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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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December 20, 2011

Best Paper You Read This Year?

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Posted by Derek

Since the year is winding down, I had a question for the readership: what's the best scientific paper you read this year? Let's restrict the field to chemistry and biology; I'm not ready for particle physics. And I don't necessarily mean "best written", although you're free to nominate some if you can find any that stood out. What I had in mind was more "Most interesting" or "Most unexpectedly useful", or "Most surprising". I've got a couple in mind myself - I'll turn the suggestions into another post or two.

Comments (58) + TrackBacks (0) | Category: The Scientific Literature


COMMENTS

1. Nate on December 20, 2011 10:06 AM writes...

NEJM
Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

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2. anchor on December 20, 2011 10:19 AM writes...

I have to say that paper by University of Kentucky team that Published data linking retinal toxicity to 21-Mer siRNAs. This was a seminal finding that foretells other surprises in store for this gene silencing technology. Many have lot of stake invested in this area.

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3. HDTV on December 20, 2011 10:25 AM writes...

Proteogenomic analysis of bacteria and archaea: a 46 organism case study

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4. enrico on December 20, 2011 10:36 AM writes...

An historical achievement in structural biology:
Rasmussen SGF et al. (2011) Crystal structure of the β(2) adrenergic receptor-Gs protein complex. Nature.
http://www.nature.com/nature/journal/v477/n7366/full/nature10361.html

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5. Nate on December 20, 2011 10:39 AM writes...

stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=22049071

Is chronic NTG worsening infarction damage in CV patients?

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6. Sarkis Dallakian on December 20, 2011 10:51 AM writes...

How were new medicines discovered?
http://www.nature.com/nrd/journal/v10/n7/full/nrd3480.html

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7. Nate on December 20, 2011 10:52 AM writes...

http://www.ncbi.nlm.nih.gov/pubmed/22049071

use this link. previous one is bad

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8. luysii on December 20, 2011 10:59 AM writes...

There were a ton of them, but to a clinician treating inherited disease, this one was the most striking, showing how little we really know about the influence of the genome on disease.

http://luysii.wordpress.com/2011/07/17/weve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/

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9. InfMP on December 20, 2011 11:03 AM writes...

Total Synthesis of Bryostatin 7 via C-C Bond-Forming Hydrogenation

Krische, 10.1021/ja205673e

Domination.

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10. Curious Wavefunction on December 20, 2011 11:11 AM writes...

The GPCR paper was a tour de force (and the GPCR guys will probably get a Nobel Prize at some point) but I don't regard it as particularly surprising or unexpected. For most unexpected result I will probably nominate the diiron protein that spontaneously generated a *covalent* bond between a phenylalanine and valine (Science). Very unusual: DOI: 10.1126/science.1205687.

Another nomination for best paper would be the piece on FoldIt, the protein folding game, which demonstrated the power of harnessing collective intelligence to solve a problem as thorny as protein folding. I think the paper paves the way to similar fascinating endeavors in the future.

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11. Virgil on December 20, 2011 12:24 PM writes...

Elucidation of the identity of the mitochondrial Ca2+ uniporter (MCU). People have been looking for this protein for nearly 50 years, and then 2 labs co-discover it [PMIDs 21685886/21685888]

This protein has such a fundamental role in mitochondrial function and pathology, its hard to believe it won't be an interesting drug target in the future.

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12. Matt on December 20, 2011 12:59 PM writes...

The total synthesis of bryostatin 1.
http://pubs.acs.org/doi/abs/10.1021/ja110198y

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13. Lu on December 20, 2011 1:01 PM writes...

Don't know about the best one but I can surely nominate the worst: "Womanspace" in Nature.
That is a truly idiotic story about two grown-up men who cannot find underwear in a store and on the basis of this proceed to make up gender-related hypotheses of cosmic proportions.

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14. bootsy on December 20, 2011 1:38 PM writes...

@InfMP (#9) and Matt (#12), seriously? If this were Masamune in 1990, maybe, but in 2011?

How about a perspective and hypothesis paper on ncRNA in general? A lot of this was already known or postulated, but I liked how this paper brought together a lot of threads into one nice woven cord:
http://www.cell.com/retrieve/pii/S0092867411008129

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15. Hap on December 20, 2011 2:07 PM writes...

Garg's synthesis of weltwindolone (C?) JACS (2011), p. 5798.

Unexpected for me - borenium ions? ACIEE (2011), pp 2098 and 2102.

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16. HDTV on December 20, 2011 2:17 PM writes...

Proteogenomic analysis of bacteria and archaea: a 46 organism case study

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17. Chris on December 20, 2011 2:30 PM writes...

NEJM paper by Porter et al. describing retroviral transduction of patient T cells with an receptor against CD19. The patients were apparently cured of chronic lymphocytic leukemia.

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33.

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18. Anonymous on December 20, 2011 3:11 PM writes...

STM paper from Atul Butte's group on repurposing old drugs using gene expression profiles (including the possibility that cimetidine might be an effective lung cancer therapeutic):

Sirota M, Dudley JT, Kim J, Chiang AP, Morgan AA, Sweet-Cordero A, Sage J, Butte AJ. Discovery and preclinical validation of drug indications using compendia of public gene expression data, Science Translational Medicine, 3(96):96ra77. 2011.

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19. James on December 20, 2011 4:00 PM writes...

The Zhu et al paper in Cell (PMID 22153080) demonstrating the role of PKR (dsRNA-activated protein kinase) in learning and memory. What a kinase involved in recognition of viral infection has to do with learning is beyond me, but a cool connection.

Alternatively, a really interesting/possibly scaleable approach to looking at RNA splicing in the Vargas et al paper in Cell as well (PMID 22118462).

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20. Useless Molecule on December 20, 2011 4:41 PM writes...

@ # 9 and 12

Seriously guys, expand your vision of science. Reading these papers won't get you anywhere. You won't even learn anything.

Like #14 said, you are in 2011. Not in the 80's...

You are both 30 years behind.

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21. Peter Ellis on December 20, 2011 5:24 PM writes...

http://www.cell.com/abstract/S0092-8674(11)00891-9

An unbiased look at the histone code - simply pull out all the core histones, do some mass spec and work out what all the different modifications actually are. In one step they nearly doubled the number of known histone marks, and that's before you start looking at variant histones.

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22. Anonymous on December 20, 2011 5:59 PM writes...

@20

Especially since Wender's already shown that a total synthesis of Bryostatin is wholly unnecessary. Function-Oriented Synthesis >> Target-Oriented Synthesis.

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23. A Nonny Mouse on December 21, 2011 4:09 AM writes...

How about DRACO, a pan-antiviral from the man who gave us CANARY.

http://web.mit.edu/newsoffice/2011/antiviral-0810.html

Nice to hear mention above of my old post-doc supervisor, Masamune; yes, macrolides were very 1981 for me.

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24. TX Raven on December 21, 2011 8:03 AM writes...

@22, @20, @14...

Why are you guys so critical? It's the holidays season, for God's sake...

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25. TX Raven on December 21, 2011 8:19 AM writes...

@22, @20, @14...

Why are you guys so critical? It's the holidays season, for God's sake...

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26. Cage the Elephant on December 21, 2011 9:38 AM writes...

@ 25

"AIN'T NO REST FOR THE WICKED!"

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27. Cage the Elephant on December 21, 2011 9:49 AM writes...

@ 25

"AIN'T NO REST FOR THE WICKED!"

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28. Cage the Elephant on December 21, 2011 10:38 AM writes...

@ 25

"AIN'T NO REST FOR THE WICKED!"

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29. Anonymous on December 21, 2011 11:26 AM writes...

How about a two paper series? Cancer Cell 20: pp. 53 - 65 and 66 - 78. Combines RNAi knockdown, gene expression, histone methylation, cell biology, medicinal chemistry and animal model. Nice example of synergy of modern drug discovery tools.

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30. Algirdas on December 21, 2011 11:39 AM writes...

I enjoyed these quite a lot:

Conversion of proteins into biofuels by engineering nitrogen flux (PMID 21378968)

Scaling up digital circuit computation with DNA strand displacement cascades (PMID 21636773) - hey, they even posted a video on the Youtube explaining, to yokels like me, what they did!

and perhaps most:

Micro-NMR for rapid molecular analysis of human tumor samples (PMID 21346169). Coupled to good antibody reagents, a simple NMR relaxation readout makes a powerful diagnostic tool.

As an aside, the paper which proved most useful, you know, for the actual work that I do (essentially enabled a new project), is "just" a piece of solid enzymology from 4 decades ago:

2-keto-4-hydroxybutyrate aldolase. Identification as 2-keto-4-hydroxyglutarate aldolase, catalytic properties, and role in the mammalian metabolism of L-homoserine (PMID 5580656).

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31. Real Legume on December 21, 2011 3:50 PM writes...

@29

Where's the medicinal chemistry? That was the most handwaving explanation for inhibitor design I've ever seen. Where was the SAR?

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32. Jackson on December 21, 2011 4:49 PM writes...

#9
Krishe did some good work, but of course he only accomplished it by using a lot of chemistry developed by Keck.

#22
Wender has made some decent simplified analogs of Bryostatin, of course his best analogs were synthesized by using Keck’s annulation chemistry.

#14 & #20
You raise a very old argument, usually posited by biologists or theorists who have rarely had to go into a synthetic chemistry lab and make something happen. Also, if this chemistry is so easy why didn’t someone just make Bryo-1 a long time ago? It’s the only Bryo NP that anyone really cares about.

With the help of the bryostatin analogs being made by Wender and Keck a lot of the biological nuances are being uncovered.

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33. You don't need to click 4 f%^&& times on December 21, 2011 4:57 PM writes...

@ TX raven, cage the elephant and real the big legume

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34. cliffintokyo on December 21, 2011 9:05 PM writes...

Balancing:
The Bryostatins syntheses are all good solid total synthesis contributions, but not frontier science for 2011 or artisanal med chem.
No Nobels here, I fear, but other recognitions and/or prizes would be well deserved IMHO.

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35. biku on December 21, 2011 9:35 PM writes...

Fawning is the best method to grow your careers.
Scientifically its a proven method.Serious # 9 (I can even give respect to Wender/Keck).Krische has found one reaction.He has been regurgitating it in several infinite ways infinitesimally with the active back-scratching policy of the JACS editors.
Go and read the papers if I have stated anything wrong.Amazing!

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36. rx90087 on December 21, 2011 9:46 PM writes...

I have two that I think are important. These papers challenge the manner in which the pharmaceutical industry conducts drug discovery. Prinz 2011 "Believe it or not: how much can we rely on published data on potential drug targets? "(http://www.nature.com/nrd/journal/v10/n9/pdf/nrd3439-c1.pdf?WT.ec_id=NRD-201109) and Swinney 2011 "How were new medicines discovered?" (http://www.nature.com/nrd/journal/v10/n7/full/nrd3480.html).

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37. Go Systems on December 22, 2011 7:01 AM writes...

How were new medicines discovered?
http://www.nature.com/nrd/journal/v10/n7/full/nrd3480.html

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38. Anonymous on December 22, 2011 7:50 AM writes...

@Jackson (#32). Being an old argument does not make it wrong. While I don't mind being tarred with the brush you use on biologists or theorists, I am actually a synthetic organic chemist by training who got my PhD working on large macrolides and I still work in the lab today. (Though certainly not as much as I did in grad school.)

Like cliffintokyo (#34), I don't see how things are much advanced by these two papers. The fact that Wender and Krische used Keck's chemistry to make some of their analogs is a much better vindication of Keck's chemistry than his own efforts to find something useful to do with it. Likewise, Krische's work has already shown its utility and this synthesis, as you point out, doesn't showcase it very well.

So, best papers of 2011? I don't agree. We didn't really even learn anything new about polyketide synthesis or macrolide synthesis from these papers. We didn't learn more about bryostatin. I think all we learned is that, while the argument may be old, we need to keep having it.

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39. bootsy on December 22, 2011 7:52 AM writes...

Sorry, #38 was me. Even if it's a pseudonym, I figure I should own up to it.

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40. Hap on December 22, 2011 10:14 AM writes...

#35: If it was so obvious and incremental, why isn't anyone else doing it? The total synthesis papers aren't that exciting, but Krische's methodology is useful. I need to see his methodology papers much more than I need to see yet another organocatalytic enantioselective prepn. of spiroindolones.

Making the bryostatins is neat, and the incremental refinements might help to find an effective analog in the future, but they probably aren't going to do a whole lot for anyone in the near term, and the syntheses weren't jaw-droppingly awesome.

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41. Mortimer Cladwell on December 22, 2011 10:55 AM writes...

Zhang et al.: " Exogenous plant MIR168a specifically targets mammalian LDLRAP1: an evidence of cross-kingdom regulation by microRNA " Publishing on Cell Research, September 20, 2011.

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42. Jackson on December 22, 2011 11:41 AM writes...

#38
I never said (nor meant to imply) that any of the Bryostatin synthesis papers should qualify as "best paper of the year". I never would have brought them up in that context. I was just responding to some comments from others. While I believe the endeavors are admirable, and the chemistry which was developed in their pursuit is creative and useful, I agree that none are going to shake the foundations of science and bring Derek to his knees weeping uncontrollably.

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43. biku on December 22, 2011 11:45 AM writes...

Hap...see the context..
Best paper in 2011...and somebody comes up with KRische from the ENTIRE chemistry and biology literature.
And the paper conatins (lets say borrows too heavily) from the previous synthesis.
Now , if you are a real scientist and objectivity is your standpoint, do you see the point now?
Seriosly , now we have fawner(s)

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44. biku on December 22, 2011 11:47 AM writes...

Hap...see the context..
Best paper in 2011...and somebody comes up with KRische from the ENTIRE chemistry and biology literature.
And the paper conatins (lets say borrows too heavily) from the previous synthesis.
Now , if you are a real scientist and objectivity is your standpoint, do you see the point now?
Seriosly , now we have fawner(s).
And to your query why nobody else tried?
Nobody , who matters, cares.

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45. Anonymous on December 22, 2011 4:22 PM writes...

You only matter if Biku says you matter.
LMFAO. Biku, I'm surprised you lowered yourself to read this blog, let alone the many comments. LOL & RE.

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46. provocateur on December 22, 2011 11:20 PM writes...

I see no problem with what biku is saying.kind of over the top but valid points

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47. IrII on December 23, 2011 6:04 AM writes...

On the one hand we have someone suggesting that if work is obvious and incremental then it would have been done (this comment comes as a response to the (allegedly obvious and incremental) work actually having been done); which implies that the commenter believes that the community is doing - not necessarily should be doing, but is doing nevertheless - obvious and incremental work. Which is probably true, whatever one might think about what they (we?) should be doing.

There is no other hand.

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48. Useless Molecule on December 23, 2011 9:22 AM writes...

@ Biku

You are absolutely right when you say "Nobody , who matters, cares"

Have a good holiday.

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49. provocateur on December 23, 2011 9:35 AM writes...

I see no problem with what biku is saying.kind of over the top but valid points

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50. biku on December 23, 2011 9:58 AM writes...

I kind of think I touched a lot of raw nerves there
with the whole Krische group going bonkers on me with names like 'Ir II' , 'Useless Molecule'.
Hey, I am just complaining abt it being labelled
best paper.Thats all, guys!
Happy holidays

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51. Anonymous on December 23, 2011 2:39 PM writes...

Biku, Usless, Provo, etc.

You are certainly entitled to your opinions. Like the saying goes, everybody's got one... But to make (or agree with) the statement "nobody, who matters, cares" is both ignorant and very arrogant. You are essentially implying that 'nobody, who cares, matters'. If that's true, then it not only applies to Krische, but also Corey, Evans, Nicolaou, Danishefsky, etc. I think you would find Big Pharma populated with MANY people who would disagree with you.

By the way, I'm not a "fawner", nor am I here to defend Krische's work. I'm just here to wish you a Merry Christmas, and a very INTERESTING New Year. May you receive the perspective you need and deserve.

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52. provocateur on December 23, 2011 4:09 PM writes...

#51
Its the bitter truth.I do not know with what intent it was said but its the bitter truth.In the posts above many ppl have expressed such sentiments, Hap said 'we dont need another synthesis of spiroindolones', some ppl hv expressed similar sentiments about macrolids, biku has the same opinion abt Krische's work.But its expressing different faces of the truth that synthesis is not as important as it once was when Corey, Nicolau Evans, Danishefsky ruled.Societies need and priorities change and is reflected in different ways of expression. I hope its not taken as a personal attack as I have seen that the opinions/dreams I had about synthesis when I was in graduate school has been drastically altered with the harsh realities of employment I faced.
happy holidays to everybody.

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53. Anonymous on December 23, 2011 4:51 PM writes...

#52
The bitter truth is in the eye of the bitter beholder. Do be bitter bro. I understand your opinion. And while my opinion is that organic synthesis is as important today as it ever was, I don't know of any synthetic papers this year that should be mentioned under the heading of this string (though I'm still open for suggestions). That said, deciding what is scientifically important (or important in life in general) based on "harsh realities of employment" or even "societies (immediate) needs and priorities" is short sided indeed. Yes, having money to pay the rent is damn important personally, but honestly, Biku and Useless couldn't give a crap about you or your rent. Another bitter truth.

As an aside... I don't know the numbers on this or how to go about getting an accurate estimate, but I would guess that there is as much or more synthetic organic chemistry going on today (R&D and Manufac) as there ever was -- it's just that a lot of it is getting done in Chindia. So maybe you should put the blame for your altered career path where it really belongs, though that my bitter friend would take us down another unpleasant road.

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54. provocateur on December 23, 2011 5:53 PM writes...

I think whatever I said can be proven by how much
money the science of synthesis gets by way of federal money since almost all synthesis is funded that way.It has decreased considerably and beyond the committees that decide who shd get what and how much, the share of the pie has decreased considerably.Money is there for newer , green methods like for Krische and thats why he is never interested in a 'full' demonstration of his methodology in bryostatin synthesis.He just wants to demonstrate 'usefulness' by doing partial synthesis.Organic synthesis is important but in a 'bio-context'.You get sneered at if you want to use thallium or tin reagents.So the 'society;s'
expectations have increased.And thats why I said
organic synthesis 'as practiced' is no more imp.
I am not bitter becos after grad school I understand the world better and in a different context.The closed shell structure of grad school
can make you ignorant of the world outside.
How many ppl here would like their children to become chemists?nothing bitter but just getting real.

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55. luysii on December 24, 2011 8:58 AM writes...

A little late in the game for an entry, but if the 6 Dec PNAS ( vol. 108 pp. 19784 - 19789 '11 6 Dec issue) actually holds up. It certainly would be a great Christmas present for the many people suffering chronic pain. They describe a naltrexone derivative which, unlike the parent compound, has analgesic activity 10x more potent than morphine, but which lacks (1) respiratory depression (2) physical dependence (3) reinforcement activity -- animals won't work to get it. The work is in mice. For details see the paper, or https://luysii.wordpress.com/2011/12/23/a-christmas-gift-for-all-of-us-if-it-holds-up/

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56. Jamshid on December 27, 2011 9:11 PM writes...

Genomic Maps of Long Noncoding RNA Occupancy
Reveal Principles of RNA-Chromatin Interactions

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57. Bill on December 28, 2011 9:56 PM writes...

The seven chemistry lab write ups that I graded in my high school chem one class that were identical to each other.

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58. gippgig on December 29, 2011 1:37 AM writes...

#55 - that should be 19778-19783.

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