported 30 compounds for the first time from Embelia. These compounds belong to 11 compound classes that suggest location-specific chemical blends of Embelia fruits. Multivariate analysis showed 94% compound diversity across the accessions. ISSR analysis suggests 95% polymorphism across the accessions. A significant positive correlation (80%) between metabolomics and genotypic data matrices validates the genotype’s influence in tuning Embelia’s metabolic profiles. We conclude that the chemical profiles of Embelia are location-specific, which can be explored for the selection of herbal trade sustainably.
Keywords:
ethnobotany
;
herbal medicine
;
genetic variation
;
geographic distribution
;
liquid chromatography-mass spectrometry
;
metabolomics
Graphical Abstract
1. Introduction
Embelia ribes Burm. f. (Embelia) [ 1 ] is a liana that belongs to the family Primulaceae. Since ancient times, the use of Embelia fruits has been widespread in the form of the drug Vidanga . Embelia’s distribution in India ranges from the outer Himalayas to the Western Ghats, at an elevation of up to 1500 m [ 2 ] in fragmented populations. The sparse distribution of Embelia in the evergreen to moist deciduous forests of Maharashtra, Karnataka, and Kerala in the Western Ghats and Tamil Nadu in the Eastern Ghats, is evident. The different plant parts of Embelia are used in herbal formulations, as it is rich in various medicinally important molecules, namely embelin and its derivatives, embeliol, 5-O-Methylembelin, and vilangin that have high commercial value. Hence, the pharmacology of Embelia has attracted global attention as a promising candidate in various traditional, complementary, and alternative systems of medicine. In traditional and tribal medicine, the fruits, stems, roots, and leaves of Embelia are used as anthelmintic, antipyretic, and antimicrobial agents. In addition, they are also used to treat diarrhea, kidney stones, snake bites, and bronchitis. However, the fruits of Embelia are more common in traditional medicine and herbal formulations than their leaves and roots. Interestingly, the use of the same plant parts varies from region to region. For example, fruit decoction of Embelia is given for intestinal worms in Kerala [ 3 ], antimicrobial medication in Karnataka [ 4 ], diarrhea in Arunachal Pradesh, and influenza and snakebite in the Khandesh region of Maharashtra [ 5 ]. However, as the climatic condition of the Khandesh region is not suitable for Embelia growth, its use in this region questions the authentication of the used fruits.
The geographical origin and climatic conditions are the notable factors that affect the metabolome of a plant. Plants are adapted to the different geographical, climatic, and edaphic conditions by genotypic and phenotypic alterations. The genotypic alteration also influences the production and accumulation of secondary metabolites in plants [ 6 , 7 ]. Though the specialized metabolite profile is unique to individuals within a species or a close taxonomic group, it may alter if its biosynthetic pathways are influenced by environmental conditions such as climate, soil, pathogens infection, and pest infestation. Therefore, regional variation in the use of the same plant parts can be due to the presence of different blends or proportions of active compounds in them, which in turn links the geography and climate of the habitat of Embelia. In 2011, Saurabh demonstrated that geographical topography and climatic conditions profoundly affect the levels of polyphenols in the bark of Bridelia retusa [ 8 ]; similarly, the effect of geographical and climatic conditions on the camptothecin content in Nothapodytes nimmoniana is also demonstrated [ 9 ]. Recently, a comparative study of the concentrations of embelin, Embelia’s principle component in its fruit from different geographical regions, underlined that the geographic location of a plant could govern the change in the concentration of its principal component [ 10 ]. Previously, a comparative analysis of fatty acid composition in the seeds of E. schimperi [ 11 ] and fatty acids and esters from E. basal have been attempted [ 12 ]; however, the non-targeted metabolomics of Embelia fruits from different geographical regions are yet to be revealed.
Metabolomics has been used for the identification of marker compounds to detect physiological changes, genotype differences, geographic origin, and quality control [ 13 , 14 ]. In a study with the fruit of Butia sp., rutin, epicatechin, isorhamnetin, and stilbene were identified as the significant markers in discriminating the geographic origins and species [ 15 ]. Moreover, with the globalization of traditional medicine systems such as Ayurvedic medicine and traditional Chinese medicine, many Asian medicinal plant species are being introduced to cultivation outside of their geographical origins, particularly in the EU and US [ 16 ]. As these ecosystems are significantly different from their native origin, these species suffer from measurable differences in chemical composition. In general, studies focus on a single compound or a class of compounds to evaluate the effect of climatic or geographical conditions [ 17 ]; however, a plant’s whole metabolome is rarely considered for intensive analysis in response to changes in its geographical conditions. To improve global health through traditional and complementary medicine, the World Health Organization (WHO) emphasizes the rational use of raw materials based on evidence and strategic research in traditional and complementary medicine. Embelia, a tremendously important medicinal plant of traditional and complementary medicine, is widely exploited. Therefore, determining the metabolic profile of Embelia is a prerequisite for developing new drugs. However, the metabolome of Embelia and the impact of different geographical regions on it is not known. Determining Embelia’s metabolic profile from different locations will provide its complete metabolic blend and reveal new compounds with potential medicinal importance. Moreover, it will allow the sustainable use of Embelia fruits. Therefore, in the current study, we analyzed the non-targeted metabolomic profiles of the Embelia fruits collected from different regions of the Western Ghats of India using liquid chromatography coupled with tandem mass spectroscopy (LC-MS/MS) to identify potential compounds for drug development, and attempt to reveal the relationship between the metabolomic and genotypic diversity.
2. Results
2.1. Molecular Identification of Fruit Samples Collected from Different Geographical Regions
Fruit samples collected across all the accessions ( Figure 1 A) were evaluated for their size and texture. Interestingly, fruits from Kodkani, Karnataka, and Wayanad, Kerala, are significantly larger and smaller than those from other accessions, respectively ( Figure 1 B). The fruit size of the Kodkani accession is significantly more than the other accessions (one way ANOVA, F 4,18 = 12.91; p = 0.0002). Moreover, the fruits from Kodkani were spherical, whereas fruits from other locations were obovate. On the other hand, Wayanad fruits are the least wrinkled among other accessions ( Figure 1 B inset). Dissimilarities in Embelia fruit morphology necessitate the molecular identification of the collected samples. Chloroplast maturase K gene ( m atK ) is one of the most variable coding genes of angiosperms and is used for the identification of plant species. Molecular identification by matK amplification is often used for the accurate genetic identification of an organism. Therefore, all the samples were evaluated by comparing the sequence homology of the matK gene with the reported sequence of E. ribes in the NCBI database ( Table S1 ). The maximum percent identity and query cover threshold was more than 98% and 85%, respectively. Further, a phylogenetic tree was constructed with the matK sequences from all the Embelia accessions, E. tsjeriam-cottam (Roem. & Schult.) A. DC. and Maesa indica (Roxb.) A. DC. sequences ( Figure 1 C); E. tsjeriam-cottam and M. indica were used as outgroup. Embelia accessions collected across the Western Ghats did not show any genetic distances, whereas the outgroups showed a significant genetic distance from the Embelia accessions ( Figure 1 C). Our results confirmed the identity of the collected fruits as E. ribes .
Figure 1.
Sampling locations of Embelia ribes (Embelia) fruit samples and their morphological and molecular identification.
(
A
) The highlighted portion of the magnified map of India depicting the four locations, namely: (1) Manoli (Maharashtra), (2) Kodkani (Karnataka), (3) Nadpal (Karnataka), (4) Wayanad (Kerala), across the range of Western Ghats. (
B
) Fruit samples corresponding to each of the four accessions show variation in their pigmentation and size (inset). The fruit diameter from the Kodkani accession is significantly more than that of other accessions (F
4,18
= 12.91;
p
= 0.0002). Values are the mean (±SE) of five replicate fruits. Significant difference was determined by one way ANOVA and Tukey’s
post hoc
test at
p
≤ 0.05. (
C
) Phylogenetic tree was constructed using the
maturase kinase
(
matk
) nucleotide sequences from different accessions of Embelia fruits with 1000 bootstrap values, and maximum composite likelihood method. It confirms the identity of the collected samples as
E. ribes
(Embelia). Sequences obtained from
E. tsjeriam-cottam
and
Maesa indica
leaves were used as an outgroup. Figures at the nodes indicate bootstrap values determined after bootstrapping the clusters 1000 times. The scale at the bottom of the tree quantifies the average distance between clusters.
2.2. Metabolic Profiles of Embelia Fruits Vary across the Accessions
The ethonopharmacological uses of Embelia fruits are different across geographical regions. The use of Embelia fruits for different ailments suggests that fruits from different locations may have a different blend of compounds that are useful for specific diseases. Therefore, we analyzed the metabolic profiles of Embelia fruits from different accessions. A total of 583 compounds are obtained from negative and positive modes from all the accessions (
Data S1
). The maximum number of compounds were present in the Kodkani accession (380 compounds); the Manoli accession is comprised of 352 compounds; Wayanad and Nadpal accessions are comprised of 346 and 341 compounds, respectively (
Data S1
).
The compounds present in all five replicates of any of the accessions are tentatively identified based on the formula. This trimmed data resulted in 149 compounds (
Table S2
), and the identity of 36 compounds was determined in MS/MS mode (
Table 1
,
Figures S1 and S2
). The identity of embelin, a prime compound of Embelia, from fruits samples was confirmed by HPLC (
Figure S3
). All further analysis was done with the 36 identified compounds. Similar to the raw data, Kodkani accession possesses the maximum number of compounds (34), followed by Wayanad (27), Manoli (8), and Nadpal (6). Interestingly, out of 36 identified compounds, 30 are reported for the first time from Embelia.
Table 1. Compounds identified from different Embelia accessions by LC-MS/MS. Total of 36 compounds were identified based on the fragment ion spectra in both negative and positive ionization modes. 1–33 in negative ionization mode and 34–36 in positive ionization mode (M—Manoli, K—Kodkani, N—Nadpal, W—Wayanad).
A heatmap was created with the identified compounds to visualize the compound diversity (
Figure 2
). Principal coordinate (PCoA) and cluster analysis determined the relationship between the accessions. PCoA ordination captured maximum variation in coordinates 1 and 2, where Kodkani and Wayanad accession form a group, but Manoli and Nadpal accession is placed separately (
Figure 3
A). Like the PCoA, the cluster analysis also placed Kodkani and Wayanad accessions in the same clade (
Figure 3
B); Manoli accession is close to this cluster but in a separate clade. The three accessions are grouped as one large cluster that is further connected to a separated clade of Nadpal accession. The high bootstrap value (99) of the cluster of Kodkani and Wayanad accessions signifies their metabolic similarity compared to the other accessions.
Figure 2.
The distribution of identified metabolites across the accessions.
The accessions showed a variation in the distribution of metabolites across the accessions. The color scheme at the top left corner codes for the Z-scores (−4 to +4) calculated over binary co-ordinates of the samples. The dendrogram at the top of the heatmap indicates the average linkage clustering computed between the samples based on the Manhattan distance.
Figure 3.
The multivariate analysis of metabolomics data.
(
A
) The plot of principle coordinate analysis (PCoA) with identified metabolites across the accessions using the Jaccard coefficient and transformation exponent value 2. The percentage of the variation is captured in Coordinates 1 and 2. The values in parentheses show the percentages of the variation. The x- and y-axes are indicated by the eigenvalue scale. (
B
) A phylogenetic tree with the single linkage algorithm and Jaccard similarity index at the 1000 bootstrapping threshold. The tree shows the clusters among the accessions based on the similarities in the metabolites in each of the five samples of a given accession. Bootstrap values of the respective clusters are depicted at each tree node. (
C
) The Venn diagram depicted the number of compounds shared and uniquely present along with all the combinations. Kodkani and Wayanad accessions show the maximum number of shared compounds, whereas Manoli and Nadpal accessions show the least number of shared compounds. Similarly, Kodkani accession showed a maximum (six) number of uniquely present compounds. However, Nadpal accession does not have any unique one.
We look further to find the compound similarities across the accessions by creating the Venn diagram ( Figure 3 C, Table 1 ). We found that only two compounds, embelin and n-propyl sec-butyl disulfide, are present in all the accessions. The number of unique compounds present in Manoli (hexenyl-(3z)-hexenoate (3z-)) and Wayanad (bolegrivialol) accessions is one; however, Kodkani accession possesses six unique compounds ( Figure 3 C, Table 1 ) that belong to the phytophenols, namely 3,4,5-Trihydroxyflavanone, Dihydro 3-coumaric acid, quercetin, isoquercitrin, naringenin, and piceatannol ( Table 1 ). On the contrary, Nadpal accession did not show the occurrence of any unique compounds. Moreover, through the pairwise analysis of similarity percentage (SIMPER test; Bray-Curtis dissimilarity index) in the compounds at a 50% cut-off, we identified 15 compounds responsible for the grouping accessions ( Table S3 ).
2.3. Identified Compounds Represent Major Chemical Groups and Potential Medicinal Properties
Compounds identified by MS/MS analysis were classified according to their chemical classes, which include quinones, phytophenols, terpenoids, organosulfur compounds, organic acids, aliphatic hydrocarbons, lipids, oxygenated hydrocarbons, organic oxygen compounds, organic heterocyclic compounds, and amino acids (
Figure 4
). Interestingly, Kodkani accession possesses all the 11 groups of compounds that suggest it as the most diverse accession among all. Compounds present in Manoli, Nadpal, and Wayanad accessions represent six, four, and 10 compound groups, respectively. Quinones and organosulfur compounds are present across all the accessions; however, different accessions show a different blend of compounds (
Figure 4
). Reports suggest that most identified compounds are active against different ailments mainly cancer, cardiac disorder, and oxidative stress (
Table S4
). There are a few new compounds, namely 1-pentanesulfenothoic acid, 2-formylglutarate, ethyl 1-methylpropyl disulfide, galactonic acid, 3-isopropylmalic acid, and 3-furoic acid whose functions are not known yet (
Table S4
).
Figure 4.
Distribution of chemical classes across the accessions
. Identified compounds were grouped according to their compound classes. A total of 11 classes of compounds were found. Kodkani accession showed all 11 groups, followed by ten groups in Wayand, six in Manoli, and four in Nadpal.
2.4. Accessions of Embelia Are Genetically Diverse
Differences in fruit phenotype hinted towards the genetic diversity of Embelia across the accessions. Moreover, genetic variability is one of the prime factors that tunes plants’ metabolic profiles. Therefore, to check if the genotypic diversity orchestrates the metabolic variations across the Embelia accessions, we examined the genotypic diversity of Embelia accessions with inter simple sequence repeat (ISSR) markers. As demonstrated in a previous study, we used nine ISSR markers ( Table S5 ) that are polymorphic for Embelia plants [ 18 ]. All the markers yielded robust and reproducible polymorphic amplification patterns. Ninety-four bands were generated, with an average of 10.4 products per primer. Among these, 90 bands (95.74%) were polymorphic and four (4.25%) were monomorphic ( Table S6 ). The number of polymorphic bands ranged from six (in the case of primer 816) to 13 (in the case of primer 857) ( Table S6 ). While the primers 809, 857, and 881, had a high percentage of polymorphic bands (PPB), primer 816 showed the lowest PPB (6.38%) ( Table S6 ). A hierarchical cluster was generated with the binary matrix using an unweighted neighbor-joining method with Jaccard’s coefficient of dissimilarity that clustered the accessions into two main clades, and the clades having Embelia accessions are further formed into three clades ( Figure 5 ). The presence of Wayanad and Kodkani accessions in the same clade suggests that they share the maximum similarity. Interestingly, Manoli accession shares similarities with Wayanad, Kodkani, and Nadpal accessions. E. tsjeriam-cottam was used as an outgroup that showed significant differences with Embelia accessions and clustered separately. In the Embelia cluster, the high percentage of polymorphism suggests high genetic variability among the accessions under study.
Figure 5.
Genotypic diversity among Embelia ribes accessions from different geographical regions.
After scoring the amplified products on Embelia and
E. tsjeriam-cottam
by nine IISR primers, obtained binary data was used to generate a phylogenetic tree.
E. tsjeriam-cottam
was used as an outgroup. Wayanad and Kodkani accession share the same clade, whereas the Manoli accession connects the Nadpal accession with Wayanad and Kodkani accessions. The outgroup is forming a separate clade. The scale at the bottom of the phylogenetic tree quantifies the Jaccard distance between the genotypes. Numbers at each tree node indicate the bootstrap value of the respective cluster computed at the 1000 bootstrapping threshold.
2.5. Metabolic Diversity in Embelia Fruits Correlates with Genotypic Diversity
As the cluster analysis with metabolite and ISSR matrix showed similar grouping of the accessions, we hypothesized that metabolomic variation in different Embelia accession is due to their genotypic diversity. Therefore, we performed Mantel’s test with both matrices. Mantel’s test showed significant positive correlation (R = 0.799; p = 0.043) between genotypic and metabolic data matrix. Therefore, we conclude that their genotype governs the metabolic diversity in Embelia fruits along the Western Ghats accessions.
3. Discussion
The different parts of Embelia plants, especially the fruits, are predominantly used in folklore medicine. However, a detailed study of the active principles and their benefits and risks need to be evaluated to integrate traditional medicine practices into healthcare systems. However, limited information on the chemical profiles of Embelia fruits made it challenging to predict the compound or blend of compounds presumably responsible for a specific ailment’s remedy. The geographical region-specific use of Embelia fruits against various ailments stemmed us to study their metabolic profiles across different geographical regions. Our study is the first attempt at the non-targeted metabolic profiling of Embelia fruits that reveals Embelia’s chemical diversity associated with their geographical location, genotypic diversity, and ethnopharmacology. Moreover, new compounds can be explored further for their functionality against ailments.
Our study highlighted that the metabolic blend of Embelia fruit varies across geographical regions. The climatic and edaphic differences restricted to a particular geographical area could govern the chemistry of a plant [ 8 ]. Chemical diversity in the plants also validates the region-specific use of the Embelia fruits against various ailments. Unfortunately, the metabolic profile of Embelia fruit is mainly unknown, as most of the studies focused on the major chemical groups, namely, quinones, flavonoids, essential oils, etc. [ 10 , 19 , 20 ]. We demonstrate a spectrum of varied compounds across the different accessions from the Western Ghats of India. On a geographical scale, two Karnataka accessions, Nadpal and Kodkani, are situated in proximity with an aerial distance of 132.35 km. Therefore, these accessions share fewer climatic and topographical variations. However, the multivariate analysis of the chemical compositions did not group Kodkani and Nadpal; surprisingly, Kodkani is grouped with Wayanad accession, which is 361.38 km (aerial distance) away from the Kodkani accession. Interestingly, the Manoli accession is 361.38 km and 632.65 km away from Kodkani and Wayanad accession, respectively, and showed similar percent similarity in the compound profile with both locations. These observations question the contribution of geographical parameters to the chemical diversity among different locations. Plant populations may respond genetically to differential selection pressures brought by environmental factors, such as climatic heterogeneity and geographic isolation [ 21 ], and plants’ genetic diversity could be the major player in their observed metabolic diversity. An analysis of genetic diversity with ISSR markers revealed high genetic variation across the accessions. Embelia requires particular geographical conditions to grow and distribute in patches; therefore, high genetic variability among the Embelia accessions contradicts the fact that geographically restricted species tend to have less genetic variation than the standard widespread species [ 22 ]. On the other hand, reports also suggest that species distributed in patches showed more significant differentiation than the more continuously distributed species [ 23 ]. Moreover, species with small populations and less genetic variability are vulnerable to extinction [ 24 ]. Therefore, presumably, being a sparsely distributed and threatened species, Embelia showed high genetic variation among the accessions, making it less prone to extinction. A significant correlation between the matrices of ISSR and metabolic data confirms that metabolic diversity in Embelia fruit is attributed to its genetic variability.
In traditional and folklore medicine, Embelia fruits are mainly used as antihelmintic, antidyspepsia, appetizer, mild-laxative, carminative, alexiteric, and antipyretic. However, to treat a particular disorder successfully, the presence of a specific compound or a blend of compounds is necessary. Chemical variation in the plant sample can influence the effectiveness of the formulated drugs against a particular disease. Therefore, the selecting of raw materials based on their chemical composition is a prerequisite. Variations in the traditional use maybe rely on this hypothesis. Therefore, we categorized the identified compounds from Embelia fruits according to their functionality. The compounds having antipyretic, antihelmintic, and antioxidant activity, is fairly equally distributed throughout all the accessions ( Table S4 ); this supports the use of Embelia fruits as antipyretic and antihelmintic across all regions. In folklore medicine, Embelia fruits are used for the treatment of cancer, mainly in Karnataka [ 25 ]. Interestingly, Embelia fruits from Kodkani, one of the Karnataka accessions, are dominated by compounds with anticancerous properties. Previous reports have designated embelin and its derivatives from Embelia as anticancerous compounds; however, we identified other compounds with similar properties but different mechanisms of action. Moreover, piceatannol, a unique compound present in Kodkani accession, is a hypoglycemic agent [ 26 , 27 ]; this correlates with the use of Embelia fruits against polyuria, which may cause by the hyperglycemic condition. Compounds that control cardiac rhythm and have anticoagulant properties from the Karnataka accessions also justified the local use of Embelia fruits against cardiac ailments. There is a growing importance of phytochemicals as male contraceptives because the anti-fertility effects of phytochemicals are reversible. For instance, sterility induced by embelin in male albino rats was reversed within 15–30 days [ 28 ]. Therefore, the chemical constituents showed that anti-fertility properties are clinically crucial for developing male contraceptives [ 29 ]. Polyphenols from Mucuna urens. can inhibit the endogenous gonadotrophic activity in male albino rats [ 30 ]; therefore, the presence of different phytophenols can be examined as a potential target to develop male contraceptives. The current study is the first non-targeted metabolomics study of Embelia fruits that highlighted the region-specific compounds blend governed by intraspecific genetic variations. We found a few compounds, namely 1-pentanesulfenothoic acid, 2-formylglutarate, ethyl 1-methylpropyl disulfide, galactonic acid, 3-isopropylmalic acid, and 3-furoic acid, whose functions are unknown. Testing these compounds against mammalian cell lines may reveal their new potential use. Moreover, the generated metabolomic profiles can be utilized as a metabolic fingerprint of the accessions during the formulation of new herbal drugs. The identification of favorable chemotypes will support quality control and the sustainable use of the plant materials.
4. Materials and Methods
4.1. Plant Material
Embelia fruits were used for metabolic and genetic diversity analysis. Fruits collected by the local villagers from the forest around Manoli, Kolhapur, were procured from local roadside sellers; fruits were also collected from the forests of Nadpal, Karnataka (Nadpal accession), Kodkani, Karnataka (Kodkani accession), and Wayanad, Kerala (Wayanad accession). The leaf tissues of E. tsjeriam-cottam and Maesa indica were collected from the Savitribai Phule Pune University (SPPU) medicinal garden and used for genetic diversity analysis as an outgroup. Specimen samples from each location and genotype are deposited at the Department of Botany, SPPU.
4.2. Metabolite Extraction and LC-MS/MS Acquisition
Dried Embelia fruits were pulverized and ~40 mg of tissue was extracted in 400 µL 70% methanol (
v
/
v
) spiked with the internal standard formononetin (2 µg ml
−1
) by vortexing overnight. The extracts were centrifuged for 20 min at 13,000 rpm at 4 °C and the supernatant was collected. Further, the supernatant was filtered through microfilters (20 µm) and subjected to LC-QTOF-MS/MS (Agilent Technologies, Stuttgart, Germany) for analysis.
A Zorbax C18 (1.7 μm, 2.1 mm × 100 mm) column was used to separate metabolites. The mobile phases used were 0.1% formic acid (solvent A) and acetonitrile containing 0.1% formic acid (solvent B). Separation was achieved at a flow rate of 0.3 mL min
−1
and a column temperature of 25 °C. The solvent gradient profile followed an initial isocratic separation with 95% A (1 min) followed by the gradient of solvent A 5%, B 95% until 12.00 min, solvent A 95%, and B 5%, until 12.5 min, that extended up to 16th minute. The mass spectrometer was used in centroid mode for both negative and positive ionization with a pump limit of 1 min, draw speed of 200 µL min
−1
, and eject speed of 400 µL min
−1
. Samples were analyzed with an injection volume of 10 µL where the pressure limit in the column was maintained at 0 to 800 bar, retention time (RT) exclusion tolerance was maintained at (±) 0.2 min, and ion source (dual ESI) with a limit of two precursors per minute.
4.3. LC-MS/MS Data Analysis
The personal compound database and library (PCDL) Mass Hunter Qualitative Analysis BO.07.00 tool (Agilent technologies) was used to analyze the compound spectra. The PCDL library was made by accessing mainly the METLIN database, all possible libraries for the medicinally important and general plant metabolites and phytochemicals associated with medicinally essential plants. MS/MS acquisition was performed with five replicate fruits to examine the biological variations within the accession and reproducibility. To eliminate the background contaminant compounds from the analysis, only the compounds with an abundance greater than 10,000 counts and a score of more than 70 are considered. These trimmed compounds were screened against PCDL library and resulted in 3574 compounds. Compounds were identified using the ‘find by formula’ function in the software package with a mass threshold of 7 ppm and a peak distance threshold of 10 ppm in MS mode. The resulting 583 compounds were further trimmed based on their presence in all five replicates of any accessions resulting in 149 compounds across the accessions. These compounds were analyzed in MS/MS mode for the presence of the daughter ions to confirm their identity. Finally, 36 compounds were identified in MS/MS mode (
Table 1
,
Figures S1 and S2
).
4.4. Genomic DNA Isolation, and Polymerase Chain Reaction (PCR)
DNA was isolated using a CTAB-STE method by Doyle and Doyle with modifications [ 31 , 32 ]. Isolated DNA was dissolved in TE buffer and quantified in Nanodrop (ND-1000 Spectrophotometer). 100 ng of isolated DNA was amplified using the matK gene-specific primer pairs (forward 5′ TCCGCTACTGGGTAAAAGATG 3′, reverse 5′ ATATCGCCCCAAATCGGTCA 3′) and nine inter simple sequence repeat (ISSR) primers ( Table S5 ) in a thermocycler (Biorad) with one cycle of initial denaturation (95 °C for 2 min), 40 cycles ( matk ) or 34 cycles (ISSR) of denaturation (95 °C for 15 s), annealing (60 °C for matK or 50–60 °C for ISSR) ( Table S5 ) for 1 min, extension (72 °C for 30 s), and one cycle of final elongation (72 °C for 7 min). The amplified DNA was separated on a 1.5% agarose gel and documented on a gel documentation system (Biorad).
4.5. Sequencing and Data Analysis
Amplified products by
matK
primers were outsourced for Sanger sequencing (Bioserve). Obtained sequences were analyzed using the CROMAS (version 2.6.6) software and aligned using multiple sequence comparison by log expectation (MUSCLE
www.ebi.ec.uk
(accessed on August 2021). Homology searches were performed within the Genbank non-reductant database using the BLAST algorithm (
http://www.ncbi.nim.nih.gov./BLAST/
(accessed on 31 August 2021). All the
matK
sequences generated have been deposited in the NCBI GenBank database (Accession numbers: Bank It2604113: Seq1-OP081086, Seq2-OP081087, Seq 3-OP081088, Seq4-OP081089, Seq5-OP081090, and Seq6-OP081091). Evolutionary analyses were conducted in the MEGA X (version 10.0.5) to generate an optimal tree with a sum of branch length 6.743 and a bootstrap of 1000 replicates. The evolutionary distances were computed using the maximum composite likelihood method with Tamura 3 parameter model and are in the units of the number of base substitutions per site. All ambiguous positions were removed for each sequence pair using the pairwise deletion option. There was a total of 831 positions in the final dataset. The tree was drawn to scale, with branch lengths in the same units as the evolutionary distances.
4.6. Analysis of Genetic Diversity and Construction of Phylogenetic Tree
Amplicons obtained from each ISSR primer are scored for their presence (1) and absence (0) across the accessions to analyze the genetic diversity. The percentage of polymorphism and polymorphic bands were calculated across the accessions and the used primers, respectively [ 18 ]. The binary data matrix was converted into a genetic similarity matrix, and a neighbor-joining tree was obtained with maximum likelihood using the Jaccard coefficient with DARwin 6 (6.0.21) genetic analysis tool. The length of the obtained tree branches was verified with the unweighted neighbor-joining method.
4.7. Statistical Analysis
Data were analyzed by one-way ANOVA followed by Tukey’s post hoc test, and the significance was determined at p ≤ 0.05. Multivariate analysis (PCoA, clustering, SIMPER) of metabolomics data was done in PAST 3 [ 33 ]. DARwin 6 genetic analysis tool [ 34 ] and MEGA X were used for genetic diversity analysis.
Supplementary Materials
The following supporting information can be downloaded at:
https://www.mdpi.com/article/10.3390/plants11212861/s1
. Data S1: compounds obtained from negative and positive modes from all the accessions in LC-MS/MS; Table S1: NCBI blast results for
matK
sequences; Table S2: compounds identified tentatively in both positive and negative mode of LC-MS; Table S3: contribution of differentially regulated compounds in groupings of the accessions; Table S4: reported functions of the identified compounds from Embelia accessions; Table S5: list of ISSR primers with their nucleotide sequences and annealing temperatures used for amplification; Table S6: analysis of genetic diversity in Embelia accession by ISSR primers. Figure S1: representative LC-MS chromatograms (BPC) from fruits samples from all accessions; Figure S2: MS and MS-MS spectra for 36 identified compounds from different accessions of Embelia fruits; Figure S3: confirmation of Embelin from fruit samples.
Author Contributions
Conceptualization, S.M.; methodology, S.R., V.P., M.S. and S.M.; software, S.R.; validation, S.R., V.P. and S.M.; formal analysis, S.R. and V.P.; investigation, S.M.; resources, S.M. and M.S.; data curation, S.R., S.M. and V.P.; writing—original draft preparation, S.R. and V.P.; writing—review and editing, S.M.; visualization, S.M.; supervision, S.M.; project administration, S.M.; funding acquisition, S.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by UGC-DSA-I and Council of Scientific and Industrial Research (CSIR), India.
Data Availability Statement
All the matK sequences generated have been deposited in the NCBI GenBank database (Accession numbers: Bank It2604113: Seq1-OP081086, Seq2-OP081087, Seq 3-OP081088, Seq4-OP081089, Seq5-OP081090, and Seq6-OP081091).
Acknowledgments
The authors thank N.B. Gaikwad, Shivaji University, Kolhapur, Maharashtra for help in obtaining Embelia fruits, the Biodiversity board of Karnataka (Permission letter no. APCCF-RU-A1-RAC-CR-37/2014-2015) and Kerala (permission letter no. KHDFQ-816/2020-CWW/WL10) for the permission of sample collection, V.T. Barvkar, Savitribai Phule Pune University for assistance with LCMS data acquisition, and P. Thakur, Agilent Technologies for helping in the LC-MS data analysis, and UGC DSA-I for funding. SR thanks the Council of Scientific and Industrial Research (CSIR), India, for the junior and senior research fellowship.
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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Figure 1. Sampling locations of Embelia ribes (Embelia) fruit samples and their morphological and molecular identification. ( A ) The highlighted portion of the magnified map of India depicting the four locations, namely: (1) Manoli (Maharashtra), (2) Kodkani (Karnataka), (3) Nadpal (Karnataka), (4) Wayanad (Kerala), across the range of Western Ghats. ( B ) Fruit samples corresponding to each of the four accessions show variation in their pigmentation and size (inset). The fruit diameter from the Kodkani accession is significantly more than that of other accessions (F 4,18 = 12.91; p = 0.0002). Values are the mean (±SE) of five replicate fruits. Significant difference was determined by one way ANOVA and Tukey’s post hoc test at p ≤ 0.05. ( C ) Phylogenetic tree was constructed using the maturase kinase ( matk ) nucleotide sequences from different accessions of Embelia fruits with 1000 bootstrap values, and maximum composite likelihood method. It confirms the identity of the collected samples as E. ribes (Embelia). Sequences obtained from E. tsjeriam-cottam and Maesa indica leaves were used as an outgroup. Figures at the nodes indicate bootstrap values determined after bootstrapping the clusters 1000 times. The scale at the bottom of the tree quantifies the average distance between clusters.
Figure 2. The distribution of identified metabolites across the accessions. The accessions showed a variation in the distribution of metabolites across the accessions. The color scheme at the top left corner codes for the Z-scores (−4 to +4) calculated over binary co-ordinates of the samples. The dendrogram at the top of the heatmap indicates the average linkage clustering computed between the samples based on the Manhattan distance.
Figure 3. The multivariate analysis of metabolomics data. ( A ) The plot of principle coordinate analysis (PCoA) with identified metabolites across the accessions using the Jaccard coefficient and transformation exponent value 2. The percentage of the variation is captured in Coordinates 1 and 2. The values in parentheses show the percentages of the variation. The x- and y-axes are indicated by the eigenvalue scale. ( B ) A phylogenetic tree with the single linkage algorithm and Jaccard similarity index at the 1000 bootstrapping threshold. The tree shows the clusters among the accessions based on the similarities in the metabolites in each of the five samples of a given accession. Bootstrap values of the respective clusters are depicted at each tree node. ( C ) The Venn diagram depicted the number of compounds shared and uniquely present along with all the combinations. Kodkani and Wayanad accessions show the maximum number of shared compounds, whereas Manoli and Nadpal accessions show the least number of shared compounds. Similarly, Kodkani accession showed a maximum (six) number of uniquely present compounds. However, Nadpal accession does not have any unique one.
Figure 4. Distribution of chemical classes across the accessions . Identified compounds were grouped according to their compound classes. A total of 11 classes of compounds were found. Kodkani accession showed all 11 groups, followed by ten groups in Wayand, six in Manoli, and four in Nadpal.
Figure 5. Genotypic diversity among Embelia ribes accessions from different geographical regions. After scoring the amplified products on Embelia and E. tsjeriam-cottam by nine IISR primers, obtained binary data was used to generate a phylogenetic tree. E. tsjeriam-cottam was used as an outgroup. Wayanad and Kodkani accession share the same clade, whereas the Manoli accession connects the Nadpal accession with Wayanad and Kodkani accessions. The outgroup is forming a separate clade. The scale at the bottom of the phylogenetic tree quantifies the Jaccard distance between the genotypes. Numbers at each tree node indicate the bootstrap value of the respective cluster computed at the 1000 bootstrapping threshold.
Table 1. Compounds identified from different Embelia accessions by LC-MS/MS. Total of 36 compounds were identified based on the fragment ion spectra in both negative and positive ionization modes. 1–33 in negative ionization mode and 34–36 in positive ionization mode (M—Manoli, K—Kodkani, N—Nadpal, W—Wayanad).
Sr. No. Molecular Formula Abundance (%) Adducts Mass m / z RT Score Compound Name M K N W 1 C 6 H 4 O 2 167.0353 (100), 108.0219 (84.96), 153.0198 (16.49), 123.0113 (0.46) (M+HCOO-), (M+CH3COO-) 108.0211 167.0556 9.141 98.87 1,2-Benzoquinone - + - + 2 C 5 H 12 S 2 195.0514 (100), 129.0197 (57.31), 177.0409 (6.16), 159.0312 (7.27) (M-H-), (M+CH3COO-) 136.0387 135.0307 2.922 81.86 1-pentanesulfenothoic acid - + - + 3 C 6 H 8 O 5 111.0092 (100), 125.0248 (11.05), 143.0351 (7.81), 169.0146 (23.32) (M-H-), (M+CH3COO-), (M+HCOO-) 160.0372 205.0361 6.443 97.15 2-Formylglutarate - + - + 4 C 15 H 12 O 5 271.061 (100), 151.0035 (32.56), 119.051 (13.26), 107.0127 (2.66), 177.0177 (4.73) (M-H-), (M+CH3COO-), (M+HCOO-) 272.0685 271.0626 10.89 93.68 3,4,5-Trihydroxyflavanone - + - - 5 C 4 H 8 O 4 136.8745 (100), 134.8767 (72.48), 119.3337 (30.23), 138.8695 (33.82), 112.4422 (23.18) (M-H-), (M+CH3COO-), (M+HCOO-) 120.0423 179.0566 3.756 94.87 3,4-Dihydroxybutyric acid - + - + 6 C 9 H 11 NO 3 163.0407 (100), 180.068 (82.43),135.0464 (91.86), 119.0486 (34.69), 121.0316 (3.34) (M-H-), (M+CH3COO-) 181.0739 180.0672 4.68 84.77 3-Amino-3-(4-hydroxyphenyl) propanoate - + - + 7 C 5 H 4 O 3 111.0091 (100), 112.9853 (59.93), 105.6042 (10.74), 137.3377 (5.76), 168.1806 (11.1) (M-H-), (M+CH3COO-) 112.016 111.0093 3.256 85.76 3-Furoic acid - + - + 8 C 7 H 12 O 5 119.0352 (100), 163.0618 (18.61), 101.0256 (5.33), 221.0677 (16.91) (M-H-), (M+CH3COO-) 176.0685 221.0675 6.781 93.91 3-Isopropylmalic acid + + - + 9 C 6 H 6 O 6 111.0089 (100), 101.049 (0.93), 117.0174 (4.29), 129.0177 (1.58), 155.0332 (5.15), 173.0828 (2.73), 175.0604 (12.66), 191.02185(0.34) (M-H-), 174.0164 173.0097 6.363 97.02 Aconitic acid - + - + 10 C 7 H 6 O 2 121.0298 (100), 120.0214 (20.48), 119.9136 (0.35), 109.8534 (0.28) (M-H-), (M+CH3COO-) 122.0368 121.0356 9.141 96.01 Benzoic acid - + - + 11 C 28 H 40 O 4 439.2885 (100), 279.2339 (8.98), 101.0243 (2.78), 170.8337 (1.48), 131.0358 (0.79), 161.0442 (0.84) (M-H-), (M+CH3COO-) 440.2954 439.2854 15.52 86.76 Bolegrevilol - - - + 12 C 6 H 8 O 7 111.0093 (100), 129.0197 (5.64), 131.9995 (0.18), 154.9984 (0.71), 173.0095 (1.3) (M-H-), (M+CH3COO-) 192.027 191.0201 4.259 95.64 Citric acid + + - + 13 C 9 H 8 O 3 119.0509 (100), 163.0407 (8.71), 117.9266 (0.38), 121.0308 (2.97) (M-H-), (M+CH3COO-) 164.0484 163.0412 8.88 93.57 Coumaric acid - + - - 14 C 10 H 18 O 4 201.1134 (100), 183.1021 (59.57), 139.7911 (65.43), 140.1177 (13.75), 141.11 (5.96), 157.0852 (5.47) (M-H-) 202.1205 201.1143 9.982 95.36 Decanedioic acid + + - + 15 C 13 H 24 O 2 213.1868 (100), 195.1759 (2.92), 193. 1605 (0.16), 211.3199 (0.06), 257.1764 (0.46), 196.179 (0.83) (M-H-), (M+CH3COO-) 212.1776 271.1918 15.268 85.1 Delta-tridecalactone + + - + 16 C 6 H 10 S 2 111.0093 (100), 191.0208 (10.89), 173.9144 (0.08), 154.9984 (0.71), 147.0297 (0.9), 130.9991 (0.88) (M-H-) 146.0224 191.0199 4.26 81.97 Di-2-propenyl disulfide - + + + 17 C 8 H 14 O 2 S 2 111.0095 (100), 125.0248 (12.2), 169.0149 (30.75), 101.0249 (0.1), 143.0356 (6.94), 154.9997 (2.13), 205.0366 (2.19), 173.0102 (1.98) (M-H-), (M+CH3COO-) 206.0435 205.0365 6.365 80.91 DL-alpha-Lipoic acid - + - + 18 C 17 H 26 O 4 293.1776 (100), 265.1822 (10.08), 152.0117(23.46), 195.1762 (0.05), 223.1980 (0.02), 265.1817 (0.98), 275.1672 (0.04), 179.0336 (0.02), 151.0399 (0.73), 163.0405 (0.03), 165.0197 (0.58), 193.1603 (0.01) (M-H-) 294.1831 293.1771 14.42 94.7 Embelin + + + + 19 C 6 H 14 S 2 195.0514 (100), 129.0197 (63.16), 101.0232 (1.78), 100.0129 (1.67) (M-H-), (M+CH3COO-) 150.0537 195.0514 2.91 83.13 Ethyl-1-methylpropyl disulfide - + - + 20 C 6 H 12 O 7 195.0541 (100), 129.0197 (63.16), 111.0089 (1.93), 101.0232 (1.78), 141.0172 (1.17), 100.0129 (1.67), 151.06 (2.87), 159.02 (4.72), 177.04 (7.5) (M+CH3COO-) 196.0583 195.0514 2.92 96.12 Galactonic acid - + - + 21 C 16 H 30 O 4 285.2076 (100), 195.1734 (0.69), 160.314 (0.24), 151.98(0.44) (M-H-), (M+CH3COO-) 286.2144 285.2083 11.57 94.66 Hexadecanedioic acid - + - + 22 C 21 H 20 O 12 463.0907 (100), 301.0354 (9.29), 316.0235 (4.15), 300.2459 (7.06), 271.0264 (1.1), 178.9978 (0.59), 287.0243 (0.21) (M-H-) 464.0948 523.1085 8.79 76.8 Isoquercitrin - + - - 23 C 4 H 6 O 5 115.0039 (100), 133.0137 (25.99), 134.0181(0.08), 103.0701 (2.41), 105.3022 (3.11) (M-H-) 134.0215 133.0148 3.16 98.24 Malic acid - + - + 24 C 15 H 12 O 5 271.062 (100), 151.0037 (37.98), 119.0509 (10.92), 177.0197 (5.23), 107.0142 (4.58) (M-H-) 272.0697 271.0623 10.90 91.8 Naringenin - + - - 25 C 7 H 14 S 2 119.0352 (100), 163.0618 (18.61), 221.0677 (16.91), 101.0256 (5.33) (M-H-), (M+CH3COO-) 162.0537 221.0675 6.78 85.79 N-propyl sec-butyl disulfide + + + + 26 C 4 H 4 O 5 111.0092 (100), 103.1223 (0.39), 106.2887 (0.38), 129.01 (7.82), 191.0208 (10.89) (M-H-), (M+CH3COO-) 132.0059 191.0201 4.26 98.76 Oxaloacetate - + - + 27 C 14 H 12 O 4 261.0395 (100), 103.0404 (17.34), 111.0115 (25.8), 135.0417 (13.41), 137.0252 (59.38), 148.0374 (31.73), 167.0366 (27.76), 231.0277 (50.05) (M+CH3COO-) 244.0736 303.0885 8.37 94.96 Piceatannol - + - - 28 C 15 H 22 O 2 293. 1772 (100), 152.01 (1.17), 124.0171 (1.09), 265.1818 (0.98), 166.0278 (0.29), 275.1665 (0.04), 195.1756 (0.01) (M+CH3COO-), (M+HCOO-) 234.1626 293.1776 14.51 95.39 Procurcumenol - + + + 29 C 15 H 10 O 7 301.0363 (100), 107.0142 (1.63), 151.0034 (19.11), 121.0294(2.17), 178.9991(14.1) (M-H-) 302.0427 301.0367 10.15 88.89 Quercetin - + - - 30 C 19 H 30 O 4 321.2089 (100), 124.0169 (0.71), 152.0117 (1.01), 293.2134 (0.66), 166.0257 (0.18), 317.8458 (0.09) (M-H-) 322.2144 321.2093 13.16 92.93 Rapanone - + - + 31 C 14 H 28 255.2335 (100), 210.9515 (6.19), 134.0953 (3.02), 119.037 (4.12), 112.98 (2.76) (M+CH3COO-) 196.2191 255.2338 0.572 96.94 Tetradecene + + - + 32 C 11 H 22 O 229.1825 (100), 112.9864 (0.85), 151.9661 (0.95), 183.1758 (43.74) (M+CH3COO-), (M+HCOO-) 170.1675 229.1817 11.31 93.1 Undecan-2-one - + - + 33 C 8 H 8 O 4 167.0354 (100),108.0222 (95.03), 168.8361 (83.37), 152.0119 (14.39), 128.0691 (3.21), 125.0234 (1.95) (M-H-) 168.0429 167.0356 9.14 83.19 Vanillic acid - + - + 34 C 18 H 28 N 2 O 4 127.1205 (100), 129.1004 (58.35), 145.1369 (55.08), 319.1974 (15.5), 273.1822 (30.12), 147.1169 (30.35), 175.1199 (44.14), 301.1838 (12.14), 109.1038 (27.28) (M+H+) 336.2049 337.2135 3.16 75.88 Acebutolol - + + - 35 C 21 H 30 O 2 127.1204 (100), 129.1005 (55.48), 145.1367 (55), 175.1199 (46.27), 147.1168 (28.57), 109.1039 (27.64), 157.1043 (14.87), 111.084 (3.29), 193.1358 (9.45), 163.1531 (4.65), 139.0882 (11.36), 273.1821 (28.48), 301.1835 (12.39), 291.1975 (7.41), 319.1984 (15.9) (M+Na+) 314.2246 337.2134 4.17 76.21 Cannabidiol - + + - 36 C 12 H 20 O 2 109.1032 (100), 219.1348 (16.32), 204.1907 (16.05), 202.1745 (25.12), 187.1584 (22.13), 169.1432 (52.16), 151.1255 (9.44), 145.1362 (3.92), 111.1186 (6.99), 106.1057 (0.58), 127.1189 (29.49) (M+Na+) 196.1463 219.1353 2.83 73.22 Hexenyl-(3z)-hexenoate (3z-) + - - -
| https://www.mdpi.com/2223-7747/11/21/2861/xml |
Balera Branch Post Office, Arki 21, Solan, Himachal Pradesh
Get Balera post office address, pincode, phone number, Balera speed post tracking, saving scheme and location map.
Balera Post Office, Arki
Balera Post Officeis located at Balera, Arki, Solanof Himachal Pradesh state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Balera POis 173221. This Postoffice falls under Solan postal division of the Himachal Pradesh postal circle. The related head P.O. for this branch office is Solan head post office and the related sub-post office (S.O.) for this branch office is Domehar post office.
Balera dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Balera. The official website fo this PO is http://www.indiapost.gov.in.
Types of Post Offices
are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Balera P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Balera Post Office & Its Pin Code
Branch Office Information
Balera Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Balera Post Office Recruitment
Location Map
Contact Details
About India Post
Balera Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Balera Post Office has the Postal Index Number or Pin Code 173221. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Balera PO Pincode 173 221
The first digit of 173221 Pin Code '1' represents the region, to which this Post Office of Balera belongs to. The first two digits of the Pincode '17' represent the sub region, i.e, Himachal Pradesh. The first 3 digits '173' represent the post-office revenue district, i.e, Solan. The last 3 digits, i.e, '221' represent the Balera Delivery Branch Office.
Branch Office Information
The Balera Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Solan, which falls under Shimla Hq region. The circle name for this PO is Himachal Pradesh and it falls under Arki Taluka and Solan District. The state in which this Dakghar is situated or located is Himachal Pradesh. The related head postoffice is Solan post office and the related sub post office is Domehar post-office. The phone number of Balera post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Solan Postal Region Shimla Hq Postal Circle Himachal Pradesh Town / City / Tehsil / Taluka / Mandal Arki District Solan State Himachal Pradesh Related Sub PO Domehar Sub Office Related Head PO Solan Head Post Office
Balera Post Office Services
Traditionally the primary function of Balera post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Balera P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Balera and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Balera Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Balera can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Balera peoples and nearby living people. The premium services provided by Balera Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Balera customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Balera Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Balera postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Balera postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Balera people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Balera post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Balera customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Balera customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Balera postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Balera can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Balera area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Balera postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Balera postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/- and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 08:00 AM or 09:00 AM or 10:00 AM and the closing time is 04:00 PM or 05:00 PM or 06:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Balera Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Balera people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Balera Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Balera postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Balera Post Office Recruitment
For latest Balera post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Balera Branch Post Office is located in Balera, Arki, Solan.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc.services in Balera Post Office, can be resolved at Balera Branch Post Office. You can send letters to "Postmaster, Balera Branch Post Office, Balera, Arki, Solan, Himachal Pradesh, India, Pincode: 173 221". The official website of the Berhampur University Sub Office is http://www.indiapost.gov.in.
Balera Branch Office
Address: Balera Branch Post Office, Balera, Arki, Solan , Himachal Pradesh , India
Pin Code: 173221
Website: www.indiapost.gov.in
About India Post
India Postis a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the Indiawith over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Balera Post Office Summary
Dak Ghar Name Balera Branch Post Office Pincode 173221 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Solan Postal Region Shimla Hq Postal Circle Himachal Pradesh Location Balera Town / City / Tehsil / Taluka / Mandal Arki District Solan State Himachal Pradesh Country India Related Sub Office Domehar Sub Office Related Head Office Solan Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
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Polymers | Free Full-Text | Rational Protein Engineering to Increase the Activity and Stability of IsPETase Using the PROSS Algorithm
Polyethylene terephthalate (PET) is the most widely used polyester plastic, with applications in the textile and packaging industry. Currently, re-moulding is the main path for PET recycling, but this eventually leads to an unsustainable loss of quality; thus, other means of recycling are required. Enzymatic hydrolysis offers the possibility of monomer formation under mild conditions and opens up alternative and infinite recycling paths. Here, IsPETase, derived from the bacterium Ideonella sakaiensis, is considered to be the most active enzyme for PET degradation under mild conditions, and although several studies have demonstrated improvements to both the stability and activity of this enzyme, stability at even moderate temperatures is still an issue. In the present study, we have used sequence and structure-based bioinformatic tools to identify mutations to increase the thermal stability of the enzyme so as to increase PET degradation activity during extended hydrolysis reactions. We found that amino acid substitution S136E showed significant increases to activity and stability. S136E is a previously unreported variant that led to a 3.3-fold increase in activity relative to wild type.
Rational Protein Engineering to Increase the Activity and Stability of Is PETase Using the PROSS Algorithm
by Andrew Rennison 1 , Jakob R. Winther 1,* and Cristiano Varrone 2,*
1
Section for Biomolecular Sciences, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark
Section for Sustainable Biotechnology, Department of Chemistry and BioScience, Aalborg University, A.C. Meyers Vænge 15, C2, 2450 Copenhagen, Denmark
Authors to whom correspondence should be addressed.
Polymers 2021 , 13 (22), 3884; https://doi.org/10.3390/polym13223884
Received: 21 October 2021 / Revised: 1 November 2021 / Accepted: 4 November 2021 / Published: 10 November 2021
Versions Notes
Abstract
:
Polyethylene terephthalate (PET) is the most widely used polyester plastic, with applications in the textile and packaging industry. Currently, re-moulding is the main path for PET recycling, but this eventually leads to an unsustainable loss of quality; thus, other means of recycling are required. Enzymatic hydrolysis offers the possibility of monomer formation under mild conditions and opens up alternative and infinite recycling paths. Here,
Is
PETase, derived from the bacterium
Ideonella sakaiensis
, is considered to be the most active enzyme for PET degradation under mild conditions, and although several studies have demonstrated improvements to both the stability and activity of this enzyme, stability at even moderate temperatures is still an issue. In the present study, we have used sequence and structure-based bioinformatic tools to identify mutations to increase the thermal stability of the enzyme so as to increase PET degradation activity during extended hydrolysis reactions. We found that amino acid substitution S136E showed significant increases to activity and stability. S136E is a previously unreported variant that led to a 3.3-fold increase in activity relative to wild type.
Keywords:
PETase
;
thermostability
;
thermal deactivation assay
;
PET hydrolysis
Graphical Abstract
1. Introduction
PET is made of repeating units of mono(2-hydroxyethyl) terephthalate (MHET) that are linked by ester bonds. Many bacterial and fungal enzymes have been identified that can convert PET into this monomer [ 5 ]. MHET, which is also an ester, can also be further hydrolysed into its constituents ethylene glycol (EG) and terephthalic acid (TPA). These PET-degrading enzymes are often lipases or cutinases, yet they often have relatively low turnover rates at the low temperatures that would be required for an economically viable recycling process [ 3 ]. In 2016, interest in PET-degrading enzymes was raised by the discovery of a bacterium, Ideonella sakaiensis , in a bottle recycling facility in Japan that could grow solely on PET as an energy and carbon source. An enzyme of the cutinase family, designated as Ideonella sakaiensis PET hydrolase ( Is PETase), was identified in this bacterium that could depolymerise PET together with the action of a second enzyme called mono(2-hydroxyethyl) terephthalate hydrolase (MHETase) [ 6 ]. Is PETase demonstrated higher PET degradation activity compared to other enzymes known at the time and, crucially, was active in mesophilic conditions, with an optimum temperature of 30 °C [ 6 , 7 ]. This seemed to indicate the potential applicability of the enzyme in biotechnological recycling and upcycling. However, Is PETase was much less thermally stable than other known PET-degrading enzymes, causing issues with expression yields and extended processing times. Although the enzyme had the highest known activity at low temperatures [ 6 ], it still did not have the required activity or stability to form part of an economically viable depolymerisation process [ 8 ].
Is
PETase has an alpha/beta hydrolase fold and uses a serine hydrolase mechanism that is similar to trypsin. It is not known to what extent
Is
PETase has evolved by natural selection in
I. sakaiensis
, but as PET has only been found at significant levels in nature for about 50 years, it is likely that the enzyme has not yet reached its full evolutionary potential. Thus, several studies have been performed to increase the activity and thermostability of the enzyme through rationally designed point mutations [
3
]. Examples of improved variants include
Austin
PETase [
9
] and
Joo
PETase [
10
], which were both produced to improve activity, and
Son
PETase [
11
], which developed with the goal of increasing stability.
Austin
PETase was devised by applying substrate docking calculations to suggest mutations and to narrow the active site cleft by introducing the substitutions W159H and S238F.
Joo
PETase was obtained in a similar manner, resulting in R280A, which removed a protruding arginine residue from the substrate binding pocket. Finally,
Son
PETase was built on the R280A variant by adding a further two substitutions, S121E and D186H, to stabilise the loop regions.
In this study, a computational approach was used in which amino acid substitutions were recommended for the stabilisation of the enzyme by the Protein Repair One Stop Shop (PROSS) method. These were visually examined in a molecular viewer (PyMol) to determine their suitability. Variants were then experimentally assessed based upon their thermostability by differential scanning fluorimetry (DSF) and a thermal deactivation assay. Activity was also assayed on standardised PET films over a range of temperatures.
2. Materials and Methods
2.1. PROSS
The online PROSS server at ( https://pross.weizmann.ac.il/step/pross-terms/ accessed: 12 Feburary 2020) was used for the design of the mutations that could be used to increase the thermostability of Is PETase. The crystal structure of Is PETase was taken from [ 10 ] (PDB code: 5XJH). The residues forming the active site, the oxyanion hole, and the binding residue at W185 were fixed during the mutation design, preventing them from being altered. The standard multiple sequence alignment (MSA) parameters for the PROSS server were used. This included only allowing proteins with an identity of over 35% and with a coverage of over 75%, both taken from a BLAST search, to be included in the alignments. The maximum number of sequences to be used in the alignment was 4000, and the energy function used in the Rosetta calculations was talaris 2014.
2.2. Plasmid Construction
The base plasmid used for the expression of all of the variants was pET21b(+)-Is-PETase, obtained from AddGene (plasmid #112202) [ 9 ]. The PETase sequence was obtained from [ 9 ], following which the gene was codon optimised for expression in E. coli and was cloned into the expression vector pET-21b(+) with a C-terminal His tag. The endogenous signal peptide was removed from the gene by polymerase chain reaction (PCR) and subsequent kinase, ligase, DpnI (KLD) treatment, as described below.
2.3. Variant Construction
Mutations were introduced to the wild-type gene by PCR with mutagenic primers, which were designed using the online tool NEBasechanger, which is available at ( https://nebasechanger.neb.com/ accessed: 16 January 2020). Codons for the new amino acids that were to be introduced were chosen from the codon usage chart in E. coli K12 genes [ 12 ]. Following the introduction of the point mutations by PCR, the linear mutated fragments were circularised using the KLD kit (NEB), which included a DpnI enzyme to remove any template DNA. The reaction mixture was incubated at room temperature for 10 min before being directly used in the transformation. The gene for Son PETase was purchased from Twist Bioscience (San Francisco, CA, USA) and was introduced into the pET-21b(+) backbone by Gibson assembly using standard protocols. All of the primers used for cloning and site-directed mutagenesis are listed in S1 .
2.4. Protein Expression and Purification
Single clones of
E.
coli
BL21(DE3) cells containing relevant plasmids were inoculated into 10 mL of LB medium with 100 µg/L of ampicillin at 37 °C at 200 rpm. The overnight culture was then inoculated into a volume of 500 mL LB-AB medium in 3 L flasks, with an initial growth temperature of 37 °C, and the samples were shaken at 200 rpm. After the culture reached OD
600
of 0.4–0.6, the temperature was then reduced to 16 °C, and expression was induced with 0.4 mM isopropyl β-D-1-thiogalactopyranoside (IPTG), and the culture was allowed to grow for 24 h. The cells were harvested by centrifugation for 15 min at 7000 rpm and 4 °C, the supernatant was discarded, and the pellet was frozen at −20 °C. The pellets were resuspended in 20 mL of lysis buffer (50 mM phosphate buffer pH 7.0) and were lysed by ultrasonication in two rounds of 8 × 30 s pulses, with the mixture kept on ice. This mixture was then centrifuged at 18,000 rpm and 4 °C for 15 min, and the supernatant was retained. His-pur Ni-NTA agarose resin (Thermo-scientific, Roskilde, Denmark) was equilibrated in lysis buffer on a gravity flow column (Bio-rad, Hercules, CA, USA) ensuring a column volume of approximately 2 mL for each 20 mL of cell lysate. The resin was then resuspended in approximately 10 mL of the phosphate buffer and was mixed with cell lysate at 4 °C overnight to allow the His-tagged proteins to bind to the Ni-NTA resin. Following this, the lysate/bound resin mixture was again added to the gravity flow column and was eluted with increasing concentrations of imidazole in 50 mM phosphate buffer at pH 7.0, with the target protein eluting at 250 mM imidazole. The eluted fraction was subjected to dialysis in 3.5 kDa molecular weight cut-off (MWCO) standard regenerated cellulose (RC) dialysis tubing (Spectrum labs) to wash out the imidazole in the dialysis buffer, and afterwards, it was stored in 50 mM phosphate buffer with a pH of 7.0. Protein concentration was determined at 280 nm using an extinction coefficient of 39,420 cm
−
1
M
−
1
.
2.5. Assessment of Melting Temperature by Differential Scanning Fluorimetry
The T m of variants was determined by DSF on a Prometheus (NanoTemper Technologies GmBH, München, Germany) according the manufactures directions. Accordingly, protein fluorescence was monitored at 330 nm and 350 nm in lysis buffer at a protein concentration of ~10 µM while the temperature increased from 20 °C to 90 °C at 0.5 °C per min. T m was determined at the inflection point of the second derivative of the E 330 /E 350 -ratio.
2.6. Assessment of Melting Temperatures by Thermal Deactivation Assay
The activity of
Is
PETase on PET can be defined as an ester hydrolysis, and as such, a medium-throughput assay was developed to quantify the reduction in the activity of the enzyme during incubation at a specific temperature over time. We used para-nitrophenyl acetate (pNPA) (Thermo-scientific, Roskilde, Denmark) as a model esterase substrate [
13
]. Purified enzyme was standardized to 5 μM in 500 μL of lysis buffer and was incubated at 45 °C for various time periods. At each timepoint, 20 μL of sample was removed from the incubation tube and was added to 170 μL of phosphate buffer in a 96-well plate kept on ice. After the incubation period, the plate was allowed to come to room temperature, and 10 μL of 20 mM
p
NPA in dimethyl sulfoxide (DMSO) (Thermo-scientific, Roskilde, Denmark) was added to each well using a multichannel pipette. The plate was then incubated at 25 °C in a spectrophotometer, and the absorbance was measured at 405 nm at 1 min intervals. All of the experiments were done in triplicate, and a blank control assay was conducted with the phosphate buffer replacing the enzyme. The linear range of the assay with respect to product
p
-nitrophenol was determined, and only absorbance values that were within this range were accepted. The slope up to the first five points on the curve of absorbance against time was then calculated for each incubation time, and this was then taken as the initial activity. The slope of the blank control assay was used to correct activity measurements for background hydrolysis. The initial rate of reaction was then plotted against incubation time in order to determine the rate of denaturation and the half-life (
t
1/2
) of the enzyme following incubation. Due to the large error resulting from background correction, any activities that were less than 5% of the initial activity or less than double that of the blank control assay were discarded. Finally, only decay curves with three or more points satisfying these data acceptance criteria were accepted. The
t
1/2
was calculated by fitting the data to conventional exponential decay, as expressed by Equation (1), where
A t
is the activity at time
t
,
A
0
is the initial activity, and
k
is the rate constant for decay:
A
t
=
A
0
e
−
k
t
(1)
The half-life of the decay of the activity of each variant upon incubation was then calculated using Equation (2), where
t
1/2
is the half-life, and
k
is the rate constant for decay:
t
1
/
2
=
L
n
2
k
(2)
2.7. Assessment of PET Hydrolysis
For simplicity, we chose an assay modified from [
14
], where standardised and commercially available PET film (Goodfellow, UK) was the substrate and the release of MHET/TPA was detected at 260 nm using an NanoDrop 1000 spectrophotometer (Thermo-scientific, Roskilde, Denmark). PET discs were cut from a 0.25 mm thick amorphous PET sheet using a standard office hole punch, creating ¼″ discs with a calculated surface area of 0.64 cm
2
. The discs were submerged in ethanol and were allowed to dry in a laminar flow bench in order to sterilise them. They were then placed in a 2 mL eppendorf tube with 100 nM of enzyme in a 50 mM tricine pH 9.0 buffer with 10% (
v
/
v
) DMSO for a total reaction volume of 250 μL. Short Pasteur pipette lengths made from polyethylene were placed on top of the discs to ensure that they did not float on top of the small volume of liquid due to the high surface tension. Samples were shaken (200 rpm) at various temperatures in a shaking incubator (IKA KS 3000i) (Staufen, Germany). Samples of 2 μL in volume were taken at regular intervals, and the absorbance was read at 260 nm. Standard curves made using the high-performance liquid chromatography (HPLC) method described below gave extinction coefficients for MHET and TPA, respectively, as 135.4 M
−
1
cm
−
1
and 118.4 M
−
1
cm
−
1
. Samples of the hydrolysis products also showed an MHET concentration that was approximately 5 times higher than that of TPA after 24 h on average. For simplicity, and since the extinction coefficients are similar, the product is reported as the MHET equivalents, i.e., the sum of TPA and MHET.
2.8. High Performance Liquid Chromatography Analysis
The method was modified from the one reported by [
15
]. Samples with a volume of 50 μL were taken and centrifuged at 20,000 rpm for 10 min, and the supernatant was diluted in a 1:1 ratio with methanol. Standards of TPA (Thermo-scientific, Roskilde, Denmark), MHET (Advance ChemBlock Inc., Burlingame, CA, USA), and Bis(2-hydroxyethyl) terephthalate (BHET) (Thermo-scientific, Roskilde, Denmark) taken also made in a 50% methanol solution (
v/v
) to ensure equivalence with the samples from 0.05 mg/mL to 25 mg/mL. Any concentrations below this range would be considered below the method’s limit of quantification. The samples were analysed using a Dionex Ultimate 3000 system (Sunnyvale, CA, USA) fitted with a UV/Vis detector. A C18 column (Phenomenex Luna 5 μm, 250 mm × 4.6 mm) (Torrance, CA, USA) at 35 °C was used for the separation of the reaction products, with a mixture of 60% Milli-Q water, 20% acetonitrile, and 20% 10 mM H2SO4 (
v/v/v
) being used as the mobile phase. The flow rate was 1 mL/min, and the injection volume was 10 μL, with detection at 260 nm.
2.9. Kinetic Analysis of Variant Hydrolysis of PET
Inverse Michaelis–Menten ( Inv MM) determinations were based on the methods outlined in [ 16 ]. Amorphous PET discs produced in the same method as described above were added to a variety of enzyme concentrations between 50 nM and 650 nM, with the amount of degradation products quantified as described above. The linearity of the progress of the reaction over time was confirmed, and final samples were taken after 6 h of hydrolysis. Rates were then reported in units of nmol Products min − 1 , where Inv V max is the maximum rate in the units above, as determined by the Inv MM kinetics as described by [ 16 ]. Calculations of Inv V max and Inv K m were performed using the Prism (GraphPad, San Diego, CA, USA) statistical software by fitting the data to a standard Michaelis–Menten equation. Confidence intervals of 95% were also determined using this software.
3. Results and Discussion
3.1. Protein Engineering to Improve Ths Stability of IsPETase Using PROSS
The upload of the structure for IsPETase (PDB ID: 5XJH) into the PROSS server resulted in an extensive list of 51 substitutions, see Supplementary Information for the full list ( S2 ). As this number was too large to be studied in the scope of this project, a limited few were selected to be studied on the basis of their alignments to three highly efficient thermostable PET hydrolysing enzymes, namely Cutinase 2 from Thermobifida fusca (TfCut2) [ 17 ], an Alpha/Beta hydrolase family protein from Saccharomonospora viridis (Cut190) [ 18 ], and the Leaf Compost Cutinase from an uncultured organism (LCC) [ 19 ], and were discarded if no agreements were found. From this process, three novel variants were selected for experimental characterization: S125R PETase, S136E PETase, and T270Q PETase. The alignments can be seen in Table 1 , and the visualization of the substitutions can be found in the Supplementary information (S3) .
From this series of alignments, we can see that the enzyme Cut190 contains the relevant amino acid corresponding to the substitutions designed by the PROSS server. As this enzyme is active on PET and since it has a higher thermostability than IsPETase, we surmised that the substitutions at these positions would at least have no deleterious effects and would therefore be studied through further experiments.
3.2. Improved Thermostability of IsPETase Variants
Variants were constructed in plasmids containing a truncated
Is
PETase gene with the
I. sakaiensis
signal peptide removed using PCR with mutagenic primers. The protein was produced intracellularly and was purified to over 85% purity, as described in the Materials and Methods section.
To examine the effect that the rationally designed substitutions had on thermostability, we used two assays: a structure-based heat inactivation and an activity-based assay that was developed during the study. In the second assay, the activity half-life was determined to create a better picture of how the protein behaves under typical hydrolysis conditions, with any partial unfolding leading to partially active enzyme or refolding upon cooling. Upon the incubation of both the variant and the wild-type enzymes at 45 °C, the samples were withdrawn for activity determination using a para-nitrophenol acetate (pNPA) substrate. From these measurements, activity half-lives were determined. Although this assay measured the hydrolysis of a small model substrate, we anticipate that it mimics the inactivation of
Is
PETase at this temperature. The difference in pH between this inactivation and the PET hydrolysis experiments is not expected to make differences in the relative stabilities between variants. Thus, when assaying PETase activity, it is likely that relative differences between the half-lives of variants (during PET hydrolysis at increased temperatures) will be similar to those seen here. Results from these stability assays are shown in
Figure 1
, with progress curves and decay curves resulting from the thermal deactivation assay in the
Supplementary information (S4)
.
The T m of Is PETase reported here, at 42.5 °C, is somewhat lower than that found in other studies, where values of 50.8 °C [ 20 ], 48.8 °C [ 10 ], and 46.8 °C [ 9 ] have been reported when using dye-based approaches at various pH levels. However, with wild-type Is PETase as reference, we found that ΔT m is the highest in S136E PETase (1.1 °C), with all of the other variants showing differences of less than a degree compared to the wild-type enzyme ( Figure 1 a). As these differences are rather small compared to the overall T m , in order to confirm that this was a genuinely improved variant, we also tested all of the enzymes with the thermal deactivation assay. The pattern of the differences in t 1/2 compared to the wild-type enzyme is broadly the same as the pattern seen in the Tm determinations. The activity half-life, t 1/2 , of the S136E PETase variant displays a 2.4-fold increase when measured at 45°C, suggesting that this variant is actually improved in terms of thermostability when compared to Is PETase ( Figure 1 b).
The relative increases of thermostability seem to be somewhat different between the two assays, with t
1/2
showing a much larger increase than T
m
. However, the direct comparison of these two related variables is difficult, as they essentially measure different properties. This does suggest some that some interesting mechanisms are at play during the loss of activity in the
S136E
PETase variant. As the enzyme samples were cooled on ice after incubation, it could be suggested that some measure of refolding into an active conformation occurs following incubation at 45 °C. This could lead to an apparent increase in the thermostability as measured by t
1/2
, which would not be discernible with the measure of T
m
. Refolding in this manner could lead to several mechanisms to retain activity, such as the prevention of aggregate formation or the reassembly of local structures that allow partial activity to be retained. The measure of t
1/2
could therefore result in a more illustrative measure of stability that applies better to the real-world applications of these enzymes.
Taking these two sets of results together, we concluded that only
S136E
PETase showed a consistent improvement in terms of thermostability. Therefore, it was decided that
S136E
PETase would be further assayed for activity on a PET discover a range of temperatures compared to the wild-type enzyme.
3.3. Increased PET Degradation Activity of S136E PETase
As stated above, comparison between various studies reporting increased IsPETase variant activity can be difficult due to the absence of a standardised PET hydrolysis activity assay and the different types/crystallinity of the PET substrates that are used. Unfortunately, it is often difficult to distinguish the effects of PETase variants over extended time-courses, as thermostability and activity become intertwined when the half-life and assay time are of a comparable magnitude. Thus, apparent increases in activity may be indistinguishable from (or at least masked by) higher stability, especially at higher temperatures. Nevertheless, as IsPETase did not produce a quantifiable amount of degradation product over shorter timescales, it was necessary to assay over a longer period. The results of this PET degradation assay for
S136E
PETase compared to IsPETase are shown in
Figure 2
, with
S125R
PETase, and
T270Q
PETase being omitted due to their marginal differences in thermostability, as stated above.
The data above show that
Is
PETase, as expected, shows a significant loss of product formation as the temperature is increased from 30 °C to 40 °C.
S136E
PETase seems to show a higher thermostability in this assay also, with a relative reduction in product formation at higher temperatures that is smaller than that seen in the wild-type enzyme. Notably,
S136E
PETase shows a significant increase in product formation compared to
Is
PETase, with 3.3 times higher absorbances at the optimum temperature of 34 °C. This increase compares favourably with the activity increases seen for other variants [
10
,
20
]. While it is somewhat surprising to find a mutation that leads to increases in both thermostability and activity, it appears to be the case here. However, there are complex factors that take place in the hydrolysis of an insoluble substrate, such as changes to the crystallinity as the plastic moves towards the glass transition temperature, or the higher motility of the termini of polymer chains at higher temperatures. As such, it cannot be expected that the simple trade-off between stability and activity be borne out in this case.
3.4. Kinetic Analysis of S136E PETase Variant
As already mentioned, it is difficult to decouple the effects of thermostability and intrinsic activity in assays of PETase variants. Given the low activity and stability of the wild-type enzyme, it was not possible to measure the degradation products during the linear part of the progress curve for the hydrolysis. Therefore, we decided to remove any effects of thermal degradation during the assay of the variants and to compare
S136E
PETase to a variant that was previously shown to have a higher stability
Son
PETase [
11
]. Unfortunately, conventional Michaelis–Menten kinetics can only be applied to conditions where substrate concentrations can be varied homogeneously in solution. With a solid substrate such as PET, this is, of course, not possible, and for this reason, an alternative approach to kinetic characterization, termed
Inv
MM kinetics, has been recently developed [
15
,
21
]. The
Inv
MM framework relies on substrate saturation and the concept that at
Inv
V
max
, each available site on the surface of a substrate, the so-called “attack sites”, is occupied by an enzyme molecule. Therefore, given two assays with identical substrates and identical surface areas,
Inv
V
max
can be seen as a measure of the intrinsic rate at which the enzyme degrades the substrate. The concentration of the enzyme at half-saturation with respect to the attack sites
Inv
K
m
can be interpreted similarly to that of the conventional K
m
as a measure for substrate affinity. As the number of attack sites cannot be easily determined, neither
Inv
K
m
nor
Inv
V
max
can be determined in absolute terms for a particular substrate; however, different enzymes can be compared under, as best as possible, identical conditions.
We thus compared the S136E PETase with Son PETase using the same substrate and assay conditions in order to compare the best performing variant in the current study with the previously described enzyme. The two curves are shown in Figure 3 ; See the Supplementary Materials for typical chromatograms showing MHET as the major product ( S5 ).
Given that these kinetic hydrolysis assessments were also performed in the linear section of the progress curve for the reactions (See
Supplementary material, S6
), these can be considered as a measure of the intrinsic activity of the enzymes. The two values of
Inv
V
max
for
S136E
PETase and
Son
PETase calculated in these assays were 1.13 nmol
MHET
.min
−
1
and 1.58 nmol
MHET
.min
−
1
, respectively, which are similar within the 95 % confidence intervals for the values calculated over all data points. The final point on the
S136E
PETase curve appears to be a slight outlier, which pulls the calculated
Inv
V
max
value down, suggesting that the actual values of the two variants could be closer. Likewise, the
Inv
K
m
values for the two enzymes are very close, indicating a similar substrate affinity.
Based on this, we can conclude that the
S136E
PETase variant performs at a similar level as
Son
PETase, an enzyme that has been previously described as a promising variant for PET degradation [
11
]. Furthermore, this experiment has demonstrated that the apparent increase in the activity of the
S136E
PETase variant relative to the wild-type enzyme, which is seen in
Figure 2
, is due to a genuine increase in the ability of the enzyme to degrade PET rather than the associated increase to thermostability. We therefore suggest that S136E is an interesting addition to the growing number of substitutions in IsPETase, which should be incorporated into further studies.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/polym13223884/s1 : S1, Primers used during the study; S2, Full list of PROSS results; S3, Visualization of substitutions; S4, Thermal deactivation assay data; S5, Example chromatograms; S6, Inverse Michaelis–Menten progress curves.
Author Contributions
Conceptualization, A.R., J.R.W., and C.V.; methodology, A.R.; formal analysis, A.R.; investigation, A.R., J.R.W., and C.V.; resources, J.R.W. and C.V.; data curation, J.R.W.; writing—original draft preparation, A.R.; writing—review and editing, C.V. and J.R.W.; visualization, A.R.; supervision, J.R.W. and C.V.; project administration, J.R.W. and C.V.; funding acquisition, J.R.W. and C.V. All authors have read and agreed to the published version of the manuscript.
Funding
H2020 UPLIFT project (Grant Agreement no. 953073).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
All pertinent data is included in the manuscript and supporting information .
Acknowledgments
The authors wish to thank the European Commission for the financial support of this work, under H2020 Grant Agreement no. 953073 (acronym: UPLIFT) and declare that there are no conflicts of interest. The authors would also like to thank Charlotte O’Shea and Lei Yang from the Section of Sustainable Biotechnology of the Aalborg University for their invaluable technical support, and all the staff and students at the Linderstrøm-Lang Centre for Protein Science, Section for Biomolecular Sciences, Department of Biology, University of Copenhagen.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Determination of thermostability of PETase variants and wild-type enzyme. Panel ( a ): Dye-free differential scanning fluorimetry measuring the ratio between fluorescence of tryptophan residues in a folded and unfolded state. Panel ( b ): Half-lives of enzyme activity on the pNPA model substrate following incubation at 45 °C.
Figure 1. Determination of thermostability of PETase variants and wild-type enzyme. Panel ( a ): Dye-free differential scanning fluorimetry measuring the ratio between fluorescence of tryptophan residues in a folded and unfolded state. Panel ( b ): Half-lives of enzyme activity on the pNPA model substrate following incubation at 45 °C.
Figure 2. Hydrolysis rates of standardized PET discs over 24 h by S136E PETase variant and wild-type enzyme at a concentration of 100 nM over a range of relevant temperatures. Error bars represent the standard deviation of triplicate measurements. Absorbances are based on a path length of 1 cm.
Figure 2. Hydrolysis rates of standardized PET discs over 24 h by S136E PETase variant and wild-type enzyme at a concentration of 100 nM over a range of relevant temperatures. Error bars represent the standard deviation of triplicate measurements. Absorbances are based on a path length of 1 cm.
Figure 3. Determination of Inv Km and Inv Vmax for S136E PETase (panel ( a ) and Son PETase (panel ( b )) after 6 h of hydrolysis of a standardised PET disc at 30 °C. The major product found by a concurrent HPLC analysis in all kinetic determinations was MHET, and given that the extinction coefficients of TPA and MHET are similar, concentrations are reported as MHET equivalents. Experimental values are shown as points on each graph. Error bars represent the standard deviations of triplicate measurements, and the line of best fit is fit to a Michaelis−Menten equation [ 15 ].
Figure 3. Determination of Inv Km and Inv Vmax for S136E PETase (panel ( a ) and Son PETase (panel ( b )) after 6 h of hydrolysis of a standardised PET disc at 30 °C. The major product found by a concurrent HPLC analysis in all kinetic determinations was MHET, and given that the extinction coefficients of TPA and MHET are similar, concentrations are reported as MHET equivalents. Experimental values are shown as points on each graph. Error bars represent the standard deviations of triplicate measurements, and the line of best fit is fit to a Michaelis−Menten equation [ 15 ].
Table 1. Alignment of mutations suggested by the PROSS server and confirmed by simulation, with the three thermostable PET hydrolases Tfcut2, LCC, and Cut190. Three of the mutations showed matches with the thermostable PET hydrolases and were experimentally produced and assessed for their thermostability and PET hydrolytic activity. Bold-labelled amino acids show agreements with the substitution suggested by PROSS; underlines are similar amino acids to those suggested by PROSS, while those that are italic are substitutions for an amino acid with a side chain of significantly different properties.
Table 1. Alignment of mutations suggested by the PROSS server and confirmed by simulation, with the three thermostable PET hydrolases Tfcut2, LCC, and Cut190. Three of the mutations showed matches with the thermostable PET hydrolases and were experimentally produced and assessed for their thermostability and PET hydrolytic activity. Bold-labelled amino acids show agreements with the substitution suggested by PROSS; underlines are similar amino acids to those suggested by PROSS, while those that are italic are substitutions for an amino acid with a side chain of significantly different properties.
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here .
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VIPM Updates
Biweekly vegetable integrated pest management updates
Section Shortcuts
Insect Management
Whitefly Management on Spring Melons 2021
Now that the produce season is essentially finished, it time to move into melons. Spring melon crops are rapidly growing, and so are insect pest populations. Cabbage loopers and leafminers are becoming evident in some areas, and PCAs should start ramping up their monitoring and sampling. More importantly, whitely populations are quietly becoming abundant on the spring melons of all sizes. Adults can easily be found on recently planted melons located at the Yuma Ag Center, and reports from local PCAs suggest that adult populations are beginning to show up on older plantings. As temperatures increase and crops/weeds mature, avoidance of excessive feeding from whitefly nymphs should be the primary concern on all melon types. Although CYSDV does occur in later spring melons, it is rarely yield limiting. But honeydew and sooty mold contamination on cantaloupes, mixed melons and watermelons can significantly reduce quality and marketability is whiteflies are not adequately controlled. Our research has shown that to prevent fruit yield and quality losses on spring melons, a foliar insecticide treatment should be applied on threshold; that is, when leaves have greater than 2 adult whiteflies per leaf, when averaged across an entire melon field. At this level of adult abundance, immature populations are just starting to colonize, and timing sprays based on the adult threshold has been shown to significantly reduce the chance of yield / quality losses during spring harvests. This threshold applies for the use of recommended IGRs ( Courier, Knack, Cormoran, and Oberon), foliar applied neonicotinoids ( Assail, Venom, Scorpion), neonicotinoid-like compounds ( Sivanto prime and Transform), diamides, ( Exirel and Minecto Pro) and the new feeding disruptors ( PQZ and Sefina). For more information on whitefly management and available insecticides, go to these documents on IPM and Whitefly Managementand Whitefly Control Options-Spring 2021.Also, be aware of honey bees and other pollinators in or around melon fields. If bees are present, be sure to carefully read labels and determine bee safety of a product before making an application in a melon field. If applications are necessary during bloom, only apply a product that is considered bee safe (e.g., PQZ, Sefina, Sivanto, Assail). We also recommend that insecticides only be applied when honeybees are not actively working in the field (e.g. 10:00 pm – 3: 00 am).
To contact John Palumbo go to: [email protected]
Soil Science
Crop Growth, Development, Nutrient, and Water Demand for Irrigated Chile (Capsicum annuum)
Southwester Chile ProductionThe Southwestern (SW) Chile Belt extends from southeast Arizona, across southern New Mexico, into far-west Texas, and northern Chihuahua, Mexico. The SW Chile Belt is dominated by production of New Mexico-type chile, also commonly referred to as “Hatch chile” and also sometimes referred to as “Anaheim” type chile.Recent acreages across the SW Chile Belt have consisted of approximately 7-8,000 acres in NM, 3-4,000 in TX, approximately 90,000 acres in Chihuahua, and about 300-500 acres in Arizona. Chiles are often associated with New Mexico, but Arizona also has a strong connection to this chile industry. For example, the Curry Chile Seed Company, based in Pearce, AZ, provides the seed for >90% of the total green chile acreage across the SW Chile Belt.Chile peppers (Capsicum species) are among the first crops domesticated in the Western Hemisphere about 10,000 BCE (Perry et al., 2007). The Capsicum genus became important to people and as result, five different Capsicum species that were independently domesticated in various regions of the Americas (Bosland &Votava, 2012). Early domestication of chile peppers by indigenous peoples was commonly driven for use as medicinal plants. Due to their flavor and heat characteristics, chile peppers are a populate food ingredient in many parts of the world, including Latin America, Africa, and Asia cuisines. Chiles have been increasingly important to the U.S. and European food industries, particularly as these populations become more familiar with chile (Guzman and Bosland, 2017).There are five domesticated species of chile peppers. 1) Capsicum annuumis probably the most common to us and it includes many common varieties such as bell peppers, wax, cayenne, jalapeños, Thai peppers, chiltepin, and all forms of New Mexico chile. 2) Capsicum frutescensincludes malagueta, tabasco, piri piri, and Malawian Kambuzi. 3) Capsicum chinenseincludes what many consider the hottest peppers such as the naga, habanero, Datil, and Scotch bonnet. 4) Capsicum pubescensincludes the South American rocoto peppers. 5) Capsicum baccatumincludes the South American aji peppers.The Capsicum annuumspecies is the most common group of chiles that we encounter and there are at least 14 very different pod types in this single species that includes: New Mexico (aka Anaheim), bell peppers, cayennes, jalapeños, paprika, serrano, pequin, pimiento, yellow wax, tomato, cherry, cascabel, ancho (mulato, pasilla), and guajillo (Guzman and Bosland, 2017).Crop PhenologyPlants vary tremendously in their physiological behavior over the course of their life cycles. As plants change physiologically and morphologically through their various stages of growth, water and nutritional requirements will change considerably as well. Efficient management of a crop requires an understanding of the relationship between morphological and physiological changes that are taking place and the input requirements.Heat units (HUs) can be used as a management tool for more efficient timing of irrigation and nutrient inputs to a crop and also pest management strategies. Plants will develop over a range of temperatures which is defined by the lower and upper temperature thresholds for growth (Figure 1). Heat unit systems consider the elapsed time that local temperatures fall within the set upper and lower temperature thresholds and thereby provide an estimate of the expected rate of development for the crop. Heat units systems have largely replaced days after planting in crop phenology models because they take into account day-to-day fluctuations in temperature. Phenology models describe how crop growth and development are impacted by weather and climate and provide an effective way to standardize crop growth and development among different years and across many locations (Baskerville and Emin, 1969; Brown, 1989).The use of HU-based phenology models are particularly important and applicable in irrigated crop production systems where water is a non-limiting factor. Water stress will alter phenological plant development and it is a major source of variation in crop development models. Accordingly, irrigated systems are more consistent in crop development patterns and HU models can be much more consistent and reliable.Chiles are a warm season, perennial plant with an indeterminant growth habit that we grow and manage as an annual crop. The fruiting cycle begins at the crown stage of growth and continues until the plant reaches a point of “cut-out” with hiatus in blooming as the plant works to mature the chile fruit crop that has been developed.The first step in developing a phenological guideline for chiles would be to look for critical stages of growth in relation to HU accumulation. Figure 2 describes the basic phenological baseline for New Mexico – type chile and was developed from field studies conducted in New Mexico and Arizona (Silvertooth et al., 2010 and 2011; Soto et al., 2006; and Soto and Silvertooth, 2007).Water and nutrient demands coincide with the fruiting cycle and efficient management of irrigation water and plant nutrients is enhanced by tracking crop development in the field. The use of HUs (86/55 oF thresholds) can be applied since the thermal environment impacts the development of all crop systems, including chiles, (Figures 2 and 3).Use of HUs to predict chile development is considered superior to using days after planting due to the simple fact that the crop responds to environmental conditions and not calendar days. This approach, using phenological timelines or baselines, works best for irrigated conditions where crop vigor and environmental growth conditions are more consistent than in non-irrigated or dryland situations where irregularity in year-to-year rainfall patterns can alter growth and development patterns significantly.Crop Phenology Relationship to Nutrient and Water DemandPhenological guidelines can be used to identify or predict important stages of crop development that impact physiological requirements. For example, a phenological guideline can help identify stages of growth in relation to crop water use (consumptive use) and nutrient uptake patterns. This information allows growers to improve the timing of water and nutrient inputs to improve production efficiency. For some crops or production situations HU based phenological guidelines can be used to project critical dates such as harvest or crop termination. Many other applications related to crop management (e.g., pest management) can be derived from a better understanding of crop growth and development patterns.ADDITIONAL NOTE:Arizona Hosts the 2022 International Pepper Conference (IPC), 26-28 September 2022, Tucson and Pearce, Arizona.Registration for the International Pepper Conference. Registration and additional information can be found athttps://extension.arizona.edu/ipc/Here’s a note from the conference Chair and Host, Mr. Ed Curry: With the final countdown to the 25th biennial International Pepper Conference just days away, we want to encourage everyone who grows, processes, conducts research, educates about, or just enjoys chile peppers to get on board! The early bird pre-registration discount ends August 26th! We are also excited to announce that for anyone interested in only the field day portion of the event (Sep. 27th), a stand-alone, one-day registration is available for $200 with walk up/ same day attendees welcome! The conference will have an active schedule with many educational opportunities including: • Farm level breeding programs • Mechanical harvest technology • Pepper diseases and their management • Basic crop management science, heat units, fertility, and irrigation protocols – Dr. Jeff Silvertooth, University of Arizona • Breeding mechanical harvest type plants with Dr. Stephanie Walker, New Mexico State University • How to grow any type of PEPPER for mechanical harvest with Dr. Ben Villalon, Texas A&M Professor Emeritus • Disease prevention at a molecular level with Dr. Steve Hansen, New Mexico State University • Pepper flavor at the molecular level with Dr. Randy Hauptmann, BioGold LLC • Biopharmaceuticals at a molecular level with Dr. Bhimu Patel, Texas A&M And the list goes on...... What we hope to encapsulate in our program is the integration of basic on-farm agriculture and advanced technologies to demonstrate the importance of both approaches in moving forward the multifaceted and beautiful world of 🌶 PEPPER!WE CORDIALLY INVITE ANY AND ALL PARTICIPANTS. WALK UP REGISTRATIONS WILL BE WELCOME! I AM EXCITED TO SEE YOU THERE! YOUR HOST OF THE 2022 INTERNATIONAL PEPPER CONFERENCE, ED CURRY
Figure 1. Typical relationship between the rate of plant growth anddevelopment and temperature. Growth and development ceases whentemperatures decline below the lower temperature threshold (A) or increaseabove the upper temperature threshold (C). Growth and development increasesrapidly when temperatures fall between the lower and upper temperaturethresholds (B).
New Mexico - Type Chile Plant Development as A Function of Heat Units
Figure 2. Basic phenological guideline for irrigated New Mexico-type chiles.
ReferencesBaskerville, G.L. and P. Emin. 1969. Rapid estimation of heat accumulation from maximum and minimum temperatures. Ecology 50:514-517.Bosland, P.W., E.J. Votava, and E.M. Votava. 2012. Peppers: Vegetable and spice capsicums. Wallingford, U.K.: CAB Intl.Brown, P. W. 1989. Heat units. Bull. 8915, Univ. of Arizona Cooperative Extension, College of Ag., Tucson, AZ.Guzmán, I. and P.W. Bosland. 2017. Sensory properties of chile pepper heat - and its importance to food quality and cultural preference. Appetite, 2017 Oct 1;117:186-190. doi: 10.1016/j.appet.2017.06.026.Perry, L., Dickau, R., Zarrillo, S., Holst, I., Pearsall, D. M., Piperno, D. R., et al. 2007. Starch fossils and the domestication and dispersal of chili peppers (Capsicum spp. L.) in the Americas. Science, 315, 986-988.Silvertooth, J.C., P.W. Brown, and S. Walker. 2010. Crop Growth and Development for Irrigated Chile (Capsicum annuum). University of Arizona Cooperative Extension Bulletin No. AZ 1529Silvertooth, J.C., P.W. Brown and S.Walker. 2011. Crop Growth and Development for Irrigated Chile (Capsicum annuum). New Mexico Chile Association, Report 32. New Mexico State University, College of Agriculture, Consumer and Environmental Science.Soto-Ortiz, Roberto, J.C. Silvertooth, and A. Galadima. 2006. Crop Phenology for Irrigated Chiles (Capsicum annuum L.) in Arizona and New Mexico. Vegetable Report, College of Agriculture and Life Sciences Report Series P-144, November, University of Arizona.Soto-Ortiz, R. and J.C. Silvertooth. 2007. A Crop Phenology Model for Irrigated New Mexico Chile (Capsicum annuum L.) The 2007 Vegetable Report. Jan 08:104-122.
Plant Pathology
Lettuce Dieback Associated Virus (2023)
Lettuce dieback is a soil-borne disease caused by two closely related viruses from the family Tombusviridae Tomato Bushy Stunt Virus(TBSV) and Lettuce Necrotic Stunt Virus(LNSV) that has been reclassified as Moroccan Pepper Virus(MPV). The disease has been observed throughout the main lettuce producing areas of California and Arizona.This year we have been receiving some samples that looked like lettuce dieback disease. The samples came positive for a new virus named as Lettuce dieback associated virus and negative for tomato bushy stunt virus. In the past we have seen symptoms in resistant cultivars (with Tvr1 gene) which suggests that the new virus is involved in the symptomology.The virus is soilborne, and has been found to have more correlation with the dieback disease more than Tomato bushy stunt virus. Flooding or poor drainage, high salinity, plant stress, and soil saturation have been associated with high incidence of virus .If you have plants showing symptoms of Tomato bushy stunt virus, please bring the samples to Yuma Plant Health Clinic for diagnosis. https://www.extension.iastate.edu
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Mechanization
Controlling Weeds and Fusarium Wilt of Lettuce with Band Steam – YAC Trial Results
Last fall, we established trials investigating the use of band-steam to control weeds and Fusarium wilt of lettuce in iceberg and romaine lettuce. Band-steam is where, prior to planting, steam is injected in narrow bands, centered on the seedline to raise soil temperatures to levels sufficient to kill weed seed and soilborne pathogens (>140 °F for > 20 minutes). After the soil cools (<1 day), the crop is planted into the strips of disinfested soil.In the study, we utilized the prototype band-steam applicator (Fig. 1) described in a previous UA Veg IPM articles (Vol. 11 (13)to inject steam into the soil as beds are shaped. The steam applicator was configured to treat a 4” wide by 3” deep band of soil. Three rates of steam (Low, Standard, High) were applied by varying travel speed. The “Standard” rate was where steam was applied at rates needed to reach the target soil temperatures (>140 °F for > 20 minutes). Higher and lower applications rate were examined to ensure target temperatures were met/exceeded to get a better understanding of the efficacy of steam treatment, and to determine if higher travel speeds (less fuel consumption) could be used and still provide effective pest control.Results showed that application of steam was highly effective at controlling weeds (nettleleaf goosefoot predominant species). At the Standard application rate, over 80% of the weeds were controlled. At High application rates, weed control approached 100%. What was particularly encouraging was that at the Low steam application rate where travel speeds were 60% faster than Standard, and target temperatures were not met, weed control was still very good – about 75%.Steam treatment was also effective at controlling Fusarium wilt of lettuce. Disease incidence in iceberg and romaine lettuce were reduced by more than 50% as compared to the untreated control (Table 2). Crop plants were noticeably larger and more vigorous throughout the growing season in all steam treated plots (Fig. 2). At the Standard and High application rates of steam, this translated into significant yield increases in iceberg (>300%) and romaine (>90%) lettuce. Significant yield increases were also found at the Low application rate of steam – iceberg (>200%) and romaine (>60%).The results are very promising, but it is important to note that steam treatment is not an end-all cure for Fusarium wilt disease. At the trial site, disease inoculum levels were considered moderate. However, when inoculum levels are very high, our trials have shown that a 4” wide by 3” band of soil is not effective at controlling the disease. We hypothesize that a wider and/or deeper band of treated soil is needed for effective control. This fall, we will be initiating trials to examine this. We will also be investigating the use of band steam to control pythium and nematodes in carrot. Trial results will be presented in future articles - so Stay Tuned.As always, if you are interested in seeing the machine operate or would like to test the machine on your farm, please feel free to contact me.AcknowledgementsThis work is supported by the Arizona Specialty Crop Block Grant Program and the Arizona Iceberg Lettuce Research Council. We greatly appreciate their support. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Department of Agriculture.
| https://acis.cals.arizona.edu/agricultural-ipm/vegetables/vegetable-ipm-updates/21?Insectpage=41&PlantDiagnosticpage=11&Trappingpage=15&Weedspage=11 |
Eupedia Forum
R1a Japanese distribution & Kofun period?
Thread: R1a Japanese distribution & Kofun period?
R1a Japanese distribution & Kofun period?
GR&A: Please, no comments about ginger warriors!! Serious responses only.
Let me pose the question outright:
Does anyone know of a large study on Japanese Y haplotypes and the percentage of R1a in Japan?
I was reading and looking at some maps in Genebase and noticed trace amounts of R1a throughout Japan, specifically concentrated in Kofun strongholds such as the Yamato area.
Here's the background:
The incipient phase of the Jomon period ceramic pottery begins about 10k b.c. and continues until the Yayoi period, being introduced from China or the Korean penninsula. I spent some time recently at the Japanese national museum and the Jomon pottery is incredibly fine, even during the incipient phase. The Yayoi brought bronze and wet rice farming and this may have involved waves extending for several hundred years from the mainland. The Kofun statuettes were a little surprising though, in that many of them appear clearly 'not local'.
So..
The Kofun period brings a radical change to Japanese culture. The Kofun period warriors are typically buried in 'Kurgan style' burials. Above the graves are terracotta men with curly hair, deep eys, pointed beards, witch hats, tunics and daggers attached at the hips. They are a horse culture and introduce iron during this period. This period brought a clan based warrior warrior chiefs and marshall law. As the period progresses, you being to see the introduction of Buddahism by way of the Yamato clan.
Now first, there are trace amounts of R1b apparently in Japan. I would entirely expect this to be from 500 years of gene flow through trade. Certainly some missionaries and traders settled and married here.
R1a, on the other hand, seems more difficult to place in a historical context. I would expect some trace R1a to enter Japan via Buddahist evangelization, with inputs coming from India, Southeast Asia or the Steppes from where it mostly spread throughout Asia.
I'm curious if the Kofun culture originated from one of the historical steppe cultures such as the WuHu (Xiongnu, Di, Qiang, etc) in North Eastern Siberia. Many artifacts in Korea and Japan, such as traditional headgear, appear to have some connection with the Siberian Steppes..
Long story short, I haven't been able to find anything useful on dna analysis or mapping of Japan. Most seem to treat Japan as an open and closed book. Looking for more informaion....
R1a and R1b are not genes that ever affected Japanese gene flow in any way; about 37-40% of Japanese men re D, about 50% are O ( O2b is 31% of Japanese males O3 is 18%).
Never heard of R1a in Japan, but I wouldn't be surprised sinceHammer et al. (2006)found 0.4% of unspecified haplogroup R in Japan (n=259), 1% in Southeast Asia (n=683), and 3.2% in Northeast Asia (n=441). It would make sense that this R be R1a brought by Bronze Age Indo-Europeans to Mongolia, which infiltrated most of East Asia in the ensuing 4000 years. The Koreans and Japanese both speak an Altaic language (distantly) related to Mongolian, and that language evolved after the Indo-European migrations. The Korean invasion of Japan only happened 2500 years ago. The Japanese otherwise have 3% of C3 and 0.5% of Q, both typical of Mongolian populations. So 0.1% to 0.5% of R1a wouldn't be out of place.
I also noticed that the Japanese from the Dodecad Project had an average of 0.9% of East European admixture in the K12 admixture, and one Japanese individual had up to 2%. I first thought that this was a mistake (noise), but it seems to be correct after all. They completely lack the West European and Mediterranean admixtures though, which means that these early Indo-Europeans who settled around Mongolia must have been pure R1a.
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The Japanese really are east Asians paternally, with high O and uniquely East Asian (Japanese+Tibetan) hg D. Their rare D element found in about 2/5 of them is what significantly differentiates them from neighbouring populations such as Chinese and Koreans, who are even higher in O or Mongolians who are high in C3. The Tibetans though also have D, but it's D1. Most Japanese males have D2. The O found in Japanese males is typical if china, Korea and Southeast Asia, thus indicating recent gene flow from possibly long lost Chinese or Vietnamese or Korean, maybe even Philippine ancestors (I would put my money on Chinese or Korean or Taiwanese though.) The D is a marker of a more ancient coastal journey from Africa across southern Asia directly to Japan.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by adamo
<here is a image 46dddfa0adf86663-975330cf6d395f00>
R1a and R1b are not genes that ever affected Japanese gene flow in any way; about 37-40% of Japanese men re D, about 50% are O ( O2b is 31% of Japanese males O3 is 18%).
In any way?? I am asking whether there are any studies showing how much R1a exists in the Japanese population and where it is most present. To say it doesn't exist is what I referred to as the 'open and closed book', for it most probably exists, even if it only flowed from Buddhist evangelization or drunk Western sailors. The culture of the Kofun people did not originate in Vietnam, Taiwan or the Philippines. It looks to have come from the steppe by every metric. If that is the case, then I should expect to see haplotypes such as Q, R, C in the general population.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Maciamo
<here is a image 46dddfa0adf86663-975330cf6d395f00>
Never heard of R1a in Japan, but I wouldn't be surprised since Hammer et al. (2006) found 0.4% of unspecified haplogroup R in Japan (n=259), 1% in Southeast Asia (n=683), and 3.2% in Northeast Asia (n=441)...The Japanese otherwise have 3% of C3 and 0.5% of Q, both typical of Mongolian populations. So 0.1% to 0.5% of R1a wouldn't be out of place...
I also noticed that the Japanese from the Dodecad Project had an average of 0.9% of East European admixture in the K12 admixture, and one Japanese individual had up to 2%. I first thought that this was a mistake (noise), but it seems to be correct after all...
One thing worth pointing out is that even within the last 10k years, the Japanese archipelago supported an incredibly large and apparently impermeable population with almost perfect continuity till the Yayoi period. So much so that there may have been a large back migration to East Asia and the Americas. So after 10k years of Jomonese increase, and probably and even larger Yayoi increase with the introduction of wet rice farming, the later intruding Kofun class could have been no less than simply an extreme minority on a very heavily populated archipelago. Just being a layman, I can't help be notice the angular faces, deep eyes and pointy beards of the men that parade on Kofun Kurgans. Their culture is decidedly NE Easian and based on the maps I saw on genebase, the peaks of R1a, albeit low, appear in places that look like Kofun hotspots. The Yamato ancestral territory is one that initially peaked my interst.
There just doesn't seem to be high resolution info on the Japanese population that I've found..
I wonder if more R1 will be found in Ainu people than the rest of Japan.
<here is a image 15402147a5021757-cccca055f364b18d>
http://en.wikipedia.org/wiki/Ainu_people
What about O if the culture you speak of migrated from china or Korea; they would have Q or C if they migrated from Siberia or very high C if their ancestors were Mongols. The Ainu are said to have come from Siberia; it seems Japan was settled by a first wave of D men who went on an ancient coastal journey across Asia to Japan. Maybe even C3 passed on Japan first but I would personally doubt it. Much later on, continental Asian men of O would migrate from china and Korea towards JapanJapan
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Maciamo
<here is a image 46dddfa0adf86663-975330cf6d395f00>
Never heard of R1a in Japan, but I wouldn't be surprised since Hammer et al. (2006) found 0.4% of unspecified haplogroup R in Japan (n=259), 1% in Southeast Asia (n=683), and 3.2% in Northeast Asia (n=441). It would make sense that this R be R1a brought by Bronze Age Indo-Europeans to Mongolia, which infiltrated most of East Asia in the ensuing 4000 years. The Koreans and Japanese both speak an Altaic language (distantly) related to Mongolian, and that language evolved after the Indo-European migrations. The Korean invasion of Japan only happened 2500 years ago. The Japanese otherwise have 3% of C3 and 0.5% of Q, both typical of Mongolian populations. So 0.1% to 0.5% of R1a wouldn't be out of place.
I also noticed that the Japanese from the Dodecad Project had an average of 0.9% of East European admixture in the K12 admixture, and one Japanese individual had up to 2%. I first thought that this was a mistake (noise), but it seems to be correct after all. They completely lack the West European and Mediterranean admixtures though, which means that these early Indo-Europeans who settled around Mongolia must have been pure R1a.
I have been thinking the same thing the Yamna people(not all Yamna people) that I guess were proto Indo Iranian and Tocharian speakers around 5,000ybp were close to 100% R1a1a1b2 Z93 or just R1a overall.
Indo Iranian and Tocherian DNA
ancient DNA totally backs this up. And It is really popular in areas they migrated while there is almost no other Y DNA they could of spread maybe some others. I have seen you argue they also spread R1b1a1 M73 and J2b but do thet both exist in Mongolia, throughout central asia, and Altaian Siberia(R1a is over 40% click
here
).
Is there any ancient DNA from Japan? I bet there is a lot to learn about Genetic stuff in eastern Asia why is Y DNA O so popular in so many different language families? Are modern Japanese mainly from the Jomom people maybe.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by LeBrok
<here is a image 46dddfa0adf86663-975330cf6d395f00>
I wonder if more R1 will be found in Ainu people than the rest of Japan.
<here is a image 15402147a5021757-cccca055f364b18d>
http://en.wikipedia.org/wiki/Ainu_people
I really doubt I guess they kind of look European but Y DNa and mtDNA studies show they are Mongliod I am sure austomal DNA will show no traces of any European or Caucasian blood. If you shave them they look east Asian its their big beards that cover their face that make them look European.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Maciamo
<here is a image 46dddfa0adf86663-975330cf6d395f00>
The Koreans and Japanese both speak an Altaic language (distantly) related to Mongolian,
This is very disputed, fact is only that Japanese is part of the "Japonic" language family. However it is true that all East and Northeast Asian languages are related.
Don't the Ainu have 15-20% hg C?
I heard that the Ainu arrived from Siberia; possibly Manchuria? They where of a stock higher in hg C.
Correction: You are correct that the majority of R1b is in fact M73 in Japan, of course that's based on what I've read off Genbase and that may be old information. I haven't seen any study. In any case, I had said before that R1b probably came from Westerners in the last five hundred years, but I'm not so sure now. The presence of M73 along with R1a is probably indicative of a Steppe population along with other typical Mongol haplotypes. Secondly, the Tocharians were not exclusively R1a, in fact, they may have had no R1a. The Tarim mummies are often cited as Tocharians, and certainly they probably did have Tocharian ancestors, but the timeframe of the burial of the most famous mummies, they were certainly Scythians/Saka and toward the end of the Tarim period were increasingly Indo-Scythian Buddhists. In fact, one of the Tarim girls was clearly a Buddhist nun and appears mixed (equal parts Scythian and Asian). And of course that all makes sense given the history of Buddhism and its spread through Central Asia and the Asian Steppes.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by LeBrok
<here is a image 46dddfa0adf86663-975330cf6d395f00>
I wonder if more R1 will be found in Ainu people than the rest of Japan.
<here is a image 15402147a5021757-cccca055f364b18d>
http://en.wikipedia.org/wiki/Ainu_people
I don't expect to find any R1a at all among the Ainu since they are not descended from the Koreans/Mongols but from the aboriginal Palaeolithic inhabitants of Japan. They did come from Siberia, but well before the Bronze Age.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Alan
<here is a image 46dddfa0adf86663-975330cf6d395f00>
This is very disputed, fact is only that Japanese is part of the "Japonic" language family. However it is true that all East and Northeast Asian languages are related.
The Altaic character of Japanese is more evident in the grammar than in the actual vocabulary. Japanese, Korean and Mongolian are agglutinative languages, like all Altaic (including Turkic), Uralic and Native American languages (in other words all languages originating in Siberia).
But I can think of a few words similar in Japanese and Mongolian. For example, black is kuro Japanese, qara in Mongolian, kara in Turkish.
Japanese is an extremely composite language. Its grammar is Altaic, its sounds and some of its vocabulary are Austronesian, its core vocabulary is native Japanese but most of the technical, religious, political, academic or other formal words are from Chinese.
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Tabaccus Maximus
<here is a image 46dddfa0adf86663-975330cf6d395f00>
Correction: You are correct that the majority of R1b is in fact M73 in Japan, of course that's based on what I've read off Genbase and that may be old information. I haven't seen any study. In any case, I had said before that R1b probably came from Westerners in the last five hundred years, but I'm not so sure now. The presence of M73 along with R1a is probably indicative of a Steppe population along with other typical Mongol haplotypes. Secondly, the Tocharians were not exclusively R1a, in fact, they may have had no R1a. The Tarim mummies are often cited as Tocharians, and certainly they probably did have Tocharian ancestors, but the timeframe of the burial of the most famous mummies, they were certainly Scythians/Saka and toward the end of the Tarim period were increasingly Indo-Scythian Buddhists. In fact, one of the Tarim girls was clearly a Buddhist nun and appears mixed (equal parts Scythian and Asian). And of course that all makes sense given the history of Buddhism and its spread through Central Asia and the Asian Steppes.
If there is R1b in Japan it is not surprising that is should be M73 since it is the variety of R1b most commonly found among the Uyghurs, Mongolians and Siberians.
I have linked
the presence of M73 around the Altai with the Afanasevo culture (c. 3600-2400 BCE).
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Maciamo
<here is a image 46dddfa0adf86663-975330cf6d395f00>
If there is R1b in Japan it is not surprising that is should be M73 since it is the variety of R1b most commonly found among the Uyghurs, Mongolians and Siberians. I have linked the presence of M73 around the Altai with the Afanasevo culture (c. 3600-2400 BCE).
Afanasevo makes sense for being the catalyst of M73's movement out of West Asia. Of course the Afanasevo horizon would later in history became dominated by people variously identified as Scythians who probably brought R1a into Pazyryk, Altai and other areas such as the Tarim basin.
Scythian influences have long been noted in Korea and Japan, this is seen in the crowns of the Korean ruling Silla who at the time were at war with the Kofun aristocracy in Japan. The uniform of the Issyk kurgan is another style that enters Korea and Japan at this time among the warring class. There are countless other examples.
The vesture of the Kofun Haniwa appears to have Scythian influences as well. The trousers, belt, hair styles, facial hair, hats and earrings are all decidedly foreign and various commentaries have noted their Western and Central Asian influences. In many cases, they are surprisingly Scythian, not just a vague example of Central Asian styles. The more I dig into the history of the three-kingdoms period I become more convenced that an Altai culture like that of Pazyryk became influencial early in Korean history which in turn became influencial in Japan.
Of course, these postulated Altai people were most likely an amalgam of Mongol, Scythian and Turkic influences. They may have been 'Hunnic-like' in their composition.
The Japanese also have trace frequencies of European mtDNA (HV, H, V and W). See my analysishere.
It could even be a possibility that the men of the Japanese Imperial family carry haplogroup R1a!
Interestingly Coon noted an Europid/Caucasoid influence amongst Japanese upper-classes.
He called their phenotype the "Aristocratic type" as opposed to the "Peasant type".
In fact Japan may be quite similar to India in that regard.
This is why more studies should be done on that country.
They should first test the aDNA to evaluate the genetic composition and evolution of Japan from the Jomon period to (at least) the early Shogunates(Middle Ages).
Then they should compare the genetic make-up(Y-DNA,autosomal,mtDNA) of modern Japanese with noble surnames with those with non-noble surnames.
Of course not mentioning the potential of discovering higher recent(post-1500's) European and South Asian admixture in the general population(especially in coastal cities known to have had such foreign influences like Kobe or Nagasaki).
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Tabaccus Maximus
<here is a image 46dddfa0adf86663-975330cf6d395f00>
In any way?? I am asking whether there are any studies showing how much R1a exists in the Japanese population and where it is most present. To say it doesn't exist is what I referred to as the 'open and closed book', for it most probably exists, even if it only flowed from Buddhist evangelization or drunk Western sailors....
Buddhist missionaries is actually a good hypothesis. Buddhism started as a sort of reform movement in Hinduism or at least sprung up in a Hindu-influenced context, and Hinduism is an Indo-European "Sky Father" religion. That makes it likely that IE people were among the first to hear about Buddhism and perhaps become many of its earliest follows.
As for the drunk Western sailors, I'd imagine that the problem may have more been due to drunk Japanese barmaids who were so intoxicated that they thought that sleeping with Western sailors was actually a good idea....
<here is a image c5540a7e181863c1-f4863c1c80f5f9e0> Originally Posted by Fire Haired
<here is a image 46dddfa0adf86663-975330cf6d395f00>
I really doubt I guess they kind of look European but Y DNa and mtDNA studies show they are Mongliod I am sure austomal DNA will show no traces of any European or Caucasian blood. If you shave them they look east Asian its their big beards that cover their face that make them look European.
Perhaps the Ainu are a mix of Steppe and Chinese ancestry, making them look not-quite-European but more European than their neighbors, all other things being equal. We know that modern Europeans are a mix of Steppe/West Asian peoples (R1a, R1b), Paleolithic Europeans (I1, I2), and other peoples. Maybe the "European-like" features that we see in Ainu are actually features of the original Steppe people that were spread in both directions. Ainu (and Japanese in general) presumably are not going to have a significant amount of WHG and other stone-age European admixture, making it unlikely that they would, say, look like French people.
The Altaic character of Japanese is more evident in the grammar than in the actual vocabulary. Japanese, Korean and Mongolian are agglutinative languages, like all Altaic (including Turkic), Uralic and Native American languages (in other words all languages originating in Siberia).
Maciamo can the agglutinative nature be a sufficient to classification? My impression is that agglutinativeness was widespread. Dravidians, Sumerian, Hurrians, Hattic and some of Caucasian languages are/were agglutinative.
About some ancient DNA from Japan.
https://heritageofjapan.wordpress.co...ously-thought/
Ancient Jomon people not like present-day East Asians
An interesting summary.
http://www.wa-pedia.com/history/orig...e_people.shtml
One of comments.
The newest research revealed Yayoi people came from Southern China and North Vietnam by sea route, far older time than 3rd CE BC. The origin of Y-Haplogroup O2b is not Korea, but Southern China and North Vietnam. Yaoi people from South China/Vietnam brought Hydroponic culture(wet rice culture)of rice to Japan and it did not come through Korea for there are no evidence of Hydroponic culture of rice in North China and North Korea. DNA sampling of ancient rice found in soil in Japan proved that they came directly from Southern China/Vietnam.
People in Vietnam(14%) and Indonesia still carry pretty high level of O2b. These people travelled up to North on boats and they came in waves, not at once. To prove this, the people who has the highest O2b in the world are living in Islands of MIyakojima and those area of OKINAWA. O2b is rare in mainland China except for Manchu.
and another that is different. So the question of route O2b is not resolved it seems.
and moreover, the birth of haplo O2b estimated 4000~10000 years ago from southern china or southern manchuria. this date is very late among major haplogroups. but considering its population, the majority of yayoi people seemed to be come from korean peninsula.
well though the route of O2b is uncertain(from southern china? or southern manchuria?), at least it is certain. O2b is mainly distribute among korean, japanese and manchurian(but the haplo of manchurians is differerent by the regions-_-;), but rare among chinese.
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16/033-11:26:04.018 ON ON ON OFF ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF 1176 0.3587 1186 2.8938
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16/033-11:27:54.026 ON ON ON OFF ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF 1177 0.3590 1183 2.8865
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<p><p>Unlike conventional synchronous circuits, asynchronous circuits are not coordinated by a clocking signal, but instead use handshaking protocols to control circuit behaviour. Asynchronous circuits have been found to offer several advantages, including high energy efficiency, flexible timing requirements, high modularity, low noise/EMI, and robustness to PVT variations. At the same time, growing pressures on the electronics industry for ever smaller, more efficient ICs are pushing the limits of conventional circuit technologies. These factors are spurring growing interest in asynchronous circuits amongst both the academic research and commercial RD communities. This book introduces a wide range of existing and potential applications for asynchronous circuits, each accompanied with the corresponding circuit design theory, sample circuit implementations, results, and analysis. It serves as an essential guide for academic researchers and students looking to broaden their thinking in advancing asynchronous applications and design methodologies, and provides practical advice to industrial engineers when considering the incorporation of asynchronous circuits in their own applications.</p></p>
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>General electrical engineering topics</a>;
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>Logic circuits</a>;
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>Analogue circuit design, modelling and testing</a>;
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>Analogue processing circuits</a>
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Introduction</a></h5>
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<p>The chapter introduces the concept of asynchronous circuits by considering the advantages of asynchronous circuits and presents an overview of their circuit applications.</p>
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Asynchronous circuits for dynamic voltage scaling</a></h5>
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<p>We have presented the appropriateness of the QDI (and pseudo-QDI) asynchronous -logic design approach to realize circuits and systems suitable for full -range DVS (from the nominal voltage near- V t voltage sub- V t voltage regions). Both block -level and gate -level pipeline structures have been presented. Using the block -level pipeline structure, we have presented an SSAVS system embodying block -level QDI asynchronous pipelines for a WSN with the objective of lowest possible power operation for the prevailing throughput and circuit conditions-V DD adjusted to within 50 mV of the minimum voltage, yet high operational robustness with minimal overheads. High robustness has been achieved by adopting the asynchronous QDI protocols, and the embodiment of our proposed PCSL. A reduced -overhead design has further been shown by adopting the asynchronous pseudo-QDI protocols, and the embodiment of PCSL. Using the gate -level pipeline structure, we have presented our proposed SABB cell design approach and evaluated an asynchronous QDI KS pipeline adder embodying SABB for full -range DVS operation. In summary, we show that QDI (and pseudo-QDI) asynchronous -logic, coupled with either PCSL or SABB cell design approaches, provides a low-cost high -reliability solution for circuits and systems exclusively designed for error free DVS.</p>
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<a href="/content/books/10.1049/pbcs061e_ch3;jsessionid=24e7u7huqeund.x-iet-live-01" title="Power-performance balancing of asynchronous circuits "
><span class="meta-value displayOrderNumber">3</span>
Power-performance balancing of asynchronous circuits</a></h5>
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<br />
<p>Asynchronous circuit designed on delay-insensitive NCL and multithreshold CMOS techniques inherits the benefit on power reduction but degrades the speed. Circuit pipeline and parallel architecture are applied to migrate the performance drawback. In the first part of the chapter, the throughput and latency of the NCL micropipeline are derived for the digital signal processing circuit optimization, including an example on generic FIR design with same performance as its synchronous count part. Scalable parallel computing architecture that incorporates homogeneous units is designed in Section 3.2 for performance escalation. Besides that, DVS achieves balanced control of performance and power consumption. An effective fullness variance predicting algorithm is implemented to employ the DVS more aggressively in a wider range of system workloads. The platform fabricated using the MITLL 90 nm process consumes 49.364 pJ per data with the best performance when the DATA to DATA cycle time is 6.02 μ,s. The schemes on fme-grain core states control and heterogeneous architecture are presented as research topics on power -performance balancing. Core enable and disabling sequence and fi ne-grain state control earns the maximum benefit of DVS. Common data I/O ports with NULL cycle reduction and asynchronous arbitration network are incorporated in the heterogeneous platform to make a highly modular interface for both horizontal and vertical scaling. Those methodologies demonstrate the advantage of asynchronous circuit in large scale, multithreads and scalable computing applications.</p>
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<h5 class="browseItemTitle">
<a href="/content/books/10.1049/pbcs061e_ch4;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous circuits for ultra-low supply voltages "
><span class="meta-value displayOrderNumber">4</span>
Asynchronous circuits for ultra-low supply voltages</a></h5>
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<span class="meta-key pageRange_label">p. </span>
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<p>Modern digital systems based on complementary metal-oxide-semiconductor (CMOS) integrated circuits (IC) are increasingly sensitive to power consumption and heat generation which has direct impact on the system's performance and reliability. Power consumption of a system can be effectively reduced by techniques such as supply voltage scaling, downsizing transistors, or limiting switching activity. Supply voltage scaling is amidst one of the most effective way to reduce power dissipation. The continuance reduction of supply voltage will require transistors to operate in subthreshold region. Process technology developed with transistors optimized for subthreshold operation offers the essential building blocks to construct digital systems that are capable of operating at ultra-low supply voltage and consuming significantly less power.</p>
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<h5 class="browseItemTitle">
<a href="/content/books/10.1049/pbcs061e_ch5;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous circuits for interfacing with analog electronics "
><span class="meta-value displayOrderNumber">5</span>
Asynchronous circuits for interfacing with analog electronics</a></h5>
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<span class="meta-value pageRange">83
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<p>Very few integrated circuits, whether they are microprocessors or ASICs, are designed with purely digital or analog components. Mixed-signal circuits and systems straddle this divide, and this chapter examines how analog components may be interfaced with asynchronous logic. This chapter presents two example systems, which cover three methods of closing the feedback loop to maintain asynchronous operation. In the first example, an asynchronous serializer/deserializer (SerDes), the analog components have known end-states and are physically included in the loop of the asynchronous logic stage. Since the completion detection occurs directly, this system maintains its quasidelay-insensitive (DI) operation. For the second example, a successive approximation analog-to-digital converter (SAR ADC), the circuit cannot be fully included in the loop, and two options for maintaining asynchronous operation are described. Due to the nature of the authors' interests and respective circuit applications, the example circuits also work in spatially distributed implementations. In these cases, different parts of the circuit may have significantly different operating environments, and may even be designed in different IC fabrication processes. Some readers of this chapter will be analog or mixed-signal designers who are curious about how delay insensitive logic can be used in their work. For that audience, a brief overview of the ring oscillator metaphor is presented here and will clarify the behaviors described later in the examples.</p>
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Asynchronous sensing</a></h5>
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<p>In this chapter, we have presented a few examples of designs from the domain of sensors that illustrate the promise of asynchronous techniques in the design of sensing systems. Such systems often impose strict performance requirements. For example, in wide area distributed networked sensors, there are constraints of tight energy budgets and low area costs. In the case of image sensors, a large array of tiny sensory pixels are packed into a single chip, and pose performance challenges if rigid global synchronization is used. Since transduction is usually followed by analog -to -digital conversion (ADC) and digital signal processing (DSP), these processing techniques must also be specialized to be highly energy efficient. Furthermore, sensing often involves long idle periods, so all sensing systems must have very low idle power consumption. In this chapter, we saw examples of frameless image sensors, asynchronous sensor processors, and continuous -time ADC and DSP, all of which exemplify the power and promise of asynchronous design in the fi eld of sensing.</p>
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<a href="/content/books/10.1049/pbcs061e_ch7;jsessionid=24e7u7huqeund.x-iet-live-01" title="Design and test of high-speed asynchronous circuits "
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Design and test of high-speed asynchronous circuits</a></h5>
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<p>This chapter explores the design and test of high-speed complementary metal oxide semiconductor (CMOS) self -timed circuits. Section 7.1 describes how the properties of CMOS technology itself limit how fast a self -timed circuit can run. Section 7.2 presents our Link and Joint model, a unified point of view of self -timed circuits that allows reasoning about them independently of circuit families and handshake protocols. The model separates communication and storage, done in Links, from computation and fl ow control, done in Joints. The model also separates actions from states. Special go signals enable or disable Joint actions on an individual basis. The individual go signals make it possible to initialize, start, and stop self -timed operations reliably, which is crucial for design as well as for at -speed test, debug, and characterization. Section 7.3 examines design and test aspects of the Weaver, a self -timed nonblocking 8 x 8 crossbar switch designed using the Link and Joint model. We report measured test results from a working Weaver chip in 40 nm CMOS with speeds up to 6 Giga data items per second. With 72 bit wide data items, this amounts to 3.5 Tera bits per second for the full crossbar.</p>
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<a href="/content/books/10.1049/pbcs061e_ch8;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous network-on-chips (NoCs) for resource efficient many core architectures "
><span class="meta-value displayOrderNumber">8</span>
Asynchronous network-on-chips (NoCs) for resource efficient many core architectures</a></h5>
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<p>In this chapter, different GALS approaches for the implementation of embedded NoC architectures were presented. The GALS approach allows for the reduction of the resource requirements at an increased scalability of the NoC without sacrificing performance. The three approaches of synchronous, mesochronous, and asynchronous NoCs were compared. For the mesochronous NoC special synchronizers between the links were implemented. For the asynchronous NoC, the routers were completely realized as an asynchronous circuits. The results have shown that modern design methods (CCOpt design fl ow) allow a good scaling of MPSoCs even for synchronous NoCs. Nevertheless, the asynchronous NoC showed lower area and energy requirement compared to the mesochronous and synchronous implementation, while still providing a comparable performance. When comparing a place and route of an MPSoC, the asynchronous NoC leads to 3.1% less area requirements. The power consumption of an asynchronous router is only 22.4% (0.94 mW in idle state) or 53% (3.94 mW during communication) of the power consumption of a clock -based router. In the last section of the chapter, the global clock tree for an MPSoC with 256 CPUs was examined. The synchronous and mesochronous NoC show almost the same power consumption of about 7.7 mW. Using the asynchronous NoC reduces the power consumption by about 25% (5.78 mW). In addition, the mesochronous and asynchronous variants achieve a 2.6% higher clock frequency.</p>
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<a href="/content/books/10.1049/pbcs061e_ch9;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous field-programmable gate arrays (FPGAs) "
><span class="meta-value displayOrderNumber">9</span>
Asynchronous field-programmable gate arrays (FPGAs)</a></h5>
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<p>Field-programmable gate arrays (FPGAs) are chips that can be electronically programmed to function as an arbitrary digital circuit or system. They were originally used to replace discrete gates in interface electronics, and over the past three decades have evolved to being used in the place of application-specific integrated circuits (ASICs) in low volume and cost-constrained situations. Modern commercially available FPGAs are sophisticated integrated circuits capable of implementing digital chips with millions of gates. In addition, some of them also have special-purpose I/O macros to support memory interfaces, as well as serial links to support high-throughput communication. FPGAs are widely used to prototype digital logic. This chapter discusses some of the challenges with using standard FPGAs to prototype asynchronous logic and summarizes research efforts that have created alternate FPGA architectures for asynchronous logic.</p>
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<a href="/content/books/10.1049/pbcs061e_ch10;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous circuits for extreme temperatures "
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Asynchronous circuits for extreme temperatures</a></h5>
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<p>This chapter presented successful physical testing results of multiple NCL circuit designs of varying size and complexity across a very large temperature range. For high-temperature applications, a SiC process developed by Raytheon was leveraged and exhibited circuits functioning at temperatures exceeding 500 °C. For low temperature applications, the industry standard IBM 0.5 μm SiGe process was leveraged and exhibited circuits functioning as temperatures approached absolute zero. Through all these tests, the NCL circuits required no special considerations (due to environmental effects on the device level) to maintain correct operation across these wide temperature swings. In the same conditions, synchronous systems would require significant effort (either through complex logical design changes or physical setup considerations) in order to meet their timing constraints which always leads to a large amount of overhead incurred. These results have proven the flexibility and robustness advantage that asynchronous systems have over synchronous designs.</p>
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<a href="/content/books/10.1049/pbcs061e_ch11;jsessionid=24e7u7huqeund.x-iet-live-01" title="Asynchronous circuits for radiation hardness "
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Asynchronous circuits for radiation hardness</a></h5>
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<p>Asynchronous circuits are inherently suitable for radiation-exposed environments due to their quasidelay insensitivity (QDI) and multirail logic systems. If an ionizing -radiation event is detected, the QDI property provides the ability to delay the current operation within the circuit until the effect has subsided. The dual -rail design provides additional support in this area because in many cases both rails must be affected in order for an SEU to occur. In addition to mitigating SEEs through asynchronous circuit -level architectures, radiation hardening techniques can be applied to transistor -level layout designs and circuit components, such as the DFF, for increased reliability.</p>
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<a href="/content/books/10.1049/pbcs061e_ch12;jsessionid=24e7u7huqeund.x-iet-live-01" title="Dual rail asynchronous logic design methodologies for side channel attack mitigation "
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Dual rail asynchronous logic design methodologies for side channel attack mitigation</a></h5>
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<p>Side channel attacks (SCAs) remain a great threat to hardware security. In most CMOS circuitries, electrical behaviors are correlated to processed data which makes them vulnerable to SCAs. Dual-rail circuitries present an advantage in mitigating SCAs due to the inherited balance in data representation. NCL circuits present more stable power traces compared to industry standard synchronous counterparts; however, NCL circuits are still vulnerable to some SCAs due to the lack of balance in data propagation. In this chapter, the vulnerability of NCL circuits to SCAs is explained, and more secure dual-rail design methodologies are presented. Derived from NCL, dual-spacer dual-rail delay-insensitive logic or D<sup>3</sup>L methodology produces crypto hardware with great resilience against SCAs. D<sup>3</sup>L resilience, overheads associated with it as well as improved methodologies for overhead reduction are explained in this chapter.</p>
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<a href="/content/books/10.1049/pbcs061e_ch13;jsessionid=24e7u7huqeund.x-iet-live-01" title="Using asynchronous clock distribution networks for timing SFQ circuits "
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Using asynchronous clock distribution networks for timing SFQ circuits</a></h5>
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<p>In this chapter, we discuss the use of asynchronous clock distribution networks (ACDNs) to provide the timing for SFQ circuits. In particular, we review the hierarchical chains of homogeneous clover-leaves clocking, or (HC)<sup>2</sup> LC [1], a self-adaptive clocking technique designed to be resilient in such uncertain environments. (HC)<sup>2</sup> LC inherits its robustness from its asynchronous nature that adapts to the spatially correlated cell delays, trading-off reasonable area, and power overheads for higher reliability and improved scalability.</p>
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<a href="/content/books/10.1049/pbcs061e_ch14;jsessionid=24e7u7huqeund.x-iet-live-01" title="Uncle—Unified NCL Environment—an NCL design tool "
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Uncle—Unified NCL Environment—an NCL design tool</a></h5>
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<p>Uncle (Unified NULL Convention Logic Environment) is a tool for creating NULL Convention Logic (NCL) designs, which can be downloaded for free. * This chapter discusses Uncle internals and a detailed walk-through of an example design.</p>
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Formal verification of NCL circuits</a></h5>
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<p>In this chapter, the author describe an equivalence checking methodology for NULL Convention Logic (NCL) circuits. Note that currently, there are no commercial equivalence checkers for quasi-delay insensitive (QDI) circuits. For commercial applications, NCL circuits, and QDI circuits in general, are often synthesized from synchronous intellectual property designs. The resulting NCL design may then be further optimized and tinkered with. Therefore, the author have designed an equivalence checker that can be used in two ways: (1) to verify the functional equivalence of two NCL designs and (2) to verify the equivalence between an NCL design and a synchronous design.</p>
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<a href="/content/books/10.1049/pbcs061e_ch16;jsessionid=24e7u7huqeund.x-iet-live-01" title="Conclusion "
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Conclusion</a></h5>
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<p>The chapter highlights a set of applications where asynchronous circuits outperform their synchronous counterparts due to one or more of their advantages, such as no clock tree, flexible timing requirement, robust operation, improved performance, high energy efficiency, high modularity and scalability, and low noise and emission.</p>
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<a href="/content/books/10.1049/pbcs061e_bm;jsessionid=24e7u7huqeund.x-iet-live-01" title="Back Matter "
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Personal Memoirs of U.S. Grant - Chapter XXVII
Read Chapter XXVII of Personal Memoirs of U.S. Grant by Ulysses S. Grant. The text begins: HEADQUARTERS MOVED TO MEMPHIS—ON THE ROAD TO MEMPHIS—ESCAPING JACKSON—COMPLAINTS AND REQUESTS—HALLECK APPOINTED COMMANDER-IN-CHIEF—RETURN TO CORINTH—MOVEMENTS OF BRAGG—SURRENDER OF CLARKSVILLE—THE ADVANCE UPON CHATTANOOGA—SHERIDAN COLONEL OF A MICHIGAN REGIMENT. My position at Corinth, with a nominal command and yet no command, became so unbearable that I asked permission of Halleck to remove my headquarters to Memphis. I had repeatedly asked, between the fall of Donelson and the evacuation of Corinth, to be relieved from duty under Halleck; but all my applications were refused until the occupation of the town. I then obtained permission to leave the department, but General Sherman happened to call on me as I was about starting and urged me so strongly not to think of going, that …
Personal Memoirs of U.S. Grant
by Ulysses S. Grant
Chapter XXVII
HEADQUARTERS MOVED TO MEMPHIS—ON THE ROAD TO MEMPHIS—ESCAPING JACKSON—COMPLAINTS AND REQUESTS—HALLECK APPOINTED COMMANDER-IN-CHIEF—RETURN TO CORINTH—MOVEMENTS OF BRAGG—SURRENDER OF CLARKSVILLE—THE ADVANCE UPON CHATTANOOGA—SHERIDAN COLONEL OF A MICHIGAN REGIMENT.
My position at Corinth, with a nominal command and yet no command, became so unbearable that I asked permission of Halleck to remove my headquarters to Memphis. I had repeatedly asked, between the fall of Donelson and the evacuation of Corinth, to be relieved from duty under Halleck; but all my applications were refused until the occupation of the town. I then obtained permission to leave the department, but General Sherman happened to call on me as I was about starting and urged me so strongly not to think of going, that I concluded to remain. My application to be permitted to remove my headquarters to Memphis was, however, approved, and on the 21st of June I started for that point with my staff and a cavalry escort of only a part of one company. There was a detachment of two or three companies going some twenty-five miles west to be stationed as a guard to the railroad. I went under cover of this escort to the end of their march, and the next morning proceeded to La Grange with no convoy but the few cavalry men I had with me.
From La Grange to Memphis the distance is forty-seven miles. There were no troops stationed between these two points, except a small force guarding a working party which was engaged in repairing the railroad. Not knowing where this party would be found I halted at La Grange. General Hurlbut was in command there at the time and had his headquarters tents pitched on the lawn of a very commodious country house. The proprietor was at home and, learning of my arrival, he invited General Hurlbut and me to dine with him. I accepted the invitation and spent a very pleasant afternoon with my host, who was a thorough Southern gentleman fully convinced of the justice of secession. After dinner, seated in the capacious porch, he entertained me with a recital of the services he was rendering the cause. He was too old to be in the ranks himself—he must have been quite seventy then—but his means enabled him to be useful in other ways. In ordinary times the homestead where he was now living produced the bread and meat to supply the slaves on his main plantation, in the low-lands of Mississippi. Now he raised food and forage on both places, and thought he would have that year a surplus sufficient to feed three hundred families of poor men who had gone into the war and left their families dependent upon the "patriotism" of those better off. The crops around me looked fine, and I had at the moment an idea that about the time they were ready to be gathered the "Yankee" troops would be in the neighborhood and harvest them for the benefit of those engaged in the suppression of the rebellion instead of its support. I felt, however, the greatest respect for the candor of my host and for his zeal in a cause he thoroughly believed in, though our views were as wide apart as it is possible to conceive.
The 23d of June, 1862, on the road from La Grange to Memphis was very warm, even for that latitude and season. With my staff and small escort I started at an early hour, and before noon we arrived within twenty miles of Memphis. At this point I saw a very comfortable-looking white-haired gentleman seated at the front of his house, a little distance from the road. I let my staff and escort ride ahead while I halted and, for an excuse, asked for a glass of water. I was invited at once to dismount and come in. I found my host very genial and communicative, and staid longer than I had intended, until the lady of the house announced dinner and asked me to join them. The host, however, was not pressing, so that I declined the invitation and, mounting my horse, rode on.
About a mile west from where I had been stopping a road comes up from the southeast, joining that from La Grange to Memphis. A mile west of this junction I found my staff and escort halted and enjoying the shade of forest trees on the lawn of a house located several hundred feet back from the road, their horses hitched to the fence along the line of the road. I, too, stopped and we remained there until the cool of the afternoon, and then rode into Memphis.
The gentleman with whom I had stopped twenty miles from Memphis was a Mr. De Loche, a man loyal to the Union. He had not pressed me to tarry longer with him because in the early part of my visit a neighbor, a Dr. Smith, had called and, on being presented to me, backed off the porch as if something had hit him. Mr. De Loche knew that the rebel General Jackson was in that neighborhood with a detachment of cavalry. His neighbor was as earnest in the southern cause as was Mr. De Loche in that of the Union. The exact location of Jackson was entirely unknown to Mr. De Loche; but he was sure that his neighbor would know it and would give information of my presence, and this made my stay unpleasant to him after the call of Dr. Smith.
I have stated that a detachment of troops was engaged in guarding workmen who were repairing the railroad east of Memphis. On the day I entered Memphis, Jackson captured a small herd of beef cattle which had been sent east for the troops so engaged. The drovers were not enlisted men and he released them. A day or two after one of these drovers came to my headquarters and, relating the circumstances of his capture, said Jackson was very much disappointed that he had not captured me; that he was six or seven miles south of the Memphis and Charleston railroad when he learned that I was stopping at the house of Mr. De Loche, and had ridden with his command to the junction of the road he was on with that from La Grange and Memphis, where he learned that I had passed three-quarters of an hour before. He thought it would be useless to pursue with jaded horses a well-mounted party with so much of a start. Had he gone three-quarters of a mile farther he would have found me with my party quietly resting under the shade of trees and without even arms in our hands with which to defend ourselves.
General Jackson of course did not communicate his disappointment at not capturing me to a prisoner, a young drover; but from the talk among the soldiers the facts related were learned. A day or two later Mr. De Loche called on me in Memphis to apologize for his apparent incivility in not insisting on my staying for dinner. He said that his wife accused him of marked discourtesy, but that, after the call of his neighbor, he had felt restless until I got away. I never met General Jackson before the war, nor during it, but have met him since at his very comfortable summer home at Manitou Springs, Colorado. I reminded him of the above incident, and this drew from him the response that he was thankful now he had not captured me. I certainly was very thankful too.
My occupation of Memphis as district headquarters did not last long. The period, however, was marked by a few incidents which were novel to me. Up to that time I had not occupied any place in the South where the citizens were at home in any great numbers. Dover was within the fortifications at Fort Donelson, and, as far as I remember, every citizen was gone. There were no people living at Pittsburg landing, and but very few at Corinth. Memphis, however, was a populous city, and there were many of the citizens remaining there who were not only thoroughly impressed with the justice of their cause, but who thought that even the "Yankee soldiery" must entertain the same views if they could only be induced to make an honest confession. It took hours of my time every day to listen to complaints and requests. The latter were generally reasonable, and if so they were granted; but the complaints were not always, or even often, well founded. Two instances will mark the general character. First: the officer who commanded at Memphis immediately after the city fell into the hands of the National troops had ordered one of the churches of the city to be opened to the soldiers. Army chaplains were authorized to occupy the pulpit. Second: at the beginning of the war the Confederate Congress had passed a law confiscating all property of "alien enemies" at the South, including the debts of Southerners to Northern men. In consequence of this law, when Memphis was occupied the provost-marshal had forcibly collected all the evidences he could obtain of such debts.
Almost the first complaints made to me were these two outrages. The gentleman who made the complaints informed me first of his own high standing as a lawyer, a citizen and a Christian. He was a deacon in the church which had been defiled by the occupation of Union troops, and by a Union chaplain filling the pulpit. He did not use the word "defile," but he expressed the idea very clearly. He asked that the church be restored to the former congregation. I told him that no order had been issued prohibiting the congregation attending the church. He said of course the congregation could not hear a Northern clergyman who differed so radically with them on questions of government. I told him the troops would continue to occupy that church for the present, and that they would not be called upon to hear disloyal sentiments proclaimed from the pulpit. This closed the argument on the first point.
Then came the second. The complainant said that he wanted the papers restored to him which had been surrendered to the provost-marshal under protest; he was a lawyer, and before the establishment of the "Confederate States Government" had been the attorney for a number of large business houses at the North; that "his government" had confiscated all debts due "alien enemies," and appointed commissioners, or officers, to collect such debts and pay them over to the "government": but in his case, owing to his high standing, he had been permitted to hold these claims for collection, the responsible officials knowing that he would account to the "government" for every dollar received. He said that his "government," when it came in possession of all its territory, would hold him personally responsible for the claims he had surrendered to the provost-marshal. His impudence was so sublime that I was rather amused than indignant. I told him, however, that if he would remain in Memphis I did not believe the Confederate government would ever molest him. He left, no doubt, as much amazed at my assurance as I was at the brazenness of his request.
On the 11th of July General Halleck received telegraphic orders appointing him to the command of all the armies, with headquarters in Washington. His instructions pressed him to proceed to his new field of duty with as little delay as was consistent with the safety and interests of his previous command. I was next in rank, and he telegraphed me the same day to report at department headquarters at Corinth. I was not informed by the dispatch that my chief had been ordered to a different field and did not know whether to move my headquarters or not. I telegraphed asking if I was to take my staff with me, and received word in reply: "This place will be your headquarters. You can judge for yourself." I left Memphis for my new field without delay, and reached Corinth on the 15th of the month. General Halleck remained until the 17th of July; but he was very uncommunicative, and gave me no information as to what I had been called to Corinth for.
When General Halleck left to assume the duties of general-in-chief I remained in command of the district of West Tennessee. Practically I became a department commander, because no one was assigned to that position over me and I made my reports direct to the general-in-chief; but I was not assigned to the position of department commander until the 25th of October. General Halleck while commanding the Department of the Mississippi had had control as far east as a line drawn from Chattanooga north. My district only embraced West Tennessee and Kentucky west of the Cumberland River. Buell, with the Army of the Ohio, had, as previously stated, been ordered east towards Chattanooga, with instructions to repair the Memphis and Charleston railroad as he advanced. Troops had been sent north by Halleck along the line of the Mobile and Ohio railroad to put it in repair as far as Columbus. Other troops were stationed on the railroad from Jackson, Tennessee, to Grand Junction, and still others on the road west to Memphis.
The remainder of the magnificent army of 120,000 men which entered Corinth on the 30th of May had now become so scattered that I was put entirely on the defensive in a territory whose population was hostile to the Union. One of the first things I had to do was to construct fortifications at Corinth better suited to the garrison that could be spared to man them. The structures that had been built during the months of May and June were left as monuments to the skill of the engineer, and others were constructed in a few days, plainer in design but suited to the command available to defend them.
I disposed the troops belonging to the district in conformity with the situation as rapidly as possible. The forces at Donelson, Clarksville and Nashville, with those at Corinth and along the railroad eastward, I regarded as sufficient for protection against any attack from the west. The Mobile and Ohio railroad was guarded from Rienzi, south of Corinth, to Columbus; and the Mississippi Central railroad from Jackson, Tennessee, to Bolivar. Grand Junction and La Grange on the Memphis railroad were abandoned.
South of the Army of the Tennessee, and confronting it, was Van Dorn, with a sufficient force to organize a movable army of thirty-five to forty thousand men, after being reinforced by Price from Missouri. This movable force could be thrown against either Corinth, Bolivar or Memphis; and the best that could be done in such event would be to weaken the points not threatened in order to reinforce the one that was. Nothing could be gained on the National side by attacking elsewhere, because the territory already occupied was as much as the force present could guard. The most anxious period of the war, to me, was during the time the Army of the Tennessee was guarding the territory acquired by the fall of Corinth and Memphis and before I was sufficiently reinforced to take the offensive. The enemy also had cavalry operating in our rear, making it necessary to guard every point of the railroad back to Columbus, on the security of which we were dependent for all our supplies. Headquarters were connected by telegraph with all points of the command except Memphis and the Mississippi below Columbus. With these points communication was had by the railroad to Columbus, then down the river by boat. To reinforce Memphis would take three or four days, and to get an order there for troops to move elsewhere would have taken at least two days. Memphis therefore was practically isolated from the balance of the command. But it was in Sherman's hands. Then too the troops were well intrenched and the gunboats made a valuable auxiliary.
During the two months after the departure of General Halleck there was much fighting between small bodies of the contending armies, but these encounters were dwarfed by the magnitude of the main battles so as to be now almost forgotten except by those engaged in them. Some of them, however, estimated by the losses on both sides in killed and wounded, were equal in hard fighting to most of the battles of the Mexican war which attracted so much of the attention of the public when they occurred. About the 23d of July Colonel Ross, commanding at Bolivar, was threatened by a large force of the enemy so that he had to be reinforced from Jackson and Corinth. On the 27th there was skirmishing on the Hatchie River, eight miles from Bolivar. On the 30th I learned from Colonel P. H. Sheridan, who had been far to the south, that Bragg in person was at Rome, Georgia, with his troops moving by rail (by way of Mobile) to Chattanooga and his wagon train marching overland to join him at Rome. Price was at this time at Holly Springs, Mississippi, with a large force, and occupied Grand Junction as an outpost. I proposed to the general-in-chief to be permitted to drive him away, but was informed that, while I had to judge for myself, the best use to make of my troops WAS NOT TO SCATTER THEM, but hold them ready to reinforce Buell.
The movement of Bragg himself with his wagon trains to Chattanooga across country, while his troops were transported over a long round-about road to the same destination, without need of guards except when in my immediate front, demonstrates the advantage which troops enjoy while acting in a country where the people are friendly. Buell was marching through a hostile region and had to have his communications thoroughly guarded back to a base of supplies. More men were required the farther the National troops penetrated into the enemy's country. I, with an army sufficiently powerful to have destroyed Bragg, was purely on the defensive and accomplishing no more than to hold a force far inferior to my own.
On the 2d of August I was ordered from Washington to live upon the country, on the resources of citizens hostile to the government, so far as practicable. I was also directed to "handle rebels within our lines without gloves," to imprison them, or to expel them from their homes and from our lines. I do not recollect having arrested and confined a citizen (not a soldier) during the entire rebellion. I am aware that a great many were sent to northern prisons, particularly to Joliet, Illinois, by some of my subordinates with the statement that it was my order. I had all such released the moment I learned of their arrest; and finally sent a staff officer north to release every prisoner who was said to be confined by my order. There were many citizens at home who deserved punishment because they were soldiers when an opportunity was afforded to inflict an injury to the National cause. This class was not of the kind that were apt to get arrested, and I deemed it better that a few guilty men should escape than that a great many innocent ones should suffer.
On the 14th of August I was ordered to send two more divisions to Buell. They were sent the same day by way of Decatur. On the 22d Colonel Rodney Mason surrendered Clarksville with six companies of his regiment.
Colonel Mason was one of the officers who had led their regiments off the field at almost the first fire of the rebels at Shiloh. He was by nature and education a gentleman, and was terribly mortified at his action when the battle was over. He came to me with tears in his eyes and begged to be allowed to have another trial. I felt great sympathy for him and sent him, with his regiment, to garrison Clarksville and Donelson. He selected Clarksville for his headquarters, no doubt because he regarded it as the post of danger, it being nearer the enemy. But when he was summoned to surrender by a band of guerillas, his constitutional weakness overcame him. He inquired the number of men the enemy had, and receiving a response indicating a force greater than his own he said if he could be satisfied of that fact he would surrender. Arrangements were made for him to count the guerillas, and having satisfied himself that the enemy had the greater force he surrendered and informed his subordinate at Donelson of the fact, advising him to do the same. The guerillas paroled their prisoners and moved upon Donelson, but the officer in command at that point marched out to meet them and drove them away.
Among other embarrassments, at the time of which I now write, was the fact that the government wanted to get out all the cotton possible from the South and directed me to give every facility toward that end. Pay in gold was authorized, and stations on the Mississippi River and on the railroad in our possession had to be designated where cotton would be received. This opened to the enemy not only the means of converting cotton into money, which had a value all over the world and which they so much needed, but it afforded them means of obtaining accurate and intelligent information in regard to our position and strength. It was also demoralizing to the troops. Citizens obtaining permits from the treasury department had to be protected within our lines and given facilities to get out cotton by which they realized enormous profits. Men who had enlisted to fight the battles of their country did not like to be engaged in protecting a traffic which went to the support of an enemy they had to fight, and the profits of which went to men who shared none of their dangers.
On the 30th of August Colonel M. D. Leggett, near Bolivar, with the 20th and 29th Ohio volunteer infantry, was attacked by a force supposed to be about 4,000 strong. The enemy was driven away with a loss of more than one hundred men. On the 1st of September the bridge guard at Medon was attacked by guerillas. The guard held the position until reinforced, when the enemy were routed leaving about fifty of their number on the field dead or wounded, our loss being only two killed and fifteen wounded. On the same day Colonel Dennis, with a force of less than 500 infantry and two pieces of artillery, met the cavalry of the enemy in strong force, a few miles west of Medon, and drove them away with great loss. Our troops buried 179 of the enemy's dead, left upon the field. Afterwards it was found that all the houses in the vicinity of the battlefield were turned into hospitals for the wounded. Our loss, as reported at the time, was forty-five killed and wounded. On the 2d of September I was ordered to send more reinforcements to Buell. Jackson and Bolivar were yet threatened, but I sent the reinforcements. On the 4th I received direct orders to send Granger's division also to Louisville, Kentucky.
General Buell had left Corinth about the 10th of June to march upon Chattanooga; Bragg, who had superseded Beauregard in command, sent one division from Tupelo on the 27th of June for the same place. This gave Buell about seventeen days' start. If he had not been required to repair the railroad as he advanced, the march could have been made in eighteen days at the outside, and Chattanooga must have been reached by the National forces before the rebels could have possibly got there. The road between Nashville and Chattanooga could easily have been put in repair by other troops, so that communication with the North would have been opened in a short time after the occupation of the place by the National troops. If Buell had been permitted to move in the first instance, with the whole of the Army of the Ohio and that portion of the Army of the Mississippi afterwards sent to him, he could have thrown four divisions from his own command along the line of road to repair and guard it.
Granger's division was promptly sent on the 4th of September. I was at the station at Corinth when the troops reached that point, and found General P. H. Sheridan with them. I expressed surprise at seeing him and said that I had not expected him to go. He showed decided disappointment at the prospect of being detained. I felt a little nettled at his desire to get away and did not detain him.
Sheridan was a first lieutenant in the regiment in which I had served eleven years, the 4th infantry, and stationed on the Pacific coast when the war broke out. He was promoted to a captaincy in May, 1861, and before the close of the year managed in some way, I do not know how, to get East. He went to Missouri. Halleck had known him as a very successful young officer in managing campaigns against the Indians on the Pacific coast, and appointed him acting-quartermaster in south-west Missouri. There was no difficulty in getting supplies forward while Sheridan served in that capacity; but he got into difficulty with his immediate superiors because of his stringent rules for preventing the use of public transportation for private purposes. He asked to be relieved from further duty in the capacity in which he was engaged and his request was granted. When General Halleck took the field in April, 1862, Sheridan was assigned to duty on his staff. During the advance on Corinth a vacancy occurred in the colonelcy of the 2d Michigan cavalry. Governor Blair, of Michigan, telegraphed General Halleck asking him to suggest the name of a professional soldier for the vacancy, saying he would appoint a good man without reference to his State. Sheridan was named; and was so conspicuously efficient that when Corinth was reached he was assigned to command a cavalry brigade in the Army of the Mississippi. He was in command at Booneville on the 1st of July with two small regiments, when he was attacked by a force full three times as numerous as his own. By very skilful manoeuvres and boldness of attack he completely routed the enemy. For this he was made a brigadier-general and became a conspicuous figure in the army about Corinth. On this account I was sorry to see him leaving me. His departure was probably fortunate, for he rendered distinguished services in his new field.
Granger and Sheridan reached Louisville before Buell got there, and on the night of their arrival Sheridan with his command threw up works around the railroad station for the defence of troops as they came from the front.
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Hullur Branch Post Office, Jewargio 12, Gulbarga, Karnataka
Hullur Post Office, Jewargio
Hullur post office is located at Hullur, Jewargio, Gulbarga of Karnataka state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Hullur PO is585212. This Postoffice falls under Gulbarga postal division of the Karnataka postal circle. The related head P.O. for this branch office is Gulbarga head post office and the related sub-post office (S.O.) for this branch office is Ghanagapur T post office.
Hullur dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Hullur.
Types of Post Offices
Post offices are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Hullur P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Hullur Post Office & Its Pin Code
Branch Office Information
Hullur Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Hullur Post Office Recruitment
Location Map
Contact Details
About India Post
Hullur Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Hullur Post Office has the Postal Index Number or Pin Code 585212. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Hullur PO Pincode 585 212
The first digit of 585212 Pin Code '5' represents the region, to which this Post Office of Hullur belongs to. The first two digits of the Pin Code '58' represent the sub region, i.e, Karnataka. The first 3 digits '585' represent the post-office revenue district, i.e, Gulbarga. The last 3 digits, i.e, '212' represent the Hullur Delivery Branch Office.
Branch Office Information
The Hullur Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Gulbarga, which falls under North Karnataka region. The circle name for this PO is Karnataka and it falls under Jewargio Taluka and Gulbarga District. The state in which this Dakghar is situated or located is Karnataka. The related head postoffice is Gulbarga post office and the related sub post office is Ghanagapur T post-office. The phone number of Hullur post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Gulbarga Postal Region North Karnataka Postal Circle Karnataka Town / City / Tehsil / Taluka / Mandal Jewargio District Gulbarga State Karnataka Related Sub PO Ghanagapur T Sub Office Related Head PO Gulbarga Head Post Office
Hullur Post Office Services
Traditionally the primary function of Hullur post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Hullur P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Hullur and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Hullur Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Hullur can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Hullur peoples and nearby living people. The premium services provided by Hullur Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Hullur customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Hullur Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Hullur postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Hullur postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Hullur people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Hullur post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Hullur customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Hullur customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Hullur postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Hullur can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Hullur area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Hullur postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Hullur postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/-and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Disclaimer: All the information in this website is published for general information purpose only. Some schemes and other postal services may not be available in Hullur Post Office. Kindly verify for all India post saving schemes and other postal services with official resources.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 09:00 AM or 10:00 AM and the closing time is 06:00 PM or 07:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Hullur Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Hullur people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Hullur Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Hullur postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Hullur Post Office Recruitment
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(PDF) Volodymyr Zelensky: What has Been Done in the Past Year? What’s Next?...
PDF | The paper sets out to assess the first year of Volodymyr Zelensky’s presidency. By analyzing the decision-making process followed by Zelensky... | Find, read and cite all the research you need on ResearchGate
Volodymyr Zelensky: What has Been Done in the Past Year? What’s Next?...
December 2020
Rocznik Integracji Europejskiej14(14):101-112
DOI: 10.14746/rie.2020.14.6
License
CC BY 4.0
Authors:
<here is a image 94d4443dc27f7b18-d1b6e43fe1fda0be>
Łukasz Donaj
Adam Mickiewicz University
Abstract
The paper sets out to assess the first year of Volodymyr Zelensky’s presidency. By analyzing the decision-making process followed by Zelensky (using the decision-making, institutional-legal, systems, induction and deduction methods), the author attempts to answer whether the process serves Ukraine and its long-term interests. By identifying the determinants affecting Ukraine’s foreign policy, the author tries to show the long term prospects for the country.
Content uploaded by Łukasz Donaj
Nr 14ROCZNIK INTEGRACJI EUROPEJSKIEJ2020
DOI : 10.14746/rie.2020.14.6
ŁUKASZ DONAJ
Adam Mickiewicz University in Poznań
ORCID: 0000-0002-7720-1260
Volodymyr Zelensky: What has Been Done in the PastYear?
What’s Next?... 1
Introduction
TadeuszIwański, an analyst from the Centerfor Eastern Studies, has noted that the
political situation in Ukraineafter theRevolution of Dignityandthe ensuing Russian
aggressioncreated apeculiarsocialcontext, inwhichtheperception oftraditional
politicianshasdramaticallychangedfortheworse. Aftertherevolution,thesociety
hasbeeneagerlyexpectingathoroughrecoveryof the state,combinedwithanew
quality ofgovernance andpublic empowerment.However, the2014 presidentialand
parliamentaryelectionschangedlittleintermsofthepoliticalelite,asthemost im -
portant statefunctionsremainedinthehandsofpoliticianswhorst emergedinthe
1990s, whentheoligarchicsystem inUkrainewasbeing formed.Thereforms intro -
duced intherst twotothree yearsafterthe revolution,mainlyunder pressurefrom
Western creditorsand the civil society, did not meetthe society’s needs. Not only did
they failtoimprovethequalityoflife,buteventually ledtotheemigrationofsome
2 millionUkrainians,whichplacedanadditionalburden ontheshouldersoftheold
and new elites.Initiated butnever completed,the painfulreforms have increasedpo -
litical volatility and sapped public trust in the political class evenfurther.A survey by
Kyiv’s RazumkovCentershowedthatjustbeforethepresidentialelectionsonly23
percentofrespondentstrustedthepresident.TheVerkhovnaRadaenjoyedthetrust
of as little as 12 percent, the government – 19 percent, the courts – 12 percent and the
prosecutor’s ofce –15 percent. Such a striking lack ofcondence in state institutions
and politicians sparked a search for“new faces,” people who havea clean record, are
from outside theestablishment and couldmeet diverse expectationsof the society. In
the rststageoftheelectoralcampaign, Ukrainianscouldchoosebetweentwosuch
newcomers:SvyatoslavVakarchuk,leadsingerofOkeanElzy ,apopularUkrainian
rockband,andVolodymyr Zelensky,acomedianandactor. Vakarchuk’sindecision
aboutwhether torunforpresidencyincreasedsupportfortheothercandidate. After
Zelensky formallyannouncedhis candidacytowards theendof 2018,thenumber of
his supporters increased even further. This way, Zelensky became the main contender
in the presidential raceand eventually wonthe rst andthen the second round.In his
1 The paperisanextended,in-depthversionof 12 months of V. Zelensky’s presidency – some
thoughts on his foreign policy ,a lectureprepared for: XІІVseukrayinsʹka Naukovo-Praktychna
– Konferentsiya“ Modernizatsiya Politychnoyi Systemy Sukhasnoyi Ukrayiny: Stan ta Perspektyvy
Rozvytku ” – Ministerstvo Osvityi Nauky Ukrayiny / SkhidnoukrayinsʹkyyNatsionalʹnyy Universitet
Imeni Volodymyra Dalya – m. Syevyerodonetsʹk, Ukrayina – 15.05.2020.
102 ŁukaszDonaj RIE 14 ’20
campaign ZelenskyadvocatedNATOmembership asaguaranteeof Ukraine’ssecu -
rity,although herepeatedly said thatthe move shouldbe precededby a referendum.He
also argued that he wanted his country to join the EU, although in press interviews he
admitted thatno-one in theEU was lookingforward to that.As forthe Donbas conict,
he spoke infavor ofa solution brokeredby the West and the EU.He expressedsimi -
larexpectationswhenaskedaboutregainingcontroloverCrimea,nowoccupiedby
Russia (Grochot, 2019;Ivansky, 2019a; Ivansky, 2019b; Ivansky, Zhochovsky, 2019;
Donaj, 2016, pp. 227–250; Aslund, 2013; Evro Revolyutsyya... , 2013).
Presidency
After the rst 100 days of Zelensky’s presidency, Hanna Bazhenova from the Cen -
tralEuropeanInstitutenotedthattherstmovesoftheUkrainianpresidentshowed
that inpriorityareashewascontinuingthepolicy ofPetroPoroshenko.Theforeign
policy remainedpro-Western, althoughit was notyet certain whether itwould be more
pro-European orpro-American. Foreignvisits tostrategic partnersdemonstrated that
the new president was keen onmaintaining close ties with the EU. Zelenskywas par -
ticularlyactiveincooperatingwithGermanyandtheEuropeanCommission.Quick
establishment ofpersonal relationsbetweenthe newUkrainian presidentand key
world leaders was one of the major achievements ofthe rst 100 days in ofce. At the
same time, Zelensky made attempts to build good relationswith Ukraine’s neighbors.
A good exampleis his visit to Poland (August 31 to September 1, 2019).At a meeting
with the Polish President Andrzej Duda, he announced some concessions to Poland in
the long-standinghistoricaldisputebetweenthetwocountries,well receivedbyPo -
land. He also spoke infavor of resuming the operationsof a working group oncecre -
ated to promotea “clean slate” approachto mutual historicalresentments. The Ukrain -
ianpresidentsawthosetalksasabreakthroughinthebilateralrelations.Zelensky’s
visit to Poland, whichtook place just after 100days of his presidency, in fact marked
the beginning of his independent foreign policy rather than a continuationof what his
predecessor did before him (Bazhenova, 2019).
And what happened in the followingmonths? Interesting views about the rst year
ofZelensky’sinternational policywere presentedin Dzerkalo Tyzhnya by Alyona
Hetʹmanchuk, ananalystandheadoftheNewEuropeCentre(themainthesesfrom
her analysis were cited by Maciej Piotrowski in a paper published by the Freedom In -
stitute). In her opinion, the strengths of Zelensky’s diplomatic policy include:
–thebeginningofthenormalizationofrelationswithWarsaw (admittedlyslow,
mostly due to the electionseason in Poland) and – to someextent – with Budapest;
–continuedsanctionsagainstRussiaandmaintainedfocusontheEUandNATO,
although Zelensky’s opponents had warned he would lose that focus;
–the President’s interpersonal skills, generally appreciatedby his partners; he listens
attentivelyinsteadofdelivering monologues (as Poroshenko often did)andhas
established personal relations with internationalleaders. What endears Zelensky to
them ishis“sincerity, opennessandnaivety, so charminginthecynicalworldof
politics.”
RIE 14 ’20 VolodymyrZelensky:WhathasBeenDoneinthePastYear?... 103
On the other hand, Hetʹmanchuk lists a number of the president’s “liabilities:”
–failure ofthe “investors,not allies” policy(there willbe noinvestors untilthe in -
vestment climate in Ukraine improves);
–difculties in dening international policy priorities: to facilitate negotiations
withRussia,ZelenskynolongerpaintsMoscowasanaggressor. As aresult,his
partners getanambiguous viewofthesituation andalsosoftentheir rhetoric. As
Hetʹmanchuk puts it: “it is unclearwhether Zelensky will manage tostop Russia’s
war against Ukraine,but he denitely managesto bring the West and Russia back
together at a dizzying pace”;
–contradictionbetweentheexternalpriority(goodrelationswiththeUS)andthe
internalpriority(endingthewarwithRussia)(Hetʹmanchuk,2020a;Piotrowski,
2020).
Alyona Hetʹmanchukalso describes thediplomatic style ofZelensky and hisentou -
rage. She notes that he listens to his internaladvisors more closely than to the foreign
ones. Agood example is the dismissal of the prosecutor general despite the objections
ofG7ambassadors. Hetʹmanchukisalsoconcerned aboutthe factthatZelensky’s
political teamhas grownincreasingly criticalof thecountry’s current economicrela -
tions withtheEU,seeing themasharmfulforUkraine. Arguably,thiscriticism may
reduce thegeneralsupportfor Europeanintegration.The analystperceivesZelensky
as a man who is distrustful of his partners and prefers bilateral relations over relations
within internationalinstitutions. Amongotherthings,this preferencemanifestsitself
in informal negotiations with Russia which have somewhat overshadowed the talksin
the Normandyformat(Hetʹmanchuk,2020a; Piotrowski,2020;Petrenko,2020; Sza -
baciuk, 2020).
Anotherimportant development during Zelensky’spresidencywerethegovern -
ment reconstructions. In March 2020, Dmytro Kuleba, the former Deputy Prime Min -
ister for European and Euro-Atlantic Integration, tookover as Head of Diplomacy. He
represents the younger generation of Ukrainian diplomatsand is considered to be one
of the brightest. From 2016to 2019, he served asUkraine’s permanent representative
to the Councilof Europe. However, his role inthe country’sforeign policy will belim -
ited mainly tomanaging the day-to-dayoperations of the ministry, while keydecisions
– especially withregard to thetalks with Russiaand relations with theUS – willstill
be made by Andriy Yermak, Head of thePresidential Ofce, to whomKuleba will be
reporting. The position of the Deputy PrimeMinister for European and Euro-Atlantic
Integration,formerlyheldbyKuleba,wenttoVadymPrystaiko,dismissedfromthe
position of Foreign Ministerin the wake ofa conict with Yermak (interestingly, this
“staff rotation”continued: Prystaiko quiton June 4,2020 and thefollowing month was
appointedAmbassador of Ukraine to the UnitedKingdom; his former position wasof -
fered to Olha V. Stefanyshyna). Despite the personal shake-up, it seems thatthe long-
term foreign policy remains unchanged. According to Daniel Szeligowski, the current
directions of Ukraine’s foreign policy will be maintained. Efforts to solve the Donbas
issueandtoretakecontrolofthecurrentlylostterritorieswillremainapriority. To
that end,bilateraltalks withRussiawill intensify. At thesametime, effortsaimed at
furtherintegrationofUkrainewiththeEUandNATOwillcontinue(publicsupport
for membershipinbothorganizationsis currentlyatanall-timehigh;any changein
104 ŁukaszDonaj RIE 14 ’20
the pro-European policy could cause further erosion of condence in the government,
or even trigger social unrest). On top ofthat, one can expect a greater emphasis on the
economic dimensionof foreignpolicy andco-operation withthe Ukrainian diaspora,
as wellas moreactivepublic diplomacy, somethingthe newforeignminister isvery
good at. Alyona Hetʹmanchuk expresses a similar view on the personnel changes. She
notesthat theHeadof thePresidentialOfce practices“backchannel diplomacy,”
which may“marginalize theMinistry ofForeign Affairs inthedecision-making pro -
cess” (Hetʹmanchuk,2020a; Piotrowski, 2020;Szeligowski, 2020; Rokita,2020; Kule-
ba stane ..., 2019;Rada with 255 ..., 2020; Zelensʹkyypryznachyv..., 2020).
Mixed emotions about Zelensky’s presidency to date can also beheard in the opin -
ions ofother Ukrainianpolitical analysts. Yevhen Mahda, head ofKyiv’s Institute of
WorldPolicy, notesthatthe rst12monthsof Zelensky’spresidencywasatimeof
missed opportunities: “Inmy opinion, it wasis a year ofmissed opportunities, because
not only didhe [the president] enjoyhigh public support, butalso had ‘his’parliament,
‘his’government, a perfectcarte blanche. Unfortunately, no signicant,actual changes
havetakenplace.”AmongZelensky’sachievements,Mahdamentions the newlaw
on the saleof farmland,which opensthe marketas from July1, 2021,and thereturn
ofUkrainian prisonersofwar.Still, heremarksthat the “terms ofPOWexchange
wereunfavorableforUkraine.”Inhisturn,Volodymyr HorbachoftheInstitutefor
Euro-Atlantic Cooperation argues that inrelations with Russia,Zelensky has consist -
ently demonstrated “a policy of retreat, offering unilateral concessions.”According to
Mahda, “thepro-Russian directionhasbeen visiblyreinforcedin Ukrainianpolitics”
after the appointmentof AndriyYermak as head of thepresidential ofce. When asked
about Russia’s attitude towards Zelensky, the expert notes that“Russia does notneed
anyUkrainian presidentwhois capable of playinghisown game.[…]Zelensky’s
teamhas beenbuildingitspolicy bytryingto showtheRussiansthat Zelenskyis
not Poroshenko [...],but without a moreelaborate vision ofhow to protectUkrainian
interests.” AccordingtoMahda,“thearmyhasnotbecomeapriority”forZelensky,
and in the eld of defense there are“serious problems with the state procurement, and
soldiers are inadequately equipped,nanced, and even fed.”The expert points out that
thenumberofsoldierskilledorwoundedintheDonbasconictintheeasternpart
of Ukraineishigherthaninthe sameperiodlastyear. As forinternationalrelations,
Mahda is ofthe opinionthat thecountry’s relations with theUS have beenadversely
affectedby theTrump-Ukrainescandal (causedbyacertain conversationbetween
Trump and Zelensky, which prompted the Democrats in the House of Representatives
toinitiateanimpeachmentinquiryagainsttheUSPresident;Trumpwascharged of
obstructing Congress and abusing the power of his ofce for personal political gains).
Mahdaadds that high-level relations with theEUare formally continued, but “are
not lled with any real meaning.” Horbach, in turn, believes thatthe president tries to
reduce his international presenceand “has delegatedmany of his functions.” Accord -
ing toHorbach,Zelensky’s presidency hasrevolvedaroundPR stunts,andZelensky
himself “isanactorin aTV drama,playingtherole ofpresident.”Mahdanotes that
duringtherstyeartherewereno“breakthrough”Ukrainianinitiativesinbilateral
relations withPoland.However, headmits thatsomeprogress hasbeenmade onthe
issue of exhumations of the victims of the massacres of Polesin Volhynia. Mahda and
RIE 14 ’20 VolodymyrZelensky:WhathasBeenDoneinthePastYear?... 105
Horbach agree thatthere were many personal changes inthe presidential team, includ -
ingthedismissalofprimeministerOleksiyHoncharukandhead ofthe presidential
ofceAndriy Bohdan.According toMahda, the changesare attributable tothe fact that
“Zelensky ispoliticallyinexperiencedand actsspontaneouslytowinmore support.”
However,“Zelensky’ssubstitutes’benchis veryshort.”AccordingtoHorbach,as
many as 30 people from Kvartal 95 (aTV entertainment content company co-founded
by Zelensky) arenow high-ranking stateofcials. “If before theelection Zelensky was
seen as aman of Kolomoisky[IhorKolomoisky, anoligarch], then now hecan be seen
as aman inwhomall oligarchsare interested”–says Mahda.The expertsagreethat
the COVID-19 pandemicactually helped Zelensky. “In the timeof a pandemic, people
want to feelassured by theauthorities and Zelenskyactively uses this”notes Mahda.
Horbachadds thatinemergencysituationslikethispeople“donotthinkrationally”
about what the presidentdoes. He expects that afterthe end of COVID-19 restrictions,
peoplewillresumebusinessasusual, but “in the autumn this economic crisis will
catch up with us and people willstart asking questions” about whether theauthorities
tookappropriatemeasuresduringthe pandemic. “ThechallengesfacedbyUkraine
will not just disappear.” Mahda adds thatKiev will soon feelthe consequences of the
economic crisisand it is notunlikely that laterthis year thegovernment will resignand
earlyparliamentary elections will follow( Ekspert...,2020; YevhenMahda... ,2020;
Volodymyr Horbach ..., 2020).
OtherexpertsfromtheCentreforEastern Studies describetherstyearofZe -
lensky’s presidency as“neither amiraclenor adisaster.” Intheir opinion,in therst
12monthsofhis presidency,Zelenskydemonstratedthatheisneithera puppet of
Kolomoisky, as someofhisopponents suggestedfromthevery beginning,norishe
willing to betraynational interests toRussia. He also managedto pass a numberof key
regulations: newelectorallaw, unbundling ofNaftohaz,or liftingthemoratorium on
farmland sales.Thesereforms couldpositivelyand permanentlychangethepolitical
and economic situation in Ukraine. Although Zelensky’s governance model has failed
to make the most ofthe opportunities offered by thevast political power he enjoys,it
seems that the gradual departurefrom the concept of “newfaces” in personnel policy
will continue. While deoligarchizationis unlikely, further attempts toinvolve the oli -
garchs inthe State’s activitiesmay beexpected. Ifso, theroleof someof them(rst
and foremostRinat Akhmetov)will grow. Thechallenge faced byZelensky’steam will
be tomaintain thecohesion of theruling party(Servant of thePeople) inthe parliament
and towin thelocalelections plannedfor October. Sofar, the partyhasnotmade an
effort to buildlocal structures, andthe regionalgovernors appointedby the president
are weak, especially inthe wealthy regions of Kharkiv and Odessa,which may further
exacerbatetensions between them and Kyiv. As fortheinstitutions responsible for
state securityand the rule oflaw, theirstability will dependon the president’s ability to
control hispersonal ambitions andto put anend to endlessstaff turnover, used asa tool
inshort-termpoliticalstruggle.CounteringRussia’sdestructiveactivitywillremain
a challenge of paramount importance. Moscow will continueits military and non-mil -
itary effortsto destabilize Ukraine, aimed atforcing Ukrainian elites intoacknowledg -
ing Russianpoliticalandeconomicinterests,andultimatelyat ensuringpoliticalsu -
premacy over Ukraine. Kiev will continue to seeka breakthrough in the Donbas talks,
106 ŁukaszDonaj RIE 14 ’20
conrming Zelensky’s genuine intention torestore peace,although atransition to the
announced (albeitenigmatic) “Plan B”is also possible.The president’s main challenge
willbe tofacethe economic consequences oftheCOVID-19 pandemic.Currently
it isdifculttosay howdeeplyUkrainewillbe affected.The IMFforecaststhatthe
country’s GDP will fall by 7.7percent thisyear, but experience showsthat the actual
impact will be greater,especially because in the rst quarter, before thelockdown,the
economyshrankby1.2percent(Iwański,Matuszak,Nieczypor,Żochowski,2020).
Obviously, such cool-headed analysis will notplease thosewho expect statesmanlike
decisionsfrom theheadofthestate.Unfortunately, thetimesaresuchthatheadsof
state aretalented technocrats,atthe verybest. Forgetabout visionaries. Anyway, the
fate(orweourselves?)willusuallysendussomeonewhoisjustskillful(orplainly
speaking:isabletotakeadvicefromhis/herPRteam,usuallyconsistingofhis/her
own people).
Similar viewshave beenexpressed by otherPolish experts.Maciej Zaniewicz
from the Polish Institute ofInternational Affairs (PISM) notes that as promised inthe
electoralcampaign,Zelensky’spriorityhasbeentosolvetheDonbasproblem.The
president hasintensied negotiationswithRussia, alsoatthe bilaterallevel.Ukraine
has not changed its position on the need to regain full control over its territories at the
border with Russia and clearly says that local elections in Donbas can take place only
after Russiantroops withdraw. As a concession,itagreed tothe so-calledSteinmeier
formula, whereby Donbaswill become a special-status territoryon the day of the local
elections. Although themove pavedtheway forthereactivation oftop-level talksin
the Normandy format (France,Germany, Russia, Ukraine)in Paris in December 2019,
thenegotiationsfailedtoproduceabreakthroughduetoRussia’sreluctance.There
was no permanentceasere or “allfor all” prisoner exchange(in total, over 300POWs
were exchanged in three rounds). While mostUkrainians saw the release ofprisoners
as asuccess ofthe president(81percent ofpositive opinions),the concessionsmade
toRussiahavebeengenerallycriticized(Zaniewicz, 2020a; Legucka,Szeligowski,
2019).
Integration with NATO and the EU remains oneof the key objectives of Ukrainian
foreign policy.Zelensky’s rstforeignvisit asPresidenttoBrusselswasasymbolic
conrmation of his pro-Western course. In Brussels, Zelensky met with the leaders of
the twoorganizations. InJune 2020,NATO recognizedUkraine asan EnhancedOp -
portunitiesPartner(EOP),thuscompletingaprocessinitiatedbyPetro Poroshenko.
EOP membershipenablesUkrainetostrengthenitscooperationwithNATO insuch
areas as planning, exercises and information exchange. However, it does not open the
way to NATO membership. Like his predecessor, Zelensky has placed great emphasis
on strengthening the country’s defensecapabilities in the Black Sea area (e.g. through
joint exercises with troopsfrom NATO countries). NATO membershipcontinues to be
Ukraine’sultimate goal. Inkeeping with theagenda announced in October2019 by the
government offormerprimeminister OleksiyHoncharuk(thegovernment ofDenys
Shambhala hasbeen inofce sinceMarch2020), Ukraineintends tomeet EUmem -
bershipconditionsby2024, inter aliabyimplementingthe Association Agreement.
Until then,Ukrainian policytowardsthe EUis tobefocused onsectoral integration,
rst and foremost including the powerindustry and the digital market. TheUkrainian
RIE 14 ’20 VolodymyrZelensky:WhathasBeenDoneinthePastYear?... 107
authorities seethe EasternPartnership asan initiativethat facilitatesintegration with
theEU’sinternal market. In 2021,Ukraineintends to renegotiate tradetermswith
the EU, hopingto seean increasein importquotas and areduction incustoms duties
imposedonUkrainian goods.Ukrainealsocontinuesthe effortsinitiatedbyPetro
Poroshenkoto concludeanAgreementon Conformity Assessmentand Acceptance
of Industrial Products(ACAA) withthe EU, whichwould allowUkrainian industrial
products to enterthe EU market onintra-community terms. OliverVárhelyi, EU Com -
missionerforNeighbourhoodandEnlargementconrmedinMay2020thattheEU
was ready to acceleratethe talks on ACAA.Relations with the US remain essential,as
Ukraine heavily relies onAmerican diplomatic, nancial and military support. During
Zelensky’s presidency, bilateralrelations have beendominated by Ukraine’s involve -
ment in DonaldTrump’simpeachment. Asa result, Trumplost some of hisenthusiasm
for Ukraine,which pushedbackthe prospectofnaming Ukrainea majornon-NATO
ally. Despite this,America’s bipartisan consensus on the need to support Ukrainewas
maintained andthe Congressgranted thecountryanother trancheof US$300million
inmilitary aid for 2020. The USalsoupheld sanctionsagainstRussia (Zaniewicz,
2020a; Szeligowski,2018; Zaniewicz,2020b;Piotrowski, 2019;Verkhovna Rada,
2020; NATOrecognises... , 2020;NATOGrants... , 2020; Hetʹmanchuk, 2020b).
The nextcouple ofweeks mayshow whetherthe Europeancourse, whichignited
theRevolutionofDignity,willbe solidied (although,inthecurrentsituation,ex -
pectations inthis regardshouldbe moderate).In histelephone conversationwiththe
Lithuanian president Gitanas Nausėda, Zelensky spoke about the Ukraine-EU summit
planned for October. As reported by Ukrinform citing theUkrainian president’s press
ofce, he allegedlysaid thatKyiv would aimto resumeworks on renewingthe com -
mercial part of the Association Agreement and to recognize Ukraine’s European aspi -
rations. Zelensky also conrmed that his countrywas ready to maximize the summit’s
efciency andto intensify cooperationwith EU structuresand memberstates. “Among
the key outcomes of the summitI’d like to see the recognitionof Ukraine’s European
aspirations andconclusionof agreementsnecessarytorenew thecommercialpart of
the Association Agreement, asit nolongerreects theeconomicrealities ofUkraine
andthe EU”saidtheUkrainian president in September2020,afew weeksbefore
the planned Ukraine-EUsummit ( Zełenskipowiedział..., 2020; Zelensʹkyyochikuye …,
2020).
Zaniewicz notes that unlike his predecessor, Zelensky puts more emphasis on eco -
nomicdiplomacy, hopingtoattractforeigninvestorsto Ukraine.During hisforeign
visits, heregularlymeets withprivatebusinesses. An investmentforum organizedin
Mariupol in October 2019 was an initiative conceived by the President. Zelensky also
continuessomeoftheinitiativeslaunchedbyPoroshenko.In August2019,Ukraine
signed afree tradeagreement withIsrael, andnegotiations arein progresson similar
agreements withTurkey and theUK. Theexistingfree tradeagreement withCanada
istobeextended.Meanwhile,thenew foreign ministerDmytroKuleba,appointed
tothepostinMarch2020,declaredhisintentiontostrengthentraderelationswith
Asian countries. However, the economicdiplomacy offensive has notbrought tangible
results so farin theform offoreign investors’ greater interest inUkraine, mainly due
tothecountry’s internalproblems,suchasubiquitous corruption.Aspreviouslyan -
108 ŁukaszDonaj RIE 14 ’20
nounced,Zelenskyhastakenstepstoimproverelationswithneighboringcountries.
InOctober2019,Ukrainegavepermissiontoresume thesearchandexhumationof
Polish victims on its territory, which improved the relationswith Poland. At the same
time, Ukrainebegantheprocess ofadjustingits lawsoneducationand minoritiesto
the recommendations ofthe Venice Commission,especially with regardto languages
of instruction. This haseased the tensionswith Hungary and ledto the resumptionof
bilateral dialogue (upto theministerial level)between thetwo countries.One ofdis -
cussed issues islifting Hungary’s banon the work ofthe NATO-Ukraine Commission.
The current Ukrainiangovernment, just likeits predecessor, has expressedinterest in
regional cooperation with neighboringcountries, especially Poland – forinstance with
regard to the construction of Via Carpatia, the E40 water route (ultimately connecting
the Black Sea with the BalticSea) or LNG imports from the US via Poland. InAugust
2019,Ukraine signedatrilateral memorandumonenergycooperationwith Poland
and the US. Conversely, the Ukrainian authorities consideredthe Ukraine-EU “energy
bridge” (a projectpromoted during thepresidency ofPetro Poroshenko) asno longer
valid (Zaniewicz, 2020a; Szeligowski, Jóźwiak, 2018).
What’s next?...
In a study called InternalDeterminantsofUkraine’sForeignPolicyunderVolody -
myr Zelensky , Tomasz Stępniewski wonders whether theforeign policy of Ukraine led
by Volodymyr Zelensky will be different than in the last three decades:
Inanswering thisquestion,itisimportanttokeepinmindtherathercomplex
situation of contemporaryUkraine. To better understand Ukraine’s internal and
externalconsiderations, let us refertoMykola Riabchuk, who once said that
a ‘warofcivilizations’ istakingplaceinUkraine. HenotesthatUkrainemust
make acivilizationalchoice.Itisnotonly achoicebetweenthe“Russianele -
ment” andthe“Ukrainian element,”but also–between the“CentralEuropean
project” and the “post-Soviet project.” Mykola Riabchuk believes that “Ukraine
is historicallypartofCentral Europe.Thepost-Soviet alternative,ontheother
hand,istantamountto searching forsome kind ofseparate Eastern European
identity:itis a melting pot ofOrthodox Church, nostalgia for theUSSRand
othercontradictions.” Therefore, the powerstrugglebetween politicalparties
is secondary(atacticalobjective), whilethetruenature ofthedilemmalies in
the need to make a strategic choice. The following question must beasked: will
theEuromaidanandtheongoing–armedconictwithRussiamake European
integration apermanentdirection inUkraine’s foreignpolicy? Orwillthe lack
of clear declarationsfrom the EU onthe prospects formembership for Ukraine
lead to the emergence of political forces that will not pursue this direction? Zel -
ensky’s electoralvictoryapparentlyindicatesthat Ukraine ismoving towards
European integration.The coming months, orrather the coming years,will show
whether ornot thisis asustainable trend(Stępniewski,2019, pp.137–139; Ri -
abchuk, 2004, pp. 12–13).
Once again, letus quote Maciej Zaniewicz fromPISM. The expert emphasizesthat
despite little progressin negotiations with Russiaon the Donbas conict,its resolution
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Subsets and Splits