text:
Talk:Science (journal)

Science magazine
The page Science magazine is currently a redirect to List of science magazines (incidentally, this article was not in that list, so I added it). Methinks the redirect should probably be to here (article). Comments? Enquire (talk) 02:17, 5 March 2015 (UTC)

 * The name of this publication is Science, not Science Magazine, so the specific addition you made to List of science magazines is incorrect. But whether Science should be there is also problematic: that list is about publications for non-expert audiences, while Science is a scientific journal and thus explicitly excluded from that list. (Note that Nature (journal) is also excluded.) Of course, everyone is a non-expert outside of their specific area, and so much of the news, commentatry, etc., in Science is written for such a non-expert (albeit well-informed) audience. But I think we should respect the exclusion of what are primarily scientific journals. ~ J. Johnson (JJ) (talk) 21:30, 5 March 2015 (UTC)

Irony
Am I the only one who finds the 'lack-of-citations notice' ironic? Also, can we please clean up the talk page so we can get rid of that four year old orange bar at the top of the main article?

137.54.23.191 (talk) — Preceding undated comment added 18:55, 26 April 2015 (UTC)

 * Yes, it was time to archive. I have done that.

 * Note to the anonymous IP if s/he should pass by again:

 * 1) New discussions should always be added at the bottom of the talk page.
 * 2) Please sign your comments with the "four tildes" (" ~ ").
 * 3) Removal of the "orange bar" (the 'refimprove' tag) is contingent on someone deciding whether there is still a need for additional citations, such as unsourced material. You could do this yourself, but please check that you understand the applicable policies (e.g., WP:Verifiability and WP:Reliable sources).
 * ~ J. Johnson (JJ) (talk) 20:01, 26 April 2015 (UTC)

Removed tag
I decided to be WP:BOLD and remove the maintenance tag placed on this article way back in 2011. There is no specific problem that the tag mentions that needs to be addressed other than more citations are needed (it still seems kind of general). And there is no related talk page discussion that I can see (see Archive 1). In answer to the tag - there are plenty of references and citations that support the text in this article - so this article is probably (and hopefully) much improved since the date of the tag - 2011. Feel free to discuss here if necessary. ---Steve Quinn (talk) 21:01, 5 June 2016 (UTC)

 * Fine with me. ~ J. Johnson (JJ) (talk) 23:23, 5 June 2016 (UTC)

Move discussion in progress
There is a move discussion in progress on Talk:Science (magazine) which affects this page. Please participate on that page and not in this talk page section. Thank you. —RMCD bot 23:31, 1 September 2017 (UTC)
 * That (now closed) discussion is now found at Talk:Science (1979–1986 magazine). —BarrelProof (talk) 19:34, 18 September 2017 (UTC)

"The journal Science" listed at Redirects for discussion
An editor has asked for a discussion to address the redirect The journal Science. Please participate in the redirect discussion if you wish to do so. Utopes (talk / cont) 02:03, 20 February 2020 (UTC)

Cover image
Per 's recommendation on my talk, I've opened a discussion on the cover image here. I uploaded the cover of the latest issue of Science, in place of the image from the discontinued series from about 130 years ago. Headbomb reverted saying that as the first issue offers more historical significance, it should be preferred over the latest issue. If the cover was maybe from 10 or even 20 years ago of a significant point, I would agree. However this cover is 130 years old, and in no way represents the branding, style and design used in Science today. A more recent cover would definitely offer more usage to the reader. WP:NFCCP #8 states that Contextual significance. Non-free content is used only if its presence would significantly increase readers' understanding of the article topic, and its omission would be detrimental to that understanding. I believe a cover from 130 years ago does not increase a reader's understanding of the topic more than one of more recent, that represents the current journal. WP:NFCI #1's footnote states cover art implicitly satisfies the "contextual significance" NFCC criterion (NFCC#8) by virtue of the marketing, branding, and identification information that the cover conveys. Using the cover of a discontinued edition that doesn't share anything with the current cover doesn't provide the same contextual significance as one that has the current the marketing, branding, and identification information that the cover conveys. I think for the reasons above, the more up to date cover should be used (it's here if anyone wants to see it), however consensus seems to be needed for this, and I don't think FFD is the correct forum for this now. — Berrely  • Talk∕Contribs 09:30, 29 July 2021 (UTC)

 * Also, and quite importantly that is, the original cover is in the public domain, whereas the new ones are copyrighted, and the new covers fail NFCC Criteria #1: No free equivalent (and all 10 criteria must be satisfied, an image is not given a pass just because it satisfies some of them). A recent cover does not illustrate or identify the topic better than an old one, especially given that is a very historied publication, that dates way back.   Headbomb {t · c · p · b} 09:38, 29 July 2021 (UTC)
 * See also WP:FREER.   Headbomb {t · c · p · b} 09:42, 29 July 2021 (UTC)
 * I don't think that a cover that in no way represents the current publication would be considered a "free equivalent". The current publications has completely different branding and identification, which is not provided with an older cover. The article already includes older covers, so the content is already in other parts of the article. WP:FREER asks whether Can this non-free content be replaced by a free version that has the same effect?. I do not think that the first cover has the same effect as the current cover. — Berrely  • Talk∕Contribs 09:46, 29 July 2021 (UTC)
 * Put differently, is this the cover of Science? If yes, it has identified the publication. That it is not a recent cover is not relevant.   Headbomb {t · c · p · b} 09:50, 29 July 2021 (UTC)
 * If you really think using a century old cover is better, I guess I can't do much. I'll just go improve other articles. — Berrely  • Talk∕Contribs 09:52, 29 July 2021 (UTC)
 * It's not a matter of better or worse, it's a matter of qualifying for fair use or not. We're aiming to be the free encyclopedia, and when free content is available, we must work with it, to the detriment of prettier, but non-free images.   Headbomb {t · c · p · b} 09:57, 29 July 2021 (UTC)
 * Yep. A modern cover might be better from a graphics standpoint, but the legal situation with the old cover is better, and that wins out. If Science is unhappy that we're making them look old, they can license an example of a modern cover for us. XOR'easter (talk) 22:54, 29 July 2021 (UTC)
 * I think a reasonable fair use rationale can be advanced for the modern cover. The difference in appearance is to such an extent that it serves a different encyclopedic purpose under NFCC#1, and NFCC#8 is satisfied as an illustration of marketing/branding that NFCI states. I will admit that second-guessed myself about this article's topic (whether this was about the modern magazine/journal that I knew) when I first read it, just based on the first volume cover in the infobox. I believe there is a distinct encyclopedic value for the modern cover as identification and its now-familiar striking use of images, just as there is with the infobox image at The New York Times (and various other articles on old newspapers). At the very least, the infobox should use the modern PD logo, and the historical cover should be moved to the body. — Goszei (talk) 19:08, 29 July 2021 (UTC)
 * Another solution would be finding a modern cover of Science that features an image licensed by Creative Commons, like at our article on Nature (journal). — Goszei (talk) 19:17, 29 July 2021 (UTC)
 * I agree with the OP that a newer cover would better convey marketing, branding, and identification information, while an older cover would better convey historical significance. I know which of these I think is more important, and it's not whatever some corporate PR people cooked up recently.  So I support Headbomb's reversion, regardless of any questions about fair use. --JBL (talk) 20:07, 29 July 2021 (UTC)
 * It doesn't have to be a binary, consider how our article on The Lancet makes use of images. — Goszei (talk) 21:54, 29 July 2021 (UTC)
 * Well, it uses them badly (all the interesting and significant images are thrown together in a pile at the bottom, not used to illustrate anything in the text) but I take your point. I don't object on principle to including newer covers in the article, as well.  For that matter, I would also support swapping the two pictures (1882 and 1883) currently in the article so at the better-quality 1883 image appears first, in the infobox, and the blurrier original cover appears in the first section.--JBL (talk) 11:54, 30 July 2021 (UTC)
 * The original is the most important one. And at 150px or so, there's very little perceivable difference.   Headbomb {t · c · p · b} 15:49, 30 July 2021 (UTC)
 * I prefer the 1880 version that Headbomb reverted back to. It has historical significance. Also, we are supposed to use the free version for any article when it is available. I don't think this takes away from the "brand" or "branding" of Science. This is clearly a front cover image of an issue of Science magazine. And I think it is best to keep in mind the reader, for whom this image is meant imho. ---Steve Quinn (talk) 01:45, 30 July 2021 (UTC)

Cover image (2)

Following up on the previous discussion, I have uploaded a 2020 cover of Science that uses a NASA image as its cover, and is therefore in the public domain (like it was done on Nature). I propose that this image replace the current image in the infobox, and that the current image be moved into the History section. The previous discussion centered on the argument that a non-fair image fail NFCC#1 (a fair point), which would not apply anymore. Per MOS:LEADIMAGE, the infobox image should be representative of its subject, and arguably a image showing the current cover layout is more representative to modern readers. In an article about a city or building, you would show an image that shows how it looks now, and not 200 years ago. Older pictures would belong in the History section. Pinging, , , , and  as participants of the previous discussion. intforce (talk) 23:52, 2 February 2022 (UTC)
 * Personally, I prefer the historic first issue cover in the infobox, as more interesting and more historical/encyclopedic in value. I don't object to having a modern cover around, just elsewhere. Others may have a different opinion.   Headbomb {t · c · p · b} 23:57, 2 February 2022 (UTC)
 * I support using a modern cover in the infobox and placing the first issue cover in the body. As intforce argues, a modern cover is most representative (some articles like The New York Times go even further, and find a non-free rationale in using a modern cover because it is distinct enough from the 1851/1914 versions). Thanks for the find. — Goszei (talk) 00:08, 3 February 2022 (UTC).
 * Just because one image used to make the cover is in the public domain, that doesn't mean the cover itself, a derivative work, is also in the public domain. NASA didn't put "Science" on top of their picture or choose any of the other wording that describes the inside of that issue of the journal. A fair-use rationale has to be advanced for the derivative work, just like for any other magazine cover. XOR'easter (talk) 01:30, 3 February 2022 (UTC)
 * The question is whether the derivative work crosses the threshold of originality, seeing as it is just text. If not, the derivative image would also be in the public domain. You are welcome to open a Commons deletion request so we can settle that question. I have followed the same procedure that was used on the Nature cover. intforce (talk) 08:36, 3 February 2022 (UTC)
 * Perhaps we could have a similar radio box image switch system like with location maps? One of them could be the default and the other could be shown by selecting the respective radio button. — Berrely  • Talk∕Contribs 11:29, 3 February 2022 (UTC)
 * The licensing for this image is incorrect. It is a fair use image and the copyright is owned by Science magazine or AAAS. The NASA image is public domain. But this magazine cover is not public domain. Again, I think the historic magazine cover image should be kept because it is in the public domain. This is in agreement with Wikipedia's goal of free images. Please stop playing games with fair use images and so on. ---Steve Quinn (talk) 15:34, 6 February 2022 (UTC)

Proposed changes
Could the updates below be made to the following?

Introductory Paragraph

1. Change both references to SCI as an “academic journal” to “scholarly journal” in the first sentence.

2. Update the second sentence’s note regarding circulation to read “…currently circulated weekly in print and updated daily online..”

3. Change the first sentence of the second paragraph to read “The major focus of the journal is publishing important original scientific research and research reviews along with science-related news, science policy and commentary on or the wide implications of science and technology.”

4. Update the impact factor in the third sentence of the second paragraph to “Science’s 2021 impact factor was 63.832.”

5. Add a corresponding reference for the impact factor to: https://jcr.clarivate.com/jcr-jp/journal-profile?journal=SCIENCE&year=2021&fromPage=%2Fjcr%2Fbrowse-journals

6. If needed (and appropriate), the reference to the acceptance rate could be cited using the official journal metrics page: https://www.science.org/content/page/journal-metrics

7. Edit the last sentence in this section to read “Science is based in Washington, D.C., United States, with offices in Cambridge, UK and Beijing, PRC.”

History

8. Add a sentence to the fifth paragraph: “AAAS opened offices in Cambridge, UK and Beijing, PRC to support Science’s international body of authors.”

9. Move the last sentence “Former Washington University in St. Louis….” to the end of the fourth paragraph (which lists the most recent editors).

Availability

10. Change the last sentence of the last paragraph to read: “Science’s First Release feature provides advance electronic publication…” and remove the link to the Phys.org reference.

a. If appropriate, this is the link to the page with the most current First Release papers: https://www.science.org/toc/science/0/0

Mphelan123 (talk) 19:36, 4 April 2023 (UTC)
 * 5 is under a paywall, FYI. PK650 (talk) 04:55, 4 June 2023 (UTC)
 * Yellow check.svg Partly done: Requested additions are not supported by reliable sources with the exception of 5) (which is pay-walled). Throast  {  { ping }} me! (talk | contribs) 15:01, 25 June 2023 (UTC)

Additional Proposed Changes
Hello!

We have some additional edit requests, listed below. Please let me know if I can provide rationale, additional information, etc.!

Bolded text indicates additions/edits to text.

Summary

 * 1) Request: Could we add the following sentence to the end of the “Summary” section?  “The journal is part of the Science Family of Journals, of which Holden Thorp is the Editor-in-Chief.”?
 * 2) Reason: For context -The Science journals have an overall Editor in Chief (Holden Thorp), but each journal is then managed by individual Editors who we prefer not to list.
 * 3) Link: https://www.science.org/content/page/leadership-and-management#HoldenThorp

 * 1) Request: Please move the sentence currently in the “Contents” section to the end of the “Summary” section, and update the Impact Factor and associated reference: “According to the Journal Citation Reports, the journal has a 2022 impact factor of 56.9.”
 * 2) Reason: The IF is old and needs to be updated.
 * 3) Link: https://jcr.clarivate.com/jcr-jp/journal-profile?journal=SCIENCE&year=2022&fromPage=%2Fjcr%2Fhome

Scope

 * 1) Request: Please create a “Scope” section separate from the “Contents” section.
 * 2) Reason: We’re aiming to have the structure of the pages as consistent as possible across the journals.

 * 1) Request: If this is possible, please move the scope text from the “Contents” section into the “Scope” section: “The major focus of the journal is publishing important original scientific research and research reviews, but Science also publishes science-related news, opinions on science policy and other matters of interest to scientists and others who are concerned with the wide implications of science and technology. Unlike most scientific journals, which focus on a specific field, Science and its rival Nature cover the full range of scientific disciplines.”

History

 * 1) Request: Would it be possible to update “In 2015 Rush D. Holt Jr., chief executive officer” to “In 2015 Rush D. Holt Jr., then chief executive officer…”
 * 2) Reason: This clarifies that Holt is no longer CEO.

Availability

 * 1) Request: Please update the sentence regarding the categories of articles made free to read:   “Significant public-health related articles and articles that report the reference sequence of a genome are also available for free immediately after publication.”
 * 2) Reason: This more accurately reflects the journal's access policies.
 * 3) Link: https://www.science.org/content/page/open-access-aaas

 * 1) Request: Please update the first section of the third paragraph and its associated references to read: “Other features of the Science website include the "News from Science" section with "up to the minute news from science"((https://www.science.org/news) commentary (https://www.science.org/commentary) , the freely-accessible Science Podcast (https://www.science.org/podcasts), and "ScienceCareers", which provides free career resources for scientists and engineers.
 * 2) Reason: This more accurately represents the sections and features Science currently has. Additionally, "ScienceNow" no longer exists and is now referred to as News from Science;

 * 1) Request: Scienceexpress no longer runs; would it be possible to remove the link and reference to this?
 * 2) Reason: Scienceexpress is no longer active.

Right Rail

 * 1) Request: Please update the impact factor to 2022’s numbers (56.9).
 * 2) Link: https://jcr.clarivate.com/jcr-jp/journal-profile?journal=SCIENCE&year=2022&fromPage=%2Fjcr%2Fhome

Mphelan123 (talk) 18:37, 22 September 2023 (UTC)

Reply 23-SEP-2023

 * Your edit request could not be reviewed because the provided references are not formatted correctly. The citation style predominantly used by the Science (journal) article is Citation Style 1 (CS1). The citation style used in the edit request consists of bare URL's. Any requested edit of yours which may be implemented will need to resemble the current style already in use in the article – in this case, CS1. (See WP:CITEVAR.) In the extended section below titled Citation style, I have illustrated two examples: one showing how the edit request was submitted, and another showing how requests should be submitted in the future:

Bare URL reference formatting: The Sun's diameter is 864,337 miles,[1] while the Moon's diameter is 2,159 miles.[2] The Sun's temperature is 5,778 Kelvin.[3]

References

1. 2.  3.

In the example above there are three URL's provided with the claim statements, but these URL's have not been placed using Citation Style 1, which is the style predominantly used by the Science (journal) article. Using this style, the WikiFormatted text should resemble the following:

Citation Style 1 formatting: The Sun's diameter is 864,337 miles, while the Moon's diameter is 2,159 miles. The Sun's temperature is 5,778 Kelvin. Which displays as: The Sun's diameter is 864,337 miles,[1] while the Moon's diameter is 2,159 miles.[2] The Sun's temperature is 5,778 Kelvin.[3]

References

^ Sjöblad, Tristan. . Academic Press, 2020, p. 1. ^ Harinath, Prisha. (2020)., Science, 51(78):46. ^ Uemura, Shū. . Academic Press, 2020, p. 2.

In the example above the references have been formatted according to Citation Style 1, which shows the author, the source's name, date, etc., all information which is lost when only the links are provided. As Wikipedia is a volunteer project, edit requests such as yours are generally expected to have this formatting done before the request is submitted for review.

Kindly resubmit the edit request below at your earliest convenience, taking care to ensure that it makes use of CS1. If you have any questions about this formatting please don't hesitate to ask myself or another editor. Additionally, the COI editor is invited to disclose the nature of their COI on their talk page per WP:COIDISCLOSE. Regards, Spintendo  22:46, 23 September 2023 (UTC)

title: Talk:Science (journal)


text:
User:Ooguy

Thanks for experimenting with Wikipedia. Your test worked, and has been reverted or removed. Please use the sandbox for any other tests you want to do. Take a look at the welcome page if you would like to learn more about contributing to our encyclopedia. Thanks.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: User:Ooguy


text:
Anadyr

Anadyr may refer to:
 * Anadyr (town), a town and the administrative center of Chukotka Autonomous Okrug, Russia
 * Anadyr District
 * Anadyr Estuary
 * Anadyr (river), a river in Chukotka Autonomous Okrug, Russia
 * Anadyr Highlands
 * Anadyr Lowlands
 * Anadyr, a Russian steamship
 * Operation Anadyr
 * Gulf of Anadyr

title: Anadyr


text:
Alpha-synuclein

Alpha-synuclein (aSyn) is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly in the axon terminals of presynaptic neurons. Within these terminals, alpha-synuclein interacts with phospholipids and proteins. Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.

In Parkinson's disease and other synucleinopathies, insoluble forms of alpha-synuclein accumulate as inclusions in Lewy bodies.

Familial Parkinson's disease is associated with mutations in the -synuclein (SNCA) gene. In the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids.

The human alpha-synuclein protein is made of 140 amino acids. An alpha-synuclein fragment, known as the non-amyloid beta (non-Abeta) component (NAC) of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, was shown to be a fragment of its precursor protein, NACP. It was later determined that NACP is the human homologue of synuclein in electric rays, genus Torpedo. Therefore, NACP is now referred to as human alpha-synuclein.

Tissue expression
Alpha-synuclein is a synuclein protein primarily found in neural tissue, making up as much as one percent of all proteins in the cytosol of brain cells. It is expressed highly in neurons within the frontal cortex, hippocampus, striatum, and olfactory bulb, but can also be found in the non-neuronal glial cells. In melanocytes, SNCA protein expression may be regulated by microphthalmia-associated transcription factor (MITF).

It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus. Synuclein is however found predominantly in the presynaptic termini, in both free or membrane-bound forms, with roughly 15% of synuclein being membrane-bound at any moment in neurons.

It has also been shown that alpha-synuclein is localized in neuronal mitochondria. Alpha-synuclein is highly expressed in the mitochondria in olfactory bulb, hippocampus, striatum and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on complex I activity of the mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.

At least three isoforms of synuclein are produced through alternative splicing. The majority form of the protein, and the one most investigated, is the full-length protein of 140 amino acids. Other isoforms are alpha-synuclein-126, which lacks residues 41-54 due to loss of exon 3; and alpha-synuclein-112, which lacks residues 103-130 due to loss of exon 5.

In the enteric nervous system (ENS)
First characterisations of aSyn aggregates in the ENS of PD patients has been performed on autopsied specimens in the late 1980s. It is yet unknown if the microbiome changes associated with PD are consequential to the illness process or main pathophysiology, or both.

Individuals diagnosed with various synucleinopathies often display constipation and other GI dysfunctions years prior to the onset of movement dysfunction.

Alpha synuclein potentially connects the gut-brain axis in Parkinson's disease patients. Common inherited Parkinson disease is associated with mutations in the alpha-synuclein (SNCA) gene. In the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids.

The Enterobacteriaceae, which are quite common in the human gut, can create curli, which are functional amyloid proteins. The unfolded amyloid CsgA, which is secreted by bacteria and later aggregates extracellularly to create biofilms, mediates adherence to epithelial cells, and aids in bacteriophage defense, forms the curli fibers. Oral injection of curli-producing bacteria can also boost formation and aggregation of the amyloid protein Syn in old rats and nematodes. Host inflammation responses in the intestinal tract and periphery are modulated by curli exposure. Studies in biochemistry show that endogenous, bacterial chaperones of curli are capable of briefly interacting with Syn and controlling its aggregation.

The clinical and pathological findings support the hypothesis that aSyn disease in PD occurs via a gut-brain pathway. For early diagnosis and early management in the phase of creation and propagation of aSyn, it is therefore of utmost importance to identify pathogenic aSyn in the digestive system, for example, by gastrointestinal tract (GIT) biopsies.

According to a growing body of research, intestinal dysbiosis may be a major factor in the development of Parkinson's disease by encouraging intestinal permeability, gastrointestinal inflammation, and the aggregation and spread of asyn.

Not just the CNS but other peripheral tissues, such as the GIT, have physiological aSyn expression as well as its phosphorylated variants. As suggested by Borghammer and Van Den Berge (2019), one approach is to recognise the possibility of PD subtypes with various aSyn propagation methods, including either a peripheral nervous system (PNS)-first or a CNS-first route.

While the GI tract has been linked to other neurological disorders such autism spectrum disorder, depression, anxiety, and Alzheimer's disease, protein aggregation and/or inflammation in the gut represent a new topic of investigation in synucleinopathies.

Structure
Alpha-synuclein in solution is considered to be an intrinsically disordered protein, i.e. it lacks a single stable 3D structure. As of 2014, an increasing number of reports suggest, however, the presence of partial structures or mostly structured oligomeric states in the solution structure of alpha-synuclein even in the absence of lipids. This trend is also supported by a large number of single molecule (optical tweezers) measurements on single copies of monomeric alpha-synuclein as well as covalently enforced dimers or tetramers of alpha-synuclein.

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement. It has been shown that alpha-synuclein significantly interacts with tubulin, and that alpha-synuclein may have activity as a potential microtubule-associated protein, like tau. Evidence suggests that alpha-synuclein functions as a molecular chaperone in the formation of SNARE complexes. In particular, it simultaneously binds to phospholipids of the plasma membrane via its N-terminus domain and to synaptobrevin-2 via its C-terminus domain, with increased importance during synaptic activity. Indeed, there is growing evidence that alpha-synuclein is involved in the functioning of the neuronal Golgi apparatus and vesicle trafficking.

Apparently, alpha-synuclein is essential for normal development of the cognitive functions. Knock-out mice with the targeted inactivation of the expression of alpha-synuclein show impaired spatial learning and working memory.

Interaction with lipid membranes
Experimental evidence has been collected on the interaction of alpha-synuclein with membrane and its involvement with membrane composition and turnover. Yeast genome screening has found that several genes that deal with lipid metabolism and mitochondrial fusion play a role in alpha-synuclein toxicity. Conversely, alpha-synuclein expression levels can affect the viscosity and the relative amount of fatty acids in the lipid bilayer.

Alpha-synuclein is known to directly bind to lipid membranes, associating with the negatively charged surfaces of phospholipids. Alpha-synuclein forms an extended helical structure on small unilamellar vesicles. A preferential binding to small vesicles has been found. The binding of alpha-synuclein to lipid membranes has complex effects on the latter, altering the bilayer structure and leading to the formation of small vesicles. Alpha-synuclein has been shown to bend membranes of negatively charged phospholipid vesicles and form tubules from large lipid vesicles. Using cryo-EM it was shown that these are micellar tubes of ~5-6 nm diameter. Alpha-synuclein has also been shown to form lipid disc-like particles similar to apolipoproteins. EPR studies have shown that the structure of alpha synuclein is dependent on the binding surface. The protein adopts a broken-helical conformation on lipoprotein particles while it forms an extended helical structure on lipid vesicles and membrane tubes. Studies have also suggested a possible antioxidant activity of alpha-synuclein in the membrane. Membrane interaction of alpha-synuclein modulates or affects its rate of aggregation. The membrane-mediated modulation of aggregation is very similar to that observed for other amyloid proteins such as IAPP and abeta. Aggregated states of alpha-synuclein permeate the membrane of lipid vesicles. They are formed upon interaction with peroxidation-prone polyunsaturated fatty acids (PUFA) but not with monounsaturated fatty acids and the binding of lipid autoxidation-promoting transition metals such as iron or copper provokes oligomerization of alpha-synuclein. The aggregated alpha-synuclein has a specific activity for peroxidized lipids and induces lipid autoxidation in PUFA-rich membranes of both neurons and astrocytes, decreasing resistance to apoptosis. Lipid autoxidation is inhibited if the cells are pre-incubated with isotope-reinforced PUFAs (D-PUFA).

Function
Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in restricting the mobility of synaptic vesicles, consequently attenuating synaptic vesicle recycling and neurotransmitter release. An alternate view is that alpha-synuclein binds to VAMP2 (a synaptobrevin) and stabilizes SNARE complexes;  though recent studies indicate that alpha-synuclein–VAMP2 binding is critical for alpha-synuclein-mediated attenuation of synaptic vesicle recycling, connecting the two seemingly divergent views. It may also help regulate the release of dopamine, a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.

Alpha-synuclein modulates DNA repair processes, including repair of double-strand breaks (DSBs). DNA damage response markers co-localize with alpha-synuclein to form discrete foci in human cells and mouse brain. Depletion of alpha-synuclein in human cells causes increased introduction of DNA DSBs after exposure to bleomycin and reduced ability to repair these DSBs. In addition, alpha-synuclein knockout mice display a higher level of DSBs, and this problem can be alleviated by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein promotes the DSB repair pathway referred to as non-homologous end joining. The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death.

Proneurogenic function of alpha-synuclein
In some neurodegenerative diseases, alpha-synuclein produces insoluble inclusion bodies. These diseases, known as synucleinopathies, are connected with either higher levels of normal alpha-synuclein or its mutant variants. The normal physiological role of Snca, however, has not yet been thoroughly explained. In fact, physiological Snca has been demonstrated to have a neuroprotective impact by inhibiting apoptosis induced by several types of apoptotic stimuli, or by regulating the expression of proteins involved in apoptotic pathways. Recently it has been demonstrated that up-regulation of alpha-synuclein in the dentate gyrus (a neurogenic niche where new neurons are generated throughout life) activates stem cells, in a model of premature neural aging. This model shows reduced expression of alpha-synuclein and reduced proliferation of stem cells, as is physiologically observed during aging. Exogenous alpha-synuclein in the dentate gyrus is able to rescue this defect. Moreover, alpha-synuclein also boosts the proliferation of dentate gyrus progenitor neural cells in wild-type young mice. Thus, alpha-synuclein represents an effector for neural stem and progenitor cell activation. Similarly, alpha-synuclein has been found to be required to maintain stem cells of the SVZ (subventricular zone, i.e., another neurogenic niche) in a cycling state.

Sequence
Alpha-synuclein primary structure is usually divided in three distinct domains:
 * Residues 1-60: An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequence KTKEGV. This sequence has a structural alpha helix propensity similar to apolipoproteins-binding domains. It is a highly conserved terminal that interacts with acidic lipid membranes, and all the discovered point mutations of the SNCA gene are located within this terminal.
 * Residues 61-95: A central hydrophobic region which includes the non-amyloid-β component (NAC) region, involved in protein aggregation. This domain is unique to alpha-synuclein among the synuclein family.
 * Residues 96-140: a highly acidic and proline-rich region which has no distinct structural propensity. This domain plays an important role in the function, solubility and interaction of alpha-synuclein with other proteins.

Autoproteolytic activity
The use of high-resolution ion-mobility mass spectrometry (IMS-MS) on HPLC-purified alpha-synuclein in vitro has shown alpha-synuclein to be autoproteolytic (self-proteolytic), generating a variety of small molecular weight fragments upon incubation. The 14.46 kDa protein was found to generate numerous smaller fragments, including 12.16 kDa (amino acids 14–133) and 10.44 kDa (40–140) fragments formed through C- and N-terminal truncation and a 7.27 kDa C-terminal fragment (72–140). The 7.27 kDa fragment, which contains the majority of the NAC region, aggregated considerably faster than full-length alpha-synuclein. It is possible that these autoproteolytic products play a role as intermediates or cofactors in the aggregation of alpha-synuclein in vivo.

Clinical significance
Alpha synuclein, having no single, well-defined tertiary structure, is an intrinsically disordered protein, with a pI value of 4.7, which, under certain pathological conditions, can misfold in a way that exposes its core hydrophobic residues to the intracellular milieu, thus providing the opportunity for hydrophobic interactions to occur with a similar, equally exposed protein. This could lead to self assembly and subsequent aggregation into large, insoluble fibrils known as amyloids. The conversion of soluble alpha synuclein into highly ordered, cross-β sheet, fibrillar structures does not, as previously thought, follow a two-step mechanism, rather, occurs through a series of transient, soluble oligomeric intermediates. In 2011, two groups published their findings that unmutated α-synuclein forms a stably folded tetramer that resists aggregation, asserting that this folded tetramer represented the relevant in vivo structure in cells, thereby relieving alpha synuclein of its disordered status. Proponents of the tetramer hypothesis argued that in vivo cross-linking in bacteria, primary neurons and human erythroleukemia cells confirmed the presence of labile, tetrameric species. However, despite numerous in-cell NMR reports demonstrating that alpha synuclein is indeed monomeric and disordered in intact E. coli cells,     it is still a matter of debate in the field despite an ever growing mountain of conflicting reports. Nevertheless, alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These disorders are known as synucleinopathies. In vitro models of synucleinopathies revealed that aggregation of alpha-synuclein may lead to various cellular disorders including microtubule impairment, synaptic and mitochondrial dysfunctions, oxidative stress as well as dysregulation of Calcium signaling, proteasomal and lysosomal pathway. Alpha-synuclein is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein; however, alpha-synuclein and tau constitute two distinctive subsets of filaments in the same inclusion bodies. Alpha-synuclein pathology is also found in both sporadic and familial cases with Alzheimer's disease.

The aggregation mechanism of alpha-synuclein is uncertain. There is evidence of a structured intermediate rich in beta structure that can be the precursor of aggregation and, ultimately, Lewy bodies. A single molecule study in 2008 suggests alpha-synuclein exists as a mix of unstructured, alpha-helix, and beta-sheet-rich conformers in equilibrium. Mutations or buffer conditions known to improve aggregation strongly increase the population of the beta conformer, thus suggesting this could be a conformation related to pathogenic aggregation. One theory is that the majority of alpha-synuclein aggregates are located in the presynapse as smaller deposits which causes synaptic dysfunction. Among the strategies for treating synucleinopathies are compounds that inhibit aggregation of alpha-synuclein. It has been shown that the small molecule cuminaldehyde inhibits fibrillation of alpha-synuclein. The Epstein-Barr virus has been implicated in these disorders.

In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. Five point mutations have been identified thus far: A53T, A30P, E46K, H50Q, and G51D; however, in total, nineteen mutations in the SNCA gene have been associated with parkinsonism: A18T, A29S, A53E, A53V, E57A, V15A, T72M, L8I, V15D, M127I, P117S, M5T, G93A, E83Q, and A30G.

It has been reported that some mutations influence the initiation and amplification steps of the aggregation process. Genomic duplication and triplication of the gene appear to be a rare cause of Parkinson's disease in other lineages, although more common than point mutations. Hence certain mutations of alpha-synuclein may cause it to form amyloid-like fibrils that contribute to Parkinson's disease. Over-expression of human wild-type or A53T-mutant alpha-synuclein in primates drives deposition of alpha-synuclein in the ventral midbrain, degeneration of the dopaminergic system and impaired motor performance.

Certain sections of the alpha-synuclein protein may play a role in the tauopathies.

A prion form of the protein alpha-synuclein may be a causal agent for the disease multiple system atrophy.

Self-replicating "prion-like" amyloid assemblies of alpha-synuclein have been described that are invisible to the amyloid dye Thioflavin T and that can acutely spread in neurons in vitro and in vivo. Antibodies against alpha-synuclein have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies. The central panel in the figure to the right shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons.

Protein-protein interactions
Alpha-synuclein has been shown to interact with
 * Dopamine transporter,
 * Parkin (ligase),
 * Phospholipase D1,
 * SNCAIP,
 * Tau protein.
 * Beta amyloid

title: Alpha-synuclein


text:
Talk:Battle of Modon (1500)

Comments
Besides the fact that this article is currently not about the battle, I'm not sure it't at the right date. List of battles (alphabetical) says the battle was in 1499. Anybody know? Isomorphic 23:31, 5 Mar 2004 (UTC)
 * The Venetians came back for a rematch the year after the First Battle of Lepanto. And lost again. (source - Collins Encylopaedia of Military History).Average Earthman 19:14, 3 Apr 2004 (UTC)

From VfD: contains just one small fact, but even that is incorrect. Cervantes was in the Battle of Lepanto (1571).

 * I've added details on the Second battle (1500) - not to be confused with the 1st (1499) or third (1571), or the Battles of Chalcis and Naupactus which took place in 429BC. Average Earthman 19:10, 3 Apr 2004 (UTC)
 * Just to add - I haven't removed the Cervantes comment yet, but - well, he wasn't even born in 1500. I'm not sure if it's the done thing for me to remove it? Average Earthman 19:15, 3 Apr 2004 (UTC)
 * Keep. Article has been fixed. Rmhermen 21:09, Apr 3, 2004 (UTC)
 * Keep fixed stub -- Cyrius | Talk 22:43, Apr 3, 2004 (UTC)

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title: Talk:Battle of Modon (1500)


text:
Talk:Interesting and uninteresting numbers

Also need to add a link to Church-Turing Thesis here. Anthony DiPierro 18:17, 8 Mar 2004 (UTC)

Why does this page keep being redirected to 1729 (number)? It seems ridiculous to suggest that 1729 is the only interesting or uninteresting number. Either the page should be deleted completely or kept as it is. The redirect is non-sensical. Angela. 23:31, Mar 5, 2004 (UTC)

 * The concept is explained in the 1729 article. The link does not imply that 1729 is the only (un)interesting number. --Wik 23:33, Mar 5, 2004 (UTC)

 * This merits being an article in its own right, with links to articles on individual interesting and uninteresting numbers. Please call off your revert war with Anthony di Pierro so that those working on WikiProject Numbers can work unfettered by page protections on revert war zones. Both of you have important, interesting things to add to Wikipedia articles and I don't wish to side with either of you. 141.217.41.219 19:54, 6 Mar 2004 (UTC)

 * Well, so far there is no such article. You can make additions to the 1729 (number) article; when there is enough substance dealing with the general concept of interesting and uninteresting numbers, I will not oppose moving it out to a separate article. But the present short paragraph isn't worth it. --Wik 20:03, Mar 6, 2004 (UTC)

This should be its own article. In particular, redirecting to 1729 (which does not currently have info on the subject) will keep such an article from appearing, by confusing people. The latest two paragraphs seem a more than acceptable stub... +sj+ 23:19, 2004 Mar 13 (UTC)

Rationale for revert
I reverted this article but I don't wish to take sides with either User:Anthony di Pierro nor User:Wik. I realize that this version is a lot like the article Wik redirected it to, but I wish that yet another third-party uncommitted to either Anthony or Wik will take on the task of editing these two articles. PrimeFan 18:20, 10 Apr 2004 (UTC)
 * how's that? looking at the two articles, I think "Interesting number paradox" is the better title and the more concisely worded article.  If you could suggest how you think this might be further edited, that would help... +sj+ 18:38, 2004 Apr 10 (UTC)

Liouville's number
I added a paragraph that asserts that Liouville's number is uninteresting. I'm honestly not sure of the value of this paragraph, because although I think there's an interesting point buried in there somewhere, the phrasing might be too tongue-in-cheek for anyone to get it out. Nevertheless I think there may be some value in mentioning it. -- Dominus 08:46, 8 May 2004 (UTC)


text:
Matrix metalloproteinase

Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.

Collectively, these enzymes are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine/cytokine inactivation. MMPs are also thought to play a major role in cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense.

They were first described in vertebrates in 1962, including humans, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence.

History
MMPs were described initially by Jerome Gross and Charles Lapiere in 1962, who observed enzymatic activity (collagen triple helix degradation) during tadpole tail metamorphosis (by placing a tadpole tail in a collagen matrix plate). Therefore, the enzyme was named interstitial collagenase (MMP-1).

Later, it was purified from human skin (1968), and was recognized to be synthesized as a zymogen.

The "cysteine switch" was described in 1990.

Structure
The MMPs have a common domain structure. The three common domains are the pro-peptide, the catalytic domain, and the haemopexin-like C-terminal domain, which is linked to the catalytic domain by a flexible hinge region.

The pro-peptide
The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of the "cysteine switch." This contains a conserved cysteine residue that interacts with the zinc in the active site and prevents binding and cleavage of the substrate, keeping the enzyme in an inactive form. In the majority of the MMPs, the cysteine residue is in the conserved sequence PRCGxPD. Some MMPs have a prohormone convertase cleavage site (Furin-like) as part of this domain, which, when cleaved, activates the enzyme. MMP-23A and MMP-23B include a transmembrane segment in this domain.

The catalytic domain
X-ray crystallographic structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 Å (3.5 × 3 x 3 nm). The active site is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site there is a catalytically important Zn2+ ion, which is bound by three histidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif.

The gelatinases, such as MMP-2, incorporate Fibronectin type II modules inserted immediately before in the zinc-binding motif in the catalytic domain.

The hinge region
The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75 amino acids long, and has no determinable structure.

The hemopexin-like C-terminal domain
The C-terminal domain has structural similarities to the serum protein hemopexin. It has a four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP's (tissue inhibitor of metalloproteinases). The hemopexin-like domain is absent in MMP-7, MMP-23, MMP-26, and the plant and nematode. The membrane-bound MMPs (MT-MMPs) are anchored to the plasma membrane via a transmembrane or a GPI-anchoring domain.

Catalytic mechanism
There are three catalytic mechanisms published.

 * In the first mechanism, Browner M.F. and colleagues proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and the Zn2+ ion.
 * In the second mechanism, the Matthews-mechanism, Kester and Matthews suggested an interaction between a water molecule and the Zn2+ ion during the acid-base catalysis.
 * In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine from the HExxHxxGxxH-motif participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate.

Classification
The MMPs can be subdivided in different ways.

Evolutionary
Use of bioinformatic methods to compare the primary sequences of the MMPs suggest the following evolutionary groupings of the MMPs:
 * MMP-19
 * MMPs 11, 14, 15, 16, and 17
 * MMP-2 and MMP-9
 * All the other MMPs

Analysis of the catalytic domains in isolation suggests that the catalytic domains evolved further once the major groups had differentiated, as is also indicated by the substrate specificities of the enzymes.

Functional
The most commonly used groupings (by researchers in MMP biology) are based partly on historical assessment of the substrate specificity of the MMP and partly on the cellular localization of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane-type MMPs (MT-MMPs).

 * The collagenases are capable of degrading triple-helical fibrillar collagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components of bone, cartilage and dentin, and MMPs are the only known mammalian enzymes capable of degrading them. The collagenases are No. 1, No. 8, No. 13, and No. 18. In addition, No. 14 has also been shown to cleave fibrillar collagen, and there is evidence that No. 2 is capable of collagenolysis. In MeSH, the current list of collagenases includes No. 1, No. 2, No. 8, No. 9, and No. 13. Collagenase No. 14 is present in MeSH but not listed as a collagenase, while No. 18 is absent from MeSH.
 * The main substrates of the gelatinases are type IV collagen and gelatin, and these enzymes are distinguished by the presence of an additional domain inserted into the catalytic domain. This gelatin-binding region is positioned immediately before the zinc-binding motif, and forms a separate folding unit that does not disrupt the structure of the catalytic domain. The gelatinases are No. 2 and No. 9.
 * The stromelysins display a broad ability to cleave extracellular matrix proteins but are unable to cleave the triple-helical fibrillar collagens. The three canonical members of this group are No. 3, No. 10, and No. 11.
 * All six membrane-type MMPs (No. 14, No. 15, No. 16, No. 17, No. 24, and No. 25) have a furin cleavage site in the pro-peptide, which is a feature also shared by No. 11.

However, it is becoming increasingly clear that these divisions are somewhat artificial as there are a number of MMPs that do not fit into any of the traditional groups.

Genes
Matrix metalloproteinases combines with the metal binding protein, metallothionine; thus helping in metal binding mechanism.

Function
The MMPs play an important role in tissue remodeling associated with various physiological or pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and metastasis. MMP-2 and MMP-9 are thought to be important in metastasis. MMP-1 is thought to be important in rheumatoid arthritis and osteoarthritis. Recent data suggests active role of MMPs in the pathogenesis of Aortic Aneurysm. Excess MMPs degrade the structural proteins of the aortic wall. Disregulation of the balance between MMPs and TIMPs is also a characteristic of acute and chronic cardiovascular diseases.

Activation
All MMPs are synthesized in the latent form (Zymogen). They are secreted as proenzymes and require extracellular activation. They can be activated in vitro by many mechanisms including organomercurials, chaotropic agents, and other proteases.

Inhibitors
The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3, and TIMP-4.

Synthetic inhibitors generally contain a chelating group that binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation of the zinc atom. Other substituents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs.

Pharmacology
Doxycycline, at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions. It is used clinically for the treatment of periodontal disease and is the only MMP inhibitor that is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex. Minocycline, another tetracycline antibiotic, has also been shown to inhibit MMP activity.

A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies that MMPs are suspected to be involved in (see above). However, most of these, such as marimastat (BB-2516), a broad-spectrum MMP inhibitor, and cipemastat (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of these drugs has been due largely to toxicity (in particular, musculo-skeletal toxicity in the case of broad spectrum inhibitors) and failure to show expected results (in the case of trocade, promising results in rabbit arthritis models were not replicated in human trials). The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal models.

title: Matrix metalloproteinase


text:
Immunostaining

In biochemistry, immunostaining is any use of an antibody-based method to detect a specific protein in a sample. The term "immunostaining" was originally used to refer to the immunohistochemical staining of tissue sections, as first described by Albert Coons in 1941. However, immunostaining now encompasses a broad range of techniques used in histology, cell biology, and molecular biology that use antibody-based staining methods.

Immunohistochemistry
Immunohistochemistry or IHC staining of tissue sections (or immunocytochemistry, which is the staining of cells), is perhaps the most commonly applied immunostaining technique. While the first cases of IHC staining used fluorescent dyes (see immunofluorescence), other non-fluorescent methods using enzymes such as peroxidase (see immunoperoxidase staining) and alkaline phosphatase are now used. These enzymes are capable of catalysing reactions that give a coloured product that is easily detectable by light microscopy. Alternatively, radioactive elements can be used as labels, and the immunoreaction can be visualized by autoradiography.

Tissue preparation or fixation is essential for the preservation of cell morphology and tissue architecture. Inappropriate or prolonged fixation may significantly diminish the antibody binding capability. Many antigens can be successfully demonstrated in formalin-fixed paraffin-embedded tissue sections. However, some antigens will not survive even moderate amounts of aldehyde fixation. Under these conditions, tissues should be rapidly fresh frozen in liquid nitrogen and cut with a cryostat. The disadvantages of frozen sections include poor morphology, poor resolution at higher magnifications, difficulty in cutting over paraffin sections, and the need for frozen storage. Alternatively, vibratome sections do not require the tissue to be processed through organic solvents or high heat, which can destroy the antigenicity, or disrupted by freeze thawing. The disadvantage of vibratome sections is that the sectioning process is slow and difficult with soft and poorly fixed tissues, and that chatter marks or vibratome lines are often apparent in the sections.

The detection of many antigens can be dramatically improved by antigen retrieval methods that act by breaking some of the protein cross-links formed by fixation to uncover hidden antigenic sites. This can be accomplished by heating for varying lengths of times (heat induced epitope retrieval or HIER) or using enzyme digestion (proteolytic induced epitope retrieval or PIER).

One of the main difficulties with IHC staining is overcoming specific or non-specific background. Optimisation of fixation methods and times, pre-treatment with blocking agents, incubating antibodies with high salt, and optimising post-antibody wash buffers and wash times are all important for obtaining high quality immunostaining. In addition, the presence of both positive and negative controls for staining are essential for determining specificity.

Flow cytometry
A flow cytometer can be used for the direct analysis of cells expressing one or more specific proteins. Cells are immunostained in solution using methods similar to those used for immunofluorescence, and then analysed by flow cytometry.

Flow cytometry has several advantages over IHC including: the ability to define distinct cell populations by their size and granularity; the capacity to gate out dead cells; improved sensitivity; and multi-colour analysis to measure several antigens simultaneously. However, flow cytometry can be less effective at detecting extremely rare cell populations, and there is a loss of architectural relationships in the absence of a tissue section. Flow cytometry also has a high capital cost associated with the purchase of a flow cytometer.

Western blotting
Western blotting allows the detection of specific proteins from extracts made from cells or tissues, before or after any purification steps. Proteins are generally separated by size using gel electrophoresis before being transferred to a synthetic membrane via dry, semi-dry, or wet blotting methods. The membrane can then be probed using antibodies using methods similar to immunohistochemistry, but without a need for fixation. Detection is typically performed using peroxidase linked antibodies to catalyse a chemiluminescent reaction.

Western blotting is a routine molecular biology method that can be used to semi-quantitatively compare protein levels between extracts. The size separation prior to blotting allows the protein molecular weight to be gauged as compared with known molecular weight markers.

Enzyme-linked immunosorbent assay
The enzyme-linked immunosorbent assay or ELISA is a diagnostic method for quantitatively or semi-quantitatively determining protein concentrations from blood plasma, serum or cell/tissue extracts in a multi-well plate format (usually 96-wells per plate). Broadly, proteins in solution are absorbed to ELISA plates. Antibodies specific for the protein of interest are used to probe the plate. Background is minimised by optimising blocking and washing methods (as for IHC), and specificity is ensured via the presence of positive and negative controls. Detection methods are usually colorimetric or chemiluminescence based.

Immuno-electron microscopy
Electron microscopy or EM can be used to study the detailed microarchitecture of tissues or cells. Immuno-EM allows the detection of specific proteins in ultrathin tissue sections. Antibodies labelled with heavy metal particles (e.g. gold) can be directly visualised using transmission electron microscopy. While powerful in detecting the sub-cellular localisation of a protein, immuno-EM can be technically challenging, expensive, and require rigorous optimisation of tissue fixation and processing methods. Protein biotinylation in vivo was proposed to alleviate the problems caused by frequent incompatibility of antibody staining with fixation protocols that better preserve cell morphology.

Methodological overview
In immunostaining methods, an antibody is used to detect a specific protein epitope. These antibodies can be monoclonal or polyclonal. Detection of this first or primary antibody can be accomplished in multiple ways.
 * The primary antibody can be directly labeled using an enzyme or fluorophore.
 * The primary antibody can be labeled using a small molecule which interacts with a high affinity binding partner that can be linked to an enzyme or fluorophore. The biotin-streptavidin is one commonly used high affinity interaction.
 * The primary antibody can be probed for using a broader species-specific secondary antibody that is labeled using an enzyme, or fluorophore.
 * In the case of electron microscopy, antibodies are linked to a heavy metal particle (typically gold nanoparticles in the range 5-15nm diameter).

As previously described, enzymes such as horseradish peroxidase or alkaline phosphatase are commonly used to catalyse reactions that give a coloured or chemiluminescent product. Fluorescent molecules can be visualised using fluorescence microscopy or confocal microscopy.

Applications
The applications of immunostaining are numerous, but are most typically used in clinical diagnostics and laboratory research.

Clinically, IHC is used in histopathology for the diagnosis of specific types of cancers based on molecular markers.

In laboratory science, immunostaining can be used for a variety of applications based on investigating the presence or absence of a protein, its tissue distribution, its sub-cellular localisation, and of changes in protein expression or degradation.

title: Immunostaining


text:
Talk:Two stroke cycle

this could use diagrams :) Kingturtle 23:36, 5 Mar 2004 (UTC)

Somebody should join the pages two-stroke cycle and two stroke cycle - 2004/4/4 20:11 CET

title: Talk:Two stroke cycle


text:
17th Golden Raspberry Awards

The 17th Golden Raspberry Awards were held on March 23, 1997, at the Hollywood Roosevelt Hotel to recognise the worst the movie industry had to offer in 1996. Striptease took home the most Razzies of the evening, winning 6 out of 7 nominations, including Worst Picture.

Awards and nominations
{{Legend|#B0C4DE|Winner (in bold)}}

Films with multiple nominations
These films received multiple nominations:

title: 17th Golden Raspberry Awards


text:
Talk:Couch

Inconsistency
This article claims that the term "couch" is both predominantly and rarely used in Ireland.

Comments
Does anyone know the origin of the word "couch"? 24.177.175.169 (talk) 01:30, 31 January 2009 (UTC)

There's still more to be done - this page is full of generalities. Perhaps someone has a furniture book or expertise in that area would like to comment on different couch styles... Someone who is more versed in the visual arts could give some examples of paintings.

It would be helpful if anyone can get their hands on:
 * the German academic paper "Das Sofa" (paper outline here) by Michaela Dantler
 * the book "An encyclodedia of sofas" by Constance King
 * the tape of the arte (French/German TV station) documentary: "Die Dinge des Lebens: Das Sofa"

—Preceding unsigned comment added by Pteron (talk • contribs)

Gendered object?

 * The couch is an extremely gendered object. It is invariably associated with femininity. In the visual arts women were represented sitting or lying on couches, oftentimes in the nude and/or in submissive positions, thereby satisfying masculinist erotic fantasies. The persistent use of this trope (still to be seen in modern cinema, e.g. in Titanic) has established an almost intrinsic connection between the female body and the couch.

I've removed the above section - it just doesn't sound right. References might help to back it up and if so it could be put back. violet/riga (t) 21:51, 7 Oct 2004 (UTC)
 * I agree. It may be for assistance|help]])   22:49, Oct 7, 2004 (UTC)
 * That smells a lot like WP:OR.--h i s  s p a c e   r e s e a r c h 20:35, 29 December 2007 (UTC)

Loveseat Merge
I've merged Loveseat into this article, I put up the suggestion a while back and got no opposition to it, just thought I'd let you know †he Bread  07:17, 6 October 2006 (UTC)

Not gonna take the time to do the research now, but I for one am appalled - appalled I tell you! - that the "S" shaped, two-seaters-facing-each-other style (albeit usually with padding), is nowhere mentioned. Back in the day, "Love Seat" meant nothing else. —Preceding unsigned comment added by 96.50.106.190 (talk) 19:50, 10 September 2010 (UTC)

I agree; a love seat is an S-shaped piece of furniture (for an unusual but clear version, see here. --91.125.204.60 (talk) 16:59, 27 August 2012 (UTC)

Couch tag
Does anyone know the history of the laws regarding the couch tags that say, "Do not remove under penalty of law." I've been trying to figure out why couches have them, but could find nothing as of yet.

It's mostly intended to be followed by retailers, as a Customer Protection because of Truth in Advertising Laws. Don't worry! As The End-Consumer, you can do anything you want to your Couch, lol. 71.233.230.223 (talk) 01:23, 25 August 2008 (UTC)

Tom Cruise?!
Is that really necessary? 203.132.67.134 10:12, 11 February 2007 (UTC)

I think the Tom Cruise information should be left in but formatted into a more standard "couches in pop culture" section similar to other wikipedia entries. Or place all that trivial information into its own entry... however that stuff gets done around here. Divadotn 23:37, 4 June 2007 (UTC)

The photo is so obviously put in there just for laughs... you can hardly see the couch! Joke photos should be less obvious.--24.85.46.33 22:52, 18 June 2007 (UTC)

 * This is one of the most irrelevant pieces of trivia I've seen in Wikipedia. It has nothing whatsoever to do with couches and I'm removing it. Angela. 14:12, 22 August 2007 (UTC)

Cry more please, Angela —Preceding unsigned comment added by 90.195.72.55 (talk) 06:01, 6 January 2011 (UTC)

developing
wow. would someone take a look at this?

it's atrocious.

developing
wow. would someone take a look at this?

it's atrocious.

Itsallaroundus (talk) 17:03, 17 October 2008 (UTC)

Actually, that's YOUR job! Feel free to edit at your leisure.Homely (talk) 21:34, 22 October 2008 (UTC)

Couch the game?
What is this section and what relevance does it have? It should definitely be removed.. —Preceding unsigned comment added by 72.195.184.117 (talk) 04:02, 4 June 2009 (UTC)

I have not heard of this game, now I am intrigued ... Smin0 (talk) 01:13, 3 December 2009 (UTC)

Rucked Up
Various editors seem to have sprawled all over this article to no great effect. Hakluyt bean (talk) 21:55, 1 August 2009 (UTC)

Second photo is not a couch
According the definition at the beginning, the second photo is not a couch (it's just a single chair, for seating one person). I'm removing it, but someone could add another one? Smin0 (talk) 01:13, 3 December 2009 (UTC)

Edit request from Institutinalized, 16 September 2010
A couch is a generic term in North America, Australia (Most commonly known as a lounge), New Zealand, and sometimes the United Kingdom for an item of furniture designed to seat more than one person and providing support for the back and arms. Typically, it will have an armrest on either side. In homes couches are normally found in the family room, living room, den or the lounge. They consist of a wooden or metal structure supplemted by padding and are covered in a variety of textiles, leather, or sometimes a combination of both. They will also be found in hotels and parts of commercial offices, furniture stores, etc.

Other terms synonymous with the above definition of couch are sofa (derived from the Arabic word suffah), settee and canapé.

The term canapé is commonly used also in Greece, for fans of Greek Football teams Olympiakos.They tend to sit on the couch and watch Panathinaikos play in the UEFA competitions.

Etymology
The traditional meaning of couch is a particular type of sofa with a half back and one raised end. By this definition it more closely resembles a daybed, chaise longue, or indeed a bed. In the UK, where the generic term for the item of living room furniture is usually "sofa" or "settee", the term "couch" retains this specific meaning, for example in a therapeutic setting (e.g. a psychiatrist's couch). A couch is therefore used while lying down, while a sofa or settee is for sitting upright. The word "couch" derives from Old French couche, meaning "bed", and from coucher, meaning "put to bed, lay down".<ref name="couch"/

Types
The most common types of couches are the "loveseat", or British two-seater, and the settee or sofa, with two or more seats. A sectional sofa, often just referred to as a "sectional", is formed from multiple sections (typically two to four) and usually includes at least two pieces that join at an angle of 90 degrees or slightly greater, used to wrap around walls or other furniture. A sectional sofa is known as a corner sofa or corner suite in the UK.

Other couch variants include the divan, the fainting couch (backless or partial-backed), the chaise longue (long with one armrest), the canapé (an ornamental 3-seater), and the ottoman (generally considered a type of footstool). To conserve space, some sofas double as beds in the form of sofa-beds, daybeds, or futons. There are also couches known by genericized trademarked names, such as a davenport or Chesterfield (named for one of the Earls of Chesterfield).

The term "chesterfield" is a Canadian term equivalent to couch or sofa. The use of the term has been found to be widespread among older Canadians, but is quickly vanishing from Canadian English according to one survey done in the Golden Horseshoe region of Ontario in 1992. In the United Kingdom, the word refers to a particular style of sofa featuring a low rolled back and deep buttoning.

The term "three-piece suite" is used to describe a furniture set consisting of a two or three-seater couch and two armchairs. Other less specific terms for sets with at least one sofa include "chesterfield suite", "lounge suite", "living-room suite" and "sofa suite".

Edit request from 62.103.215.199, 16 September 2010
Please change "The term canapé is commonly used also in Greece and Cyprus, for fans of Greek and Cypriot Football teams Panathinaikos and Omonoia.They tend to sit on the couch and watch Olympiakos, APOEL and Anorthosis play in the UEFA Champions League." to "The term canapé is commonly used also in Greece for fans of Greek team Olympiakos. They tend to sit on the couch and watch Panathinaikos play in the UEFA Champions League" because historically Panathinaikos has given many more international games than any other Greek team and especially more than Olympiakos.

62.103.215.199 (talk) 14:01, 16 September 2010 (UTC)

Not done: please provide reliable sources that support the change you want to be made. Celestra (talk) 15:25, 16 September 2010 (UTC)

Edit request from Ak200969, 16 September 2010
The article sais

"The term canapé is commonly used also in Greece and Cyprus, for fans of Greek and Cypriot Football teams Panathinaikos and Omonoia.They tend to sit on the couch and watch Olympiakos, APOEL and Anorthosis play in the UEFA Champions League."

The truth is the exact opposite. The term is used only for Olympiakos fans who sit on the couch and watch arch-rivals Panathinaikos play in all european competitions, while Olympiakos is either eliminated earlier, or eliminated from August.... The fact that Panathinaikos has played more games in all European competitions than Olympiakos is undoubtable and can be confirmed by a brief research in UEFA history.

Ak200969 (talk) 14:48, 16 September 2010 (UTC)

Not done: please provide reliable sources that support the change you want to be made. Celestra (talk) 15:29, 16 September 2010 (UTC)

Edit request from ChriskLGate13, 16 September 2010
The term canapé is commonly used also in Greece and Cyprus, for fans of Greek and Cypriot Football teams Olympiakos and Omonoia.They tend to sit on the couch and watch Panathinaikos, APOEL and Anorthosis play in the UEFA Champions League.

The information is wrong. Correct it with the upper add-on.

ChriskLGate13 (talk) 15:26, 16 September 2010 (UTC)

Not done: please provide reliable sources that support the change you want to be made. Celestra (talk) 15:31, 16 September 2010 (UTC)

South Australian terms
English, Irish and Scottish migration to South Australia over nearly 175 years has brought different spoken terminology to the vernacular. Couch is the main older Australian word used but English and Scottish settlers from the 1950s onward use the term settee. Offspring from these settlers use a variety of terms, namely couch, sofa, lounge and less often, settee. The term sofa is not generally used in South Australia though it appears in furniture catalogues so may appear in the younger gererations' vocabularies given time. Gradual media-influenced Americanization of Australian English may see some words soon becoming acceptable when they were scorned in the past. —Preceding unsigned comment added by Trevorheywood (talk • contribs) 10:18, 18 September 2010 (UTC)

is the word sofa really americanisation? in england it is a sofa or setee NOT a couch. therefore, I don't think sofa is an american word. —Preceding unsigned comment added by 86.21.4.251 (talk) 21:38, 23 October 2010 (UTC)

I'm taking the United Kingdom part out of the list of places that use the word couch as I'm English and have never in my 22 years heard anyone call it a couch! —Preceding unsigned comment added by 90.195.72.55 (talk) 06:14, 6 January 2011 (UTC)

I've restored the United Kingdom to the list of places that use the word couch since the above is almost certainly OR and, to make it worse, incorrect OR. For example, http://www.nhs.uk/LiveWell/c25k/Pages/couch-to-5k.aspx — Preceding unsigned comment added by Feefa (talk • contribs) 20:48, 20 May 2012 (UTC)

Ottoman
Also known as an ottoman? Since when? If that's the case, why do we have a separate article for Ottoman? Suggest either we remove this from the first line or merge pages. 81.100.244.9 (talk) 11:07, 4 November 2010 (UTC)

How much material do i need yo buy for a 3 seat cushioned couch? How much for a 2 seat cushion love seat? It is mission style, so all wood on the sides.... —Preceding unsigned comment added by 76.182.36.133 (talk) 14:38, 13 November 2010 (UTC)

 * An ottoman is also known as a hassock, a well-cushioned footrest often used with an armchair. Watch the start of Private Benjamin where she complains that the ottoman isn't quite mushroom colored enough. She's picking it up. Even after boot camp she would not have been able to pick up a sofa.

100.15.127.199 (talk) 22:12, 4 June 2022 (UTC)

Definition change? (or maybe just the third picture )
In the beginning of the article it says "A couch, also called a sofa, is an item of furniture designed to seat more than one person and providing support for the back and arms"

Towards the end of the page the caption reads "A single seater couch". This poor excuse for a couch also does not feature support for the arms.

Clearly one of them is incorrect. Thought I would post here rather than removing the picture of the monstrosity of a couch. Adam BSR (talk) 23:10, 1 May 2011 (UTC)

Images: settee and chaise longue = couch ???
The definition of "couch" has been interpreted too broadly in this article. A couch or sofa is an upholstered piece furniture that can seat at least two people, made for sitting or lying down upon. The word "couch" is from French (couche) originating in the verb "to lie down" (coucher), and "sofa" is from Turkish for carpet or a divan (suffa). --- If the piece of furniture under discussion here is not upholstered, or at least padded, and made for comfort, it's not a couch -- it's something else. The photo of the wood and cane Portuguese settee in this article is not a "couch" and I don't know anyone who would call it that. Also, the chaise longue, designed for one person, is also not a "couch". --- I plan to remove these two images from this article soon. Comments? Charvex (talk) 09:35, 14 August 2012 (UTC)
 * go by the sources174.114.11.60 (talk) 13:55, 30 October 2013 (UTC)

Furniture layers (inside construction)
What are the names of materials used inside furniture (for example: the cloth inside used to sandwich sponge between it and the outside material and saw it in place)?

Couch of Loriot?
Does anyone outside Germany know who Loriot was? A more relevant caption perhaps ... 79.213.11.5 (talk) 11:10, 18 May 2016 (UTC)

External links modified
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Use of sofa in American English
Does anyone else find the idea that "sofa" is not used in American English quite bizarre? It's used all the time. It's used regularly in the vernacular, and is also the term in the furniture industry, where I work. There is a subtle difference in how the terms are used, but they are both used constantly. I wanted to ask for comment from other Americans before changing the article. 12.118.186.226 (talk) 16:16, 23 January 2020 (UTC)
 * Reply to myself: Well, I just asked two people at work, both Americans, and they both said they grew up calling it a "couch" and maybe occasionally a "sofa" but didn't really start using "sofa" regularly until they started working in the furniture industry. I should also note that I grew up partly in the UK. Any other Americans want to comment? 12.118.186.226 (talk) 16:24, 23 January 2020 (UTC)

American here. Anecdotally, “couch” might be a little more common, but “sofa” is still used very often. —Will(B) 18:32, 4 June 2020 (UTC)

 * American here. I grew up using sofa but I know that some people here also say divan.

100.15.127.199 (talk) 22:12, 4 June 2022 (UTC)

Another American checking in. I have always used "couch" and "sofa" interchangeably. Rreagan007 (talk) 03:05, 14 January 2023 (UTC)

External Link: Reference 11 has incorrect URL
It is supposed to point to an entry for chesterfield suite on Merriam-Webster (https://www.merriam-webster.com/dictionary/chesterfield%20suite), but it instead links to The Free Dictionary's listing for couch. — Preceding unsigned comment added by 134.153.30.218 (talk) 17:30, 2 June 2022 (UTC)

English
English was around the world for a long period of time 116.240.51.119 (talk) 10:28, 17 October 2023 (UTC)

title: Talk:Couch


text:
User talk:Mat-C

--==Welcome==--

Talk:Stacy's Mom
I removed your vote on the deletion of Stacy's Mom at Talk:Stacy's Mom because that vote was closed and stored there for archival purposes.

Not that I blame you for doing so, since there were no notices to that effect. I added some to hopefully avoid future confusion. -- Cyrius|&#9998 17:46, Apr 17, 2004 (UTC)

Geosynchronous orbit
The empty Free Body Diagram section still served a purpose in that it would be useful if it was not blank. Leaving it there may motivate someone to add a diagram, without it, it is far less likely. { MB | マイカル } 18:20, Apr 30, 2004 (UTC)

 * I am not disputing the value of such a diagram should it ever appear. Until it does a "todo" list on a main article looks extremely unprofessional and belongs on the discussion page, which is why I put it there.  If you believe this is in contravention of WP policy then please provide a link to the appropriate page in the general editing section. Mat-C 20:22, 30 Apr 2004 (UTC)

The Price of Milk
I noticed that you added a couple of paragraphs to The Price of Milk which have since been moved to The price of milk. I'm just writing because, while I found your take on the phrase interesting, I'm not sure it's entirely correct. The phrase that I've always heard has been 'what's that got to do with the price of milk', or 'what does that have to do with the price of milk', where the price of milk just stands for 'anything'. I think the phrase is definitely more common in the Antipodean colonies. Anyway, I was wondering if this directly conflicts with your experience of the phrase, or if you just made the connection between the title of the movie and 'the price of a pint of milk' questions. --Dom 11:43, 2 July 2006 (UTC)

AfD nomination of Matrioshka brain
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ArbCom elections are now open!
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Proposed deletion of The Big Issue Foundation

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title: User talk:Mat-C