Multiple Sclerosis Scientific Molecular Map

The molecular structure, described in the February 17, 2012 issue of the journal Science, is unique as the first-ever-to-be-determined lipid G protein-coupled receptor (GPCR). Molecules of this type play important roles in everything from cancer to metabolism, and this recent success should pave the way for researchers to establish the structures of other family members.
“There’s something special about the S1P1 receptor,” said Hugh Rosen, MD, PhD, a Scripps Research chemical biologist who co-led the work with Raymond Stevens, PhD, a structural biologist also from The Scripps Research Institute. “The biological consequences of even small changes with this receptor are profound. Understanding its structure provides clues about fundamental processes important in both health and disease.”
“Being able to finally look at a lipid GPCR and the occluded cell surface binding pocket was a surprise but explains many of the issues we wondered about,” said Stevens. “It is likely that other members of this subfamily will have a similar protein architecture.”
The study is a result of decades of research by the Stevens lab to develop methods to determine the structure of GPCRs, much work in the Rosen lab on the receptor biology and chemical tools to stabilize such molecules, and a multi-disciplinary collaboration between the two labs, which Rosen notes is one of the hallmarks of research at The Scripps Research Institute. The scientists acknowledge the support of the National Institutes of Health Common Fund as making the new findings possible.
“This work promises to underscore the importance of research collaboration to accelerate scientific discovery and development of new drug therapies,” said James M. Anderson, MD, PhD, director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund. “Combining structure-based analysis with small molecule screening serves as a model for effective drug design.”
Controlling Multiple Sclerosis

The new work reveals the structure of the S1P1 receptor, a protein embedded in the membranes of various cell types. When natural ligands such as the signaling lipid sphingosine 1-phosphate or potential drugs make specific interactions deep in receptor, portions of the receptor change shape to trigger cascades of chemical reactions inside the cell important to the maintenance of health.
Researchers have long known that S1P1 receptors play critical roles in controlling multiple sclerosis and other diseases. One way these receptors do this is by regulating the flow of certain white blood cells, or lymphocytes, out of lymph nodes.

This is critical because in patients with multiple sclerosis, auto-reactive lymphocytes attack the protective sheaths of nerve cells in the brain, causing malfunctions in the way the central nervous system transmits signals through the body. The S1P1 receptors are also involved in the progressions of harmful scarring and swelling in response to lymphocyte damages in the brain.
Gilenya, the first oral drug approved to treat multiple sclerosis, reduces this lymphocyte flow out of the lymph nodes in ways first identified by Rosen’s lab about 10 years ago. Based on a screening lead from the National Institutes of Health Molecular Libraries Small Molecule Repository, Rosen and Scripps Research Chemistry Professor Ed Roberts discovered and optimized other modulators of S1P1 receptors. This led to RPC-1063, a compound in clinical trials for multiple sclerosis by Receptos, a company co-founded by Rosen and Stevens.
Rosen’s lab has also shown that modulating S1P1 receptors can protect mice from a pandemic flu virus. This shows that the receptors may also be good drug development targets for other conditions tied to immune responses.
A Shifting Binding Pocket
The new study used the technique of x-ray crystallography to reveal the high-resolution three-dimensional image of the S1P1 receptor. The results provide scientists with important new details about the receptor’s mechanism of action.
One aspect of the receptor structure that is of particular interest is the binding pocket for the natural ligand or potential drugs that activate the receptor responses. The structure revealed how the binding pocket shifts to activate signaling. Understanding how that occurs makes it easier to identify additional compounds that might have effects in controlling the receptors.
With this structural information in hand, the scientists can now advance efforts to understand the specific chemical transformations that drive the cellular responses tied to multiple sclerosis and other diseases. “Better understanding always allows you to think about applications in a variety of ways that you might not have thought about before,” said Rosen. “This is an area that will keep us busy for many years to come.”
The S1P1 receptor structure has already yielded benefits, according to Michael Hanson, a scientist and director at Receptos, and lead author of the new paper. “The structure has helped us understand the details regarding receptor-ligand interactions for this receptor and structural data can be used more routinely for drug discovery projects of other GPCRs,” he said.

From: http://ping.fm/dGq3z

Researchers Gather for Shared Resources Fair and Drug Discovery Forum | Miller School of Medicine | University of Miami

The Miller Office of Research hosted two events this month at the Miller School for the research community – a Shared Resources Fair on the morning of February 17, and a Collaborative Research Exchange Forum (CREF) on drug discovery in the afternoon.

More than 200 researchers attended the third Shared Resources Fair, which featured nearly 50 posters with information about the varied core laboratories, facilities, and shared resources supporting discovery science, translational, and clinical research. Later, more than 50 faculty, staff, and students gathered at the Lois Pope LIFE Center for the forum to share information on drug discovery.

Led by Norma Sue Kenyon, Ph.D., the Martin Kleiman Professor of Surgery, Microbiology and Immunology, and Biomedical Engineering and senior associate dean for translational science, and Andrew Vinard, manager of biotechnology resources, the Core and Shared Facilities Office within the Miller Office of Research supports research excellence at the University. The fair was co-hosted by the Sylvester Comprehensive Cancer Center and the Wallace H. Coulter Center for Translational Research. Kenyon said events such as the Shared Resources Fair and the CREF reflect the University’s continuing support of its research community.

“The Miller School is committed to developing state-of-the art facilities, encouraging their use, and advancing scientific collaboration in areas of key importance to biomedical research,” said Kenyon, who is also director of the Coulter Center.

Claes Wahlestedt, M.D., Ph.D., professor of psychiatry and behavioral sciences and associate dean for therapeutic innovation, who led the drug discovery forum, added that topics like drug discovery especially benefit from an interdisciplinary team science approach.

“The Miller School has the expertise and laboratory resources needed to identify compounds that can be developed into the next generation of therapeutics,” Wahlestedt said

The CREF began with presentations and a panel discussion on:

• Chemoinformatics and drug discovery by Stephan Schürer, Ph.D., research assistant professor of molecular and cellular pharmacology and the Center for Computational Science’s lead scientist for chemoinformatics;

• Molecular oncology and drug discovery by Anthony Capobianco, Ph.D., professor of surgery and director of the Molecular Oncology Research Program, Division of Surgical Oncology;

• Cell biology and drug discovery by Glen Barber, Ph.D., chair of cell biology and anatomy, professor of medicine, and associate director of basic research at Sylvester.

Additional presentations and another panel discussion followed on these projects:

• Drug discovery at The Miami Project to Cure Paralysis by Vance Lemmon, Ph.D., the Walter G. Ross Distinguished Chair in Developmental Neuroscience and professor of neurological surgery;

• Peggy and Harold Katz Family Drug Discovery Center by Vineet Gupta, Ph.D., assistant professor of medicine, biochemistry and molecular biology, and the founding co-director of the Katz Center;

• Center for Therapeutic Innovation by Nagi Ayad, Ph.D., associate professor of psychiatry and behavioral sciences; and Shaun Brothers, Ph.D., research assistant professor of psychiatry and behavioral sciences.

From: http://ping.fm/TfYiU

Cancer charity halts grants to Planned Parenthood :: WRAL.com

Image by ladybugbkt via Flickr

NEW YORK — The nation’s leading breast-cancer charity, Susan G. Komen for the Cure, is halting its partnerships with Planned Parenthood affiliates — creating a bitter rift, linked to the abortion debate, between two iconic organizations that have assisted millions of women.

The change will mean a cutoff of hundreds of thousands of dollars in grants, mainly for breast exams.

Planned Parenthood says the move results from Komen bowing to pressure from anti-abortion activists. Komen says the key reason is that Planned Parenthood is under investigation in Congress — a probe launched by a conservative Republican who was urged to act by anti-abortion groups.

The rupture, which has not been publicly announced as it unfolded, is wrenching for some of those who’ve learned about it and admire both organizations.

“We’re kind of reeling,” said Patrick Hurd, who is CEO of Planned Parenthood of Southeastern Virginia — recipient of a 2010 grant from Komen — and whose wife, Betsi, is a veteran of several Komen fundraising races and is currently battling breast cancer.

“It sounds almost trite, going through this with Betsi, but cancer doesn’t care if you’re pro-choice, anti-choice, progressive, conservative,” Hurd said. “Victims of cancer could care less about people’s politics.”

Planned Parenthood said the Komen grants totaled roughly $680,000 last year and $580,000 the year before, going to at least 19 of its affiliates for breast-cancer screening and other breast-health services.

Komen spokeswoman Leslie Aun said the cutoff results from the charity’s newly adopted criteria barring grants to organizations that are under investigation by local, state or federal authorities. According to Komen, this applies to Planned Parenthood because it’s the focus of an inquiry launched by Rep. Cliff Stearns, R-Fla., seeking to determine whether public money was improperly spent on abortions.

Cecile Richards, president of the Planned Parenthood Federation of America, has depicted Stearns’ probe as politically motivated and said she was dismayed that it had contributed to Komen’s decision to halt the grants to PPFA affiliates.

“It’s hard to understand how an organization with whom we share a mission of saving women’s lives could have bowed to this kind of bullying,” Richards told The Associated Press. “It’s really hurtful.”

Reaction to the news was swift and passionate. On Twitter, it was one of the most discussed topics Tuesday evening, with some tweets praising Komen’s decision and others angrily vowing never to give to it again.

Two Democrats in Congress — Sen. Patty Murray of Washington and Rep. Michael Honda of California — issued statements denouncing Komen’s action.

“I am stunned and saddened,” said Honda, whose longtime chief of staff, Jennifer VanderHeide, had breast cancer last year. “I call on Komen to reconsider this decision, stand strong in the face of political pressure and do the right thing for the health of millions of women everywhere.”

Anti-abortion groups, in contrast, welcomed the news. The Alliance Defense Fund praised Komen “for seeing the contradiction between its lifesaving work and its relationship with an abortionist that has ended millions of lives.”

From: http://ping.fm/BBLn3

Sexual Transmitted Diseases Genital chlamydia genital herpes Trichomonas

 Abstract
BACKGROUND:

The aim of this study was to assess the prevalence of women reporting ever having genital chlamydia, genital herpes, Trichomonas vaginalis, and gonorrhea, and to identify factors associated with each of these sexually transmitted infections (STIs).
METHODS:

The study was based on a large cross-sectional survey conducted in 2004-2005 among randomly sampled women (18-45 years) from the computerized population registries in Denmark, Iceland, Norway, and Sweden. A total of 69,567 women were included in the study.
RESULTS:

The overall prevalence in Denmark, Iceland, Norway, and Sweden was 1.5% for reporting ever having had Trichomonas vaginalis, 1.9% for gonorrhea, 4.8% for genital herpes, and 17.0% for genital chlamydia. The prevalence of each of these STIs varied with birth cohort and country. In addition, they were strongly associated with lifetime number of partners and having a previous diagnosis of another sexually transmitted infection. Moreover, a diagnosis of genital chlamydia or gonorrhea was associated with early age at first intercourse and smoking initiation. Finally, reporting genital chlamydia was associated with early age at drinking initiation, and ever use of hormonal contraceptives and condoms.
CONCLUSION:

Genital chlamydia occurs frequently among women in the Nordic countries. Risk-taking behavior, particularly sexual behavior, is strongly associated with STIs, which suggest that further information is needed about STIs and their consequences, targeting high-risk groups. There is also a need for continued monitoring of STIs in order to follow the prevalence and to gain further knowledge about risk factors.

From: Ping.fm

Advances in Immunology and AIDS Research

Just over a month ago, the medical world marked the 20th anniversary of the report that first identified the strange and apparently fatal disease that we now know as AIDS (for acquired immunodeficiency syndrome). During the 1980s the worldwide scientific and medical community struggled to understand the nature of the disease, to track down the human immunodeficiency virus (HIV) responsible for it, and to develop rudimentary treatments — an effort that continued throughout the 1990s.

In the meantime, AIDS has continued to destroy lives. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that 36.1 million individuals around the world were living with HIV infections or full-blown AIDS at the end of last year.
In 2000 alone HIV/AIDS caused the deaths of approximately 3 million individuals, making a cumulative death toll of 21.8 million by year’s end. UNAIDS’ figures also indicate that roughly one in every 100 adults between the ages of 15 and 49 is now infected with HIV. More than 80 percent of all adult HIV infections have resulted from heterosexual intercourse.

Throughout the past decade the scientific and medical communities have sought better understanding of the HIV virus in hopes of developing more effective therapies, possibly including vaccines for individuals not exposed to the virus and for AIDS patients. Policy makers realize that they have a long road to travel before they begin to think about having this disease in check. “You not only have the effect of the virus infecting the cell,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). “The HIV envelope itself is an extraordinary entity in its ability to have an aberrant effect on the immune system. In addition to being a disease of immune deficiency, it is a disease of aberrant immune system activations. These effects are really quite profound. Unfortunately for the human species HIV/AIDS is proving to be an extraordinary experiment of nature with regard to its effects on the immune system.”

Marie Chow, professor of microbiology and immunology at the University of Arkansas, expands that thought. “Certainly other viruses have had some effects on immune systems before, but we never saw anything as devastating as the HIV,” she explains. That devastation is amplified by HIV’s ability to destroy the immune system. “The virus has been very difficult to pin down. HIV is making a precision surgical hit, knocking out the cells that direct and regulate the immune response,” Chow continues. “AIDS victims succumb to diseases caused by other fungal, parasitic, bacterial, and viral infections owing to the loss of T cell function from the underlying HIV infection. On the one hand we’re still learning so much about the immune system and how it works. But at the same time we can’t defer research on HIV therapeutics and vaccine development until we understand how to help the immune system combat infections. It is really guerilla warfare at several levels, developing treatments and therapies for the variety of different infections seen in AIDS patients that are symptoms of the HIV infection itself.”

Multidisciplinary approaches, involving collaborations between basic researchers and clinicians and among research scientists with different skills, have become mandatory for that effort and for treating the conditions that the virus causes. “HIV has forced us to deal with this disease on multiple fronts with individuals who have different backgrounds,” says Chow.

From: http://ping.fm/P9PkF

Strawberry and Feta Salad Recipe Great Aphrodisiac

SOME INTERESTING FACTS ABOUT STRAWBERRIES AS APHRODISIACS:

Strawberries gained their reputation as an aphrodisiac due to their large number of tiny seeds symbolizing fertility. In art and literature, the strawberry was usually portrayed as a symbol of sensuality and earthly desire and has been described as fruit nipples. Strawberries contain more vitamin C than any other berry. They also contain a good amount of potassium, folic acid and some iron and fiber. So strawberries can aid in boosting an otherwise lacklustre libido by providing essential vitamins and minerals needed to supply energy and keep the fires burning.

source

Ingredients

1 cup slivered almonds
2 cloves garlic, minced
1 teaspoon honey
1 teaspoon Dijon mustard
1/4 cup raspberry vinegar
2 tablespoons balsamic vinegar
2 tablespoons brown sugar
1 cup vegetable oil
1 head romaine lettuce, torn
1 pint fresh strawberries, sliced
1 cup crumbled feta cheese

Directions

In a skillet over medium-high heat, cook the almonds, stirring frequently, until lightly toasted. Remove from heat, and set aside.
In a bowl, prepare the dressing by whisking together the garlic, honey, Dijon mustard, raspberry vinegar, balsamic vinegar, brown sugar, and vegetable oil.
In a large bowl, toss together the toasted almonds, romaine lettuce, strawberries, and feta cheese. Cover with the dressing mixture, and toss to serve.

From: http://ping.fm/f9WGn

DNA Sequence Discovered That Causes Lupus

A “genetic accelerator” is responsible for the most severe cases of Lupus (systemic lupus erythemathosus), an autoimmune disease: the accelerator, called enhancer HS1.2, speeds up the activity of some critical genes of the immune system involved in the disease.

A team of Italian researchers at the Catholic University of Sacred Heart in Rome found that the enhancer HS1.2 is like the accelerator of the car and boosts the pathological immune response typical of the disease by enhancing the production of the pathological antibodies that attack the patient’s body instead of defending it (autoantibodies).

Professor Gianfranco Ferraccioli, Head of the Rheumatology Unit of Rheumatology and Internal Medicine of the Catholic University led the research in collaboration with Professor Domenico Frezza at Tor Vergata University of Rome and Professor Raffaella Scorza at University of Milan and they published their results in the Annals of the Rheumatic Diseases.

The discovery could lead to more targeted and effective therapies against this complex disease, in particular against the most severe cases, Professor Ferraccioli explained.

Systemic lupus erythematosus is an autoimmune disease, that is a condition in which the patient’s immune system goes haywire and begins to attack the body rather than defend it. Lupus affects about 60,000 people in Italy, with a major prevalence among females. Lupus affects several different organs and tissues and causes a variety of symptoms, including joint pain, fever, skin rashes, hair loss, Raynaud’s disease, anemia, nephritis.

The therapies currently used are based on cortisone, anti-malarial drugs and immunosuppressants (azathioprine, mycophenolate, cyclophosphamide) and biologic drugs (rituximab, Belimumab).

But in many cases Lupus is more aggressive and so far the origin of this particular severity was quite unclear.

Italian researchers discovered that the cause of the most severe cases is the accelerator HS1.2 enhancer. Enhancers are DNA sequences that accelerate the activation of neighboring genes and enhance their functioning, hence the name.

HS1.2 leads to enhanced activation of the “transcription factor NF-KB” (a transcription factor is a molecule that “reads” the genes to make them work), which in turn dramatically increases the aggressiveness of the inflammatory processes underlying the disease.

Italian researchers have discovered that over 30 per cent of the patients has the enhancer HS1.2 in their Dna and that it causes a more severe form of Lupus.

The researchers reached this finding after demonstrating that the enhancer HS1.2 promotes also other autoimmune diseases such as rheumatoid arthritis and identified how the enhancer causes increased susceptibility to autoimmune diseases.

“Our results suggest that new drugs that turn off the enhancer HS1.2, or inhibit its effect on NF-KB, can stop the disease without the need for immunosuppressive drugs or other therapies with many side effects,” Ferraccioli said. “Moreover the discovery of the role of this enhancer allows us to better classify patients and formulate a precise prognosis for each one moving toward more personalized care.”

From: http://ping.fm/SEp0F

Resveratrol Scientists React to Fraud Scandal

January 13, 2012 (New York, New York) — As the controversy over the research fraud allegations against Dr Dipak Das enter its third day, researchers, clinicians, and red-wine enthusiasts more generally are wondering just what the news means for the field of resveratrol research. At the very least, scientists told heartwire , plans for an international meeting scheduled for later this year have been turned upside down: Das was one of just eight international experts on the scientific committee for Resveratrol 2012.

As previously reported by heartwire , the University of Connecticut found evidence that Das had fabricated and falsified data in dozens of published papers, many asserting that resveratrol, found in red wine, improved cardiovascular health. The university is in the process of dismissing Das and has already returned $890 000 of the federal research funding awarded to Das.

The case is attracting more than the usual flurry of interest for a research fraud case, in part because red wine has long enjoyed a reputation as a heart-smart accompaniment to a healthy diet: resveratrol has emerged as a key candidate in molecular studies looking at just how wine benefits the cardiovascular system. Interest in the compound culminated in the first international resveratrol meeting, held in Denmark in 2010, and led to a position paper published in PLoS One on which Das was an author [1].

Resveratrol 2012 is to be held in Lucknow, India, December 10-12, 2012.

Chair of the scientific committee, Dr Ole Vang, told heartwire by email that he was too ill to speak by phone Friday. Instead, he referred calls to Dr Joseph Wu (New York Medical College, Valhalla, NY), who told heartwire he’s been invited to the meeting, but “now I don’t really know if it’s going to be held or not! I hope so, because I think the field of resveratrol could benefit from a group of scientists [getting together] who have a common interest on trying to understand how this molecule works. But given the current interest and climate surrounding Dr Das, I don’t know.”

Another member of the scientific committee, however, Dr John M Pezzuto (University of Hawaii, Hilo), told heartwire the meeting “absolutely” will go ahead as planned.

“First of all, if you look at the 4000 [published] papers, resveratrol has potential in many different therapeutic areas. . . . There’s a big laundry list of therapeutic areas and many workers in addition to Das, in cardiac work as well. So I don’t think [the controversy] is going to affect that adversely at all–it might actually gain it more attention.”

Pezzuto also confirmed that Vang has written to the other members of the scientific committee “and said, basically, chill out,” while the investigation into Das plays out.

The case “looks pretty bleak,” Pezzuto said, “but we don’t fully know. . . . If he is proven guilty I would assume he would resign and if he doesn’t I expect Ole will consult with us and we’ll take action.”

This “Won’t Impact Body of Science”

Another member of the scientific committee, Dr Nihal Ahmad (University of Wisconsin), told heartwire that he believed he and other committee members would be “review[ing] the situation.”

“I am myself following the story very closely,” Ahmad said. “However, I do not believe that this is going to have much effect on the body of science, especially because the effect of resveratrol has been verified by a number of researchers and there is a comprehensive amount of data in a variety of experimental models suggesting that resveratrol may be useful against certain diseases. Thus, even if some of Dr Das’s work is false and retracted, it will not likely impact the body of science on this very promising agent.”

Those views, not surprisingly, were echoed by Pezzuto and Wu, the latter noting that Das’s work was concentrated in a specific ischemia-reperfusion model, but that he was not the only researcher using this model.

Pezzuto also pointed to the position paper derived from the 2010 meeting on which he, as well as Das, Vang, Wu, and Ahmad are all coauthors, noting that it clearly concludes that the existing evidence is not strong enough to recommend administration of resveratrol to humans. “I can say that during the course of that meeting there were no signs of any impropriety from Das or anyone else in terms of lack of integrity or pushing an agenda or trying to bias the report in any way,” Pezzuto told heartwire . “There is a broad body of scientific investigation that supports certain perceived benefits for heart health, beyond Dr Das, and ultimately you can see in our report, and we state it pretty unequivocally, to say that the compound has clinical activity you need to perform clinical trials.”

He continued: “My personal opinion is, if Dr Das or his people doctored some Western blots, it’s not going to affect the pathway forward [for resveratrol] because ultimately the same body of evidence exists beyond what he’s published indicating that there’s some potential, and ultimately trials need to be conducted to prove that it’s efficacious or not.”

heartwire contacted the American Heart Association for its views on the Das debacle. Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD), speaking in generalities rather than commenting on the specifics of the Das case, made the point that research misconduct happens. It remains key, he said, that scientific process and clinical recommendations never rely too heavily on work conducted by a single group or a single laboratory. Nor, he added, should a single instance of malfeasance unduly influence an entire field.

“On balance here, the evidence is in favor of improvement in cardiovascular risk with [moderate red-wine consumption], because of the components that are part of alcohol and red wine in particular,” Tomaselli told heartwire . “The message here is that a single incident like this doesn’t undermine the overall hypothesis about wine/alcohol and CV risk.”

From: http://ping.fm/eHdHy

Related articles

• Resveratrol and Fraud (forbes.com)
• ‘Fabrication’: Professor accused of falsifying red wine health research (winebees.wordpress.com)
• Never Trust Health Food Fads (eoghann.com)

Alternative Splicing of RNA Triplets Regulated and Accelerates Proteome Evolution PART I

Abstract Top
Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3′ splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue-specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ~15-fold increase in the frequency of three base pair gaps at 3′ splice sites relative to nearby exon positions in both mammals and in Drosophila.
Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exon boundaries in rodents, and a model involving point mutations that create, destroy, or alter NAGNAGs can explain both the increased frequency and biased codon composition of gained/lost sequence observed at the beginnings of exons. This study shows that NAGNAG alternative splicing generates widespread differences between the proteomes of mammalian tissues, and suggests that the evolutionary trajectories of mammalian proteins are strongly biased by the locations and phases of the introns that interrupt coding sequences.

Author Summary Top
In order to translate a gene into protein, all of the non-coding regions (introns) need to be removed from the transcript and the coding regions (exons) stitched back together to make an mRNA. Most human genes are alternatively spliced, allowing the selection of different combinations of exons to produce multiple distinct mRNAs and proteins. Many types of alternative splicing are known to play crucial roles in biological processes including cell fate determination, tumor metabolism, and apoptosis. In this study, we investigated a form of alternative splicing in which competing adjacent 3′ splice sites (or splice acceptor sites) generate mRNAs differing by just an RNA triplet, the size of a single codon. This mode of alternative splicing, known as NAGNAG splicing, affects thousands of human genes and has been known for a decade, but its potential regulation, physiological importance, and conservation across species have been disputed. Using high-throughput sequencing of cDNA (“RNA-Seq”) from human and mouse tissues, we found that single-codon splicing often shows strong tissue specificity. Regulated NAGNAG alternative splice sites are selectively conserved between human and mouse genes, suggesting that they are important for organismal fitness. We identified features of the competing splice sites that influence NAGNAG splicing, and validated their effects in cultured cells. Furthermore, we found that this mode of splicing is associated with accelerated and highly biased protein evolution at exon boundaries. Taken together, our analyses demonstrate that the inclusion or exclusion of RNA triplets at exon boundaries can be effectively regulated by the splicing machinery, and highlight an unexpected connection between RNA processing and protein evolution.

Citation: Bradley RK, Merkin J, Lambert NJ, Burge CB (2012) Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution. PLoS Biol 10(1): e1001229. doi:10.1371/journal.pbio.1001229

Academic Editor: Laurence D. Hurst, University of Bath, United Kingdom

Received: June 23, 2011; Accepted: November 18, 2011; Published: January 3, 2012

Copyright: © 2012 Bradley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship (RKB: DRG 2032-09), by a major equipment grant from the National Science Foundation (no. 0821391), and by grants from the US National Institutes of Health (CBB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: BPS, branch point sequence; EST, expressed sequence tag; FDR, false discovery rate; PSI, percent spliced in; SNP, single nucleotide polymorphism

* E-mail: cburge@mit.edu

¤ Current address: Computational Biology Program, Public Health Sciences Division, and Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

From: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001229

Improved Access to Primary Care Reduces Mortality

DRA MARTHA CASTRO NORIEGA (DR. MARTHA CASTRO MD)

A linear relationship exists between patient access to primary care and mortality, according to the findings of a large, retrospective study.

Anthony Jerant, MD, from the University of California, Davis, in Sacramento, and colleagues published their findings in the January/February 2012 issue of the Annals of Family Medicine.

The authors noted that despite findings of reduced mortality among individuals with access to primary care at the population level, it remains unclear whether these findings are applicable at the individual patient level. “A potential pitfall in interpreting the findings of [previous] studies is the ecologic fallacy: falsely concluding that aggregate statistics collected for a group are applicable to individuals within the group,” the authors write. “Studies with individuals as the unit of analysis are needed to examine the association of specific primary care attributes with mortality at the patient level.”

In this study, the authors used individual patient-level data from the 2000 to 2005 Medical Expenditure Panel Survey, which includes questions on primary care attributes, linked to the National Death Index. They included 52,241 survey participants aged 18 to 90 years for whom mortality ascertainment and all healthcare attribute items were available. Of those, 1717 died during up to 6 years of follow-up. Overall, the primary care attributes score was inversely associated with mortality (adjusted hazard ratio, 0.79; 95% confidence interval [CI], 0.64 – 0.98; P = .03). Ethnicity, age, sex, mental and physical health, and total annual healthcare expenditures were also significantly associated with mortality.

The authors categorized primary care facilities according to 5 criteria (care for new health problems, preventative care, referrals to other healthcare professionals, enhanced access, and patient-centeredness), assigning a score of 1 (yes) or 0 (no) to each attribute and averaging the score for each participant. Mental and physical health were measured using the 12-Item Short-Form Health Survey Mental Component (MCS-12) and Physical Component (PCS-12) scores, with scores ranging from 0 (poor health) to 100 (excellent health). The authors categorized mortality as death before December 31, 2006.

Mortality was significantly lower among participants with a primary care attributes score of 1.0 (adjusted hazard ratio, 0.81; 95% CI, 0.66 – 0.99) than among those with a score of 0 to 0.5, after adjusting for smoking status and body mass index (P = .04). More than 25% of participants had an attributes score of 1.0, and these individuals were more likely to be white and women, live in the Northeast, have private insurance, report more chronic health problems, have lower MCS-12 and PCS-12 scores, have higher healthcare expenditures, and be an older age.

From: Ping.fm