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Posts Tagged ‘Stanford’


The Stanford Center for Clinical and Translational Research and Education, or Spectrum – NIH Awards Stanford $45.3M

Reporter: Aviva Lev-Ari, PhD, RN

NIH Awards Stanford $45.3M for Translational Research

October 07, 2013

NEW YORK (GenomeWeb News) – The Stanford Center for Clinical and Translational Research and Education, or Spectrum, is being awarded $45.3 million over four and a half years by the National Institutes of Health to push forward translational research in medicine.

Spectrum is one of 15 institutions to receive such an award being funded as part of the Clinical and Translational Sciences Awards, which were launched in 2006 by NIH “to help meet the nation’s urgent need to provide better healthcare to more people for less money,” the Stanford School of Medicine said.

Stanford won a first round of CTSA funding in 2008 of $30 million.

The new funding will be used to support two new programs at Stanford, one in disease diagnostics and one in population health sciences.

The diagnostics program seeks to develop new methods of testing and preventing disease through advances in omics, immune monitoring, molecular imaging, single-cell analysis, computation, and informatics, the school said. Atul Butte, chief of systems medicine and associate professor of pediatrics and genetics, will lead the program.

The Population Health Sciences Initiative will design systems to serve as a new source of practice-based evidence. The systems will be based on the daily experiences of practicing physicians and information drawn from clinical data warehouses, Stanford said.

This initiative is led by Robert Harrington, professor and chair of medicine; Mark Cullen, professor of medicine and chief of the Division of General Medical Disciplines; and Douglas Owens, professor of medicine and director of the Stanford Center for Primary Care and Outcomes Research and the Center for Health Policy.

The new CTSA award also will be used to address the shortage of qualified clinical and translational researchers across the US by funding new training programs and online courses in clinical research, Stanford said.

Related Stories

SOURCE

http://www.genomeweb.com//node/1290106?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Stanford%20Nabs%20$45M%20NIH%20Award;%20Signal%20Genetics’%20BCBS%20Coverage;%20$1.4M%20Approval%20for%20Geisinger;%20More%20-%2010/07/2013%2003:45:00%20PM

 

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Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 9/16/2013

VIDEO CLIPS
Enzymes That Are Not Proteins: The Discovery of Ribozymes
Listen to past HHMI President Dr. Thomas Cech discussing his Nobel Prize-winning discovery of RNA’s catalytic properties.

http://www.hhmi.org/biointeractive/enzymes-are-not-proteins-discovery-ribozymes

Stanford Report, March 15, 2013

Long-term evolution is ‘surprisingly predictable,’ Stanford experiment shows

A protein-folding simulation shows that the debated theory of long-term evolution is not only possible, but that the outcomes are predictable. The Stanford experiment provides a framework for testing evolutionary outcomes in living organisms.

BY BJORN CAREY

L.A. CiceroVisiting scholar Mike Palmer left, and Professor Marcus FeldmanDr. Michael Palmer, left, and Professor Marcus Feldman, with co-author Arnav Moudgil (not pictured), found that the long-term evolutionary dynamics were surprisingly predictable in a model of protein folding and binding.

Two birds are vying for food. One bird’s beak is shaped, by virtue of a random mutation, such that it’s slightly more adept at cracking seeds. This sets the bird on the road toward acquiring more food, a better chance of scoring a mate and, most important, passing on its genetic endowment.

This individual’s success is an example of short-term evolution, the widely accepted Darwinian process of natural selection by which individual organisms that have better adapted to their surroundings prevail.

In recent years, however, some scientists have argued that natural selection occurs not just at the individual organism level, but also between lineages over the course of many generations. In a new study, Stanford biologists have demonstrated that not only is this long-term evolution possible, but that long-term evolutionary outcomes can be surprisingly predictable.

The group set up a computer simulation in which 128 lineages of proteins continuously folded into new shapes, competing to bind with other molecules, called ligands, in each new configuration. The better each protein could attach itself to the ligands, the more ligands it would scoop up, and the higher its fitness – that is, its average number of “offspring” – would be. The simulation was run for 10,000 generations.

Although the chaos of 128 lineages – a total of more than 16,000 individual proteins – mutating over thousands of generations might seem unpredictable, and that it would be nearly impossible for the same thing to happen twice, it’s actually the opposite.

“Even though things look complicated, the possible evolutionary trajectories are quite constrained,” said lead author Michael Palmer, a computational biologist at Stanford. “There are only a few viable mutations at any point, which makes the dynamics predictable and repeatable, even over the long term.”

The study, co-authored by Marcus Feldman, a biology professor at Stanford, and Stanford research biologist Arnav Moudgil, was recently published in the Journal of the Royal Society Interface.

In some experiments, the lineages that consistently came out on top in the long term were not initially the best adapted at binding to ligands. “The immediate fitness is not the only important thing,” Palmer said. “Yes, a lineage does have to survive in the short term. But just as important is how it is able to adapt to new and potentially variable environments over the longer term.”

A good example of this scenario is Darwin’s famous finches. It’s thought that individuals – perhaps just a single pair of birds – from a South American species ended up on the Galápagos Islands about 1 million years ago. Today their descendants have diversified into about 15 modern species. Some eat seeds, some eat insects, or flowers. Some eat ticks, or even drink the blood of other birds.

“If there was some catastrophe that removed one of those food sources, it might wipe out one or more of the 15 species, but the rest of the lineage – the descendants of that initial pair of birds – would persist,” Palmer said. “Now say there was a competing lineage that was great at cracking seeds, but unable to evolve to other diets due to some prior genetic constraint. The same catastrophe could wipe it out.”

The finding, and others like it, could represent a significant shift in viewpoint for biologists. For one thing, it means that in certain situations, scientists should look beyond the details at the level of the individual organism, as the evolutionary dynamics can be accurately understood as lineage selection.

It also has implications on a species’ genomic architecture, or how a genome is organized on the lineage level. While a lineage’s genome might primarily select for a particular set of traits in order for individuals to survive in the short term, in order to out-compete other lineages, it must also be able to adapt to new conditions over the long term.

“An individual can have a lucky mutation that produces an immediate adaptation,” said Palmer. “Or a lineage can have a lucky mutation that happens to position it to adapt to the range of environments it will experience over the next thousand generations. A single mutation can have a distinct short-term and long-term fitness.”

The authors believe that the work can be replicated in microorganisms, and are now hoping that microbiologists will apply the new metrics of selection in vitro.

“There is already some evidence in vitro that there is a lot of constraint on evolutionary trajectories,” Palmer said, “and we think we’ve come up with a good framework to quantify evolutionary predictability and long-term fitness.”

Media Contact

Michael Palmer, Biology: (415) 867-3653, mepalmer@charles.stanford.edu

Bjorn Carey, Stanford News Service: (650) 725-1944, bccarey@stanford.edu

SOURCE:

http://news.stanford.edu/news/2013/march/long-term-evolution-031513.html

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Reporter: Aviva Lev-Ari, PhD, RN

 

Stanford Launches Computational Genomics Center

December 03, 2012

NEW YORK (GenomeWeb News) – Stanford University has launched a new genomics research center that will foster collaboration across its seven schools and harness new computational technologies, it said today.

The Stanford Center for Computational, Evolutionary and Human Genomics, headed by the university’s School of Medicine and School of Humanities and Sciences, has been authorized for five years of funding, the university said.

Created with the goal of spurring and nurturing cross-cutting research collaborations, the new center will be open to all university faculty and labs. It will provide support for small project grants and computational genomics analysis services for member labs, faculty, students, and staff.

The center also will consult with academic institutions, industry, government, and research organizations on collaborations, will support graduate and postdoctoral students, and in its first year will launch public outreach programs in three areas – genomics and social systems, medical genomics, and agricultural, ecological, and environmental genomics. The center’s focus, regardless of the particulars of the project at hand, will be on using expertise and methods for sorting through, integrating, and analyzing large-scale data sets.

Stanford Professor Carlos Bustamante, who also is one of the center’s two founding directors, told GenomeWeb Daily News today that the university has not yet set the funding amount for the center but has committed to five years and will be “sufficient to catalyze all of the programs that we want to get started.” Ultimately, the center will seek funding from beyond the university, he noted.

“The incredible thing about a place like Stanford is that we’ve got the medical school co-located with the main campus, the traditional arts and sciences and humanities programs, and an exceptional engineering school, so we really are looking to create interdisciplinary programs that cut across traditional academic boundaries,” Bustamante said.

He explained that the new center will pursue and support projects that cut a broad swath across Stanford’s academic research areas, including paleo-anthropology, population genetics, agriculture, climate science, and biomedicine, as well as pursue bioethical questions that have arisen alongside human genomic science.

For example, Bustamante said, the research may involve integrating genetics and history studies.

“How can we use technologies from genomics to improve our understanding of the great human diaspora? That’s an area that [Founding Director and Stanford Biology Professor] Mark Feldman and I have been interested in for years.

“But now we can begin to do things that are cross-cutting in, say, funding archaeology students that want to study ancient DNA, or beginning to do projects that have to do with race, genetics, and ethnicity,” he said. “Now we can fund graduate students and post-docs to really work on interdisciplinary issues that are very hard to fund through traditional mechanisms.”

Bustamante pointed out that Stanford has “a tremendous amount of expertise in machine learning and statistical learning,” and the center will try to bring people and projects together with clinicians who are pursuing cutting-edge projects in a wide array of fields, such as cancer genomics.

“Traditionally, these people would know about each other but they haven’t necessarily had the mechanisms to initiative [joint] pilot projects and collaborations,” Bustamante said, and that is where the new center might fit in.

One of the key aims of the center also is to forge collaborations between biomedical researchers with those in the humanities and social sciences.

For example, one of the center’s executive committee members, Stanford Biology Professor Noah Rosenberg, is co-directing a program focused on Jewish genetics and Jewish history. Another executive member, Professor Dmitri Petrov, will head a year-long project focused on ecological genetics.

Bustamante, who previously was a researcher at Cornell University, said he expects that the center will branch out into agricultural genomics as well.

“Genomics is transforming agriculture. It is probably where genomics is having some of its biggest impacts,” he said.

Aside from the wide range of research areas that the new center may support, it will have one core mission, Bustamante told GWDN.

“It really is, first and foremost, a center focused on computational analysis, both in terms of developing methods and computing on big data. That is a particular expertise of those of us involved in launching the center.”

 

 

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Stanford Study Finds miRNA-320a a Broad Regulator of Glycolysis, Potential Drug Target

 Reporter: Aviva Lev-Ari, PhD, RN

A study by Stanford researchers has found that microRNA-320a appears to regulate glycolysis in response to oxidative stress in several biological systems, including lung cancer and wasting of disused muscle.

The Stanford team was initially interested in better understanding the wasting of diaphragm muscles due to mechanical ventilation, but expanded its study to look at lung cancer and an experimental in vitro model of oxidative stress, as well as the similarity of pathogenic glycolytic pathways across these biological systems.

The group profiled miRNA and protein expression in samples from human diaphragm muscles under mechanical ventilation to identify miRNAs associated with the glycolytic rate-limiting enzyme phosphofructokinase, or PFKm, without which glycolysis is reduced.

The group initially identified 28 miRNAs that were significantly downregulated and three that were upregulated in the ventilated human diaphragm samples. Using predictive software, the group pinpointed miR-320a as being potentially involved in the regulation PFKm.

To validate miR-320a, the researchers looked at all three experimental systems — samples of diaphragm tissue, lung cancer, and an in vitro cell model under oxidative stress. In all three, miR-320a was down-regulated in the samples versus the control.

The group also confirmed that miR-320a influences PFKm in each system, and further demonstrated that miR-320a knockdown increased lactate levels in vitro; and thathigher miR-320a levels reduced lactate levels in in vivo mouse experiments.

The group wrote that the study shows for the first time that glycolytic activity “is increased in diaphragm tissue that is noncontractile as a result of full mechanical ventilator support.” The results also confirmed that glycolysis up-regulation, or the Warburg effect, is present in lung adenocarcinoma, and that both otherwise divergent disorders are in fact linked by the influence of miR-320a.

The finding has implications for cancer treatment, as well as more effective treatment for dysfunctional diaphragm muscles following breathing support using a ventilator, according to the team, which published the study online in the FASEB Journal earlier this month.

Glycolysis is the process of converting sugar into energy, and is implicated in the growth of some cancers through a process called the Warburg effect. To the Stanford team, the Warburg effect seen in lung adenocarcinoma “appears to closely mimic” that of dysfunctional human diaphragm tissue after mechanical ventilation therapy, a condition called ventilator-induced diaphragm dysfunction, or VIDD.

The Stanford researchers claim that their study shows that these very divergent biological systems share the same glycolysis regulatory apparatus involving miR-320a, which the authors believe they are the first to identify.

Additionally, “miR-320 regulation of glycolysis may represent a general mechanism underlying other clinical diseases that are associated with changes in energy supply,” the researchers wrote, such as cardiac ischemia, to insulin resistance.

In cancer specifically, down-regulation of miR-320a has been previously reported in a number of malignancies, the group reported. Coupled with the fact that the Warburg effect is thought to be important in many cancers, and the results of the group’s study in adenocarcinoma, this suggests that miR-320a “may be directly related” to the development of cancer, and that the associated glycolysis may be a potential drug target.

FASEB J. 2012 Jul 5. [Epub ahead of print]

Oxidative stress-responsive microRNA-320 regulates glycolysis in diverse biological systems.

Tang HLee MSharpe OSalamone LNoonan EJHoang CDLevine SRobinson WHShrager JB.

Source

*Division of Thoracic Surgery, Department of Cardiothoracic Surgery.

Abstract

Glycolysis is the initial step of glucose catabolism and is up-regulated in cancer cells (the Warburg Effect). Such shifts toward a glycolytic phenotype have not been explored widely in other biological systems, and the molecular mechanisms underlying the shifts remain unknown. With proteomics, we observed increased glycolysis in disused human diaphragm muscle. In disused muscle, lung cancer, and H(2)O(2)-treated myotubes, we show up-regulation of the rate-limiting glycolytic enzyme muscle-type phosphofructokinase (PFKm, >2 fold, P<0.05) and accumulation of lactate (>150%, P<0.05). Using microRNA profiling, we identify miR-320a as a regulator of PFKm expression. Reduced miR-320a levels (to ∼50% of control, P<0.05) are associated with the increased PFKm in each of these diverse systems. Manipulation of miR-320a levels both in vitro and in vivo alters PFKm and lactate levels in the expected directions. Further, miR-320a appears to regulate oxidative stress-induced PFKm expression, and reduced miR-320a allows greater induction of glycolysis in response to H(2)O(2) treatment. We show that this microRNA-mediated regulation occurs through PFKm’s 3′ untranslated region and that Ets proteins are involved in the regulation of PFKm via miR-320a. These findings suggest that oxidative stress-responsive microRNA-320a may regulate glycolysis broadly within nature.-Tang, H., Lee, M., Sharpe, O., Salamone, L., Noonan, E. J., Hoang, C. D., Levine, S., Robinson, W. H., Shrager, J. B. Oxidative stress-responsive microRNA-320 regulates glycolysis in diverse biological systems.

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