From gene to function: Genome wide study into new gene functions in the formation of platelets

ScienceDaily (Nov. 30, 2011) — In a study into the genetics of blood cell formation, researchers have identified 68 regions of the genome that affect the size and number of platelets. Platelets are small cells that circulate in the blood and are key to the processes of blood clotting and wound healing.

In this genome-wide study, the team used a multidisciplinary approach to successfully identify new genetic variants involved in the formation of platelets and more importantly, defined the function of genes near these variants using a series of biological analyses.

Abnormally high or low platelet counts can lead to disease. An increase in the number of platelets, or an increase in their size can lead to an increased risk for thrombotic events, like heart attacks and strokes. A very low number of platelets or platelets that do not function well, increases the risk of bleeding.

"This is a detective story starting with the initial genetic discovery and allowing us to identify new genes that could contribute to platelet associated diseases," says Professor Willem H Ouwehand, senior co-author at the University of Cambridge and NHS Blood and Transplant. "Our aim of this genome-wide meta-analysis study was to discover which genes control the size and number of platelets, to understand how these genes instruct blood stem cells to orchestrate every day the formation of billions of platelets and finally to investigate whether genes associated with heart attacks and strokes overlap with the genes that affect platelet formation."

In this collaborative study, the team first developed a prioritisation strategy that allowed them to identify and pinpoint the genes underlying the formation of platelets through biological annotations of these genes. This effort laid the foundation for the construction of a protein-protein interaction network that shows how the different genetic players interact. Finally, they analysed the role of the genes in model organisms and found their function to be conserved in evolution.

The researchers found the newly identified genes associated with platelet characteristics overlap with other genes implicated in inherited bleeding disorders. This genetic overlap suggests that this study may help discover new genes implicated in severe forms of bleeding disorders, providing evidence that the new findings will be significant in clinical research for improvements in the care of patients.

This study involved about 68,000 individuals from different ancestries (European, South & East Asian) making it the largest genome-wide meta-analysis study to be conducted globally on platelet number and volume.

"This is the largest dataset of this type ever produced, and yields a wealth of new exciting biological discoveries and insights into the genetic control of blood cell formation," says Dr Nicole Soranzo,senior co-author from the Wellcome Trust Sanger Institute. "Our findings will be relevant not only to better understand the mechanisms leading to the formation of blood cells, but also to pinpoint new genes involved in diseases with altered blood clotting."

The team examined the role of the genes they identified in the fruit fly and zebrafish. They found that reducing the activity of one of these genes, ARHGEF3, in fish abrogates not only the production of platelets but also of red blood cells because the blood forming cells cannot capture iron. The study has shown that the human equivalent, ARHGEF3 gene is an important new regulator of the uptake of iron from the diet.

Tropomyosin 1 is a member of a family of genes already known to be involved in the regulation of muscle contraction and plays a role in heart disease. This study found a novel role for this well-known protein in platelet formation.

"This study provides a paradigm for how to successfully translate genome-wide association studies into function" says Dr Christian Gieger, senior co-author from the Institute of Genetic Epidemiology at the Helmholtz Center Munich."We have shown that biologic and functional annotation can greatly enhance our ability to interpret genetic data."

"These genes could be used in the future as new targets to develop better and safer platelet inhibitors for treatments of patients with heart attacks or strokes."

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Christian Gieger et al. New gene functions in megakaryopoiesis and platelet formation. Nature, 2011; DOI: 10.1038/nature10659

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In a star's final days, astronomers hunt 'signal of impending doom'

ScienceDaily (Nov. 30, 2011) — An otherwise nondescript binary star system in the Whirlpool Galaxy has brought astronomers tantalizingly close to their goal of observing a star just before it goes supernova.

The study, submitted in a paper to the Astrophysical Journal, provides the latest result from an Ohio State University galaxy survey underway with the Large Binocular Telescope, located in Arizona.

In the first survey of its kind, the researchers have been scanning 25 nearby galaxies for stars that brighten and dim in unusual ways, in order to catch a few that are about to meet their end. In the three years since the study began, this particular unnamed binary system in the Whirlpool Galaxy was the first among the stars they've cataloged to produce a supernova.

The astronomers were trying to find out if there are patterns of brightening or dimming that herald the end of a star's life. Instead, they saw one star in this binary system dim noticeably before the other one exploded in a supernova during the summer of 2011.

Though they're still sorting through the data, it's likely that they didn't get any direct observations of the star that exploded -- only its much brighter partner.

Yet, principal investigator Christopher Kochanek, professor of astronomy at Ohio State and the Ohio Eminent Scholar in Observational Cosmology, does not regard this first result as a disappointment. Rather, it's a proof of concept.

"Our underlying goal is to look for any kind of signature behavior that will enable us to identify stars before they explode," he said. "It's a speculative goal at this point, but at least now we know that it's possible."

"Maybe stars give off a clear signal of impending doom, maybe they don't," said study co-author Krzystof Stanek, professor of astronomy at Ohio State, "But we'll learn something new about dying stars no matter the outcome."

Postdoctoral researcher Dorota Szczygiel, who led the study of this supernova, explained why the galaxy survey is important.

"The odds are extremely low that we would just happen to be observing a star for several years before it went supernova. We would have to be extremely lucky," she said.

"With this galaxy survey, we're making our own luck. We're studying all the variable stars in 25 galaxies, so that when one of them happens go supernova, we've already compiled data on it." The supernova, labeled 2011dh, was first detected on May 31 and is still visible in telescopes. It originated from a binary star system in the Whirlpool Galaxy -- also known as M51, one of the galaxies that the Ohio State astronomers have been observing for three years.

The system is believed to have contained one very bright blue star and one even brighter red star. From what the astronomers can tell, it's likely that the red star is the one that dimmed over the three years, before the blue star initiated the supernova.

When the Ohio State researchers reviewed the Large Binocular Telescope data as well as Hubble Space Telescope images of M51, they saw that the red star had dimmed by about 10 percent over three years, at a pace of three percent per year.

Szczygiel believes that the red star likely survived its partner's supernova.

"After the light from the explosion fades away, we should be able to see the companion that did not explode," she said.

As astronomers gather data from more supernovae -- Kochanek speculates that as many as one per year could emerge from their data set -- they could assemble a kind of litmus test to predict whether a particular star is near death. Whether it's going to spawn a supernova or shrink into a black hole, there may be particular signals visible on the surface, and this study has shown that those signals are detectable.

The team won't be watching our sun for any changes, however. At less than 10 percent of the mass of the star in supernova 2011dh, our star will most likely meet a very boring end.

"There'll be no supernova for our sun -- it'll just fizzle out," Kochanek said. "But that's okay -- you don't want to live around an exciting star."

This research was supported by the National Science Foundation.

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Researchers examine role of inflammatory mechanisms in a healing heart

ScienceDaily (Nov. 30, 2011) — Virginia Commonwealth University researchers have found that an inflammatory mechanism known as inflammasome may lead to more damage in the heart following injury such as a heart attack, pointing researchers toward developing more targeted strategies to block the inflammatory mechanisms involved.

Following a heart attack, an inflammatory process occurs in the heart due to the lack of oxygen and nutrients. This process helps the heart to heal, but may also promote further damage to the heart. The mechanisms by which the heart responds to injury are not fully understood, so researchers have been examining the cellular pathways involved to gain further insight.

In a study published online the week of Nov. 21 in the Proceedings of the National Academy of Sciences, researchers addressed the role of a specific inflammatory mechanism, called inflammasome, during the process of healing in the heart. Using an animal model, the team found that inflammasome amplifies the response by generating the production of a key inflammatory mediator known as Interleukin-1ß. Further, they described that pharmacologic inhibition of the formation of inflammasome prevents heart enlargement and dysfunction.

"Defining the role of the inflammasome in the response to injury in the heart and the possibility to intervene opens a new area of investigation for the prevention and treatment of heart failure following a heart attack," said Antonio Abbate, M.D., assistant professor of medicine in the VCU Department of Internal Medicine and Division of Cardiology.

According to Abbate, who serves as the interim director for the cardiac intensive care unit at the VCU Pauley Heart Center, this study supports the team's previous findings that showed that Interleukin-1ß affects the heart, and blocking Interleukin-1ß benefits patients of heart attack and heart failure.

"Based on the findings of the current study we are even more convinced that blocking Interleukin-1ß may be safe and beneficial, and we are now exploring novel ways to do so," he said.

Abbate said there are four ongoing clinical trials at the VCU Pauley Heart Center in patients with various heart conditions treated with a drug called anakinra which blocks Interleukin-1ß.

Abbate and his team continue to examine the molecular mechanisms of inflammasome formation and heart injury, and hope to determine new ways to intervene with potentially more targeted strategies in the future.

The study was conducted in the Victoria W. Johnson Center for Research at VCU, which is directed by Norbert Voelkel, M.D, professor of medicine in the Pulmonary and Critical Care Division.

Abbate led with a multidisciplinary team of VCU researchers biologists, physicians, and pharmacists including Eleonora Mezzaroma, Ph.D., and Stefano Toldo, Ph.D., post-doctoral associates in the VCU Pauley Heart Center; Daniela Farkas, B.S., research specialist in the Victoria Johnson Research Laboratory; Benjamin Van Tassell, Pharm.D., assistant professor of pharmacology and outcome sciences; and Fadi Salloum, Ph.D., assistant professor of medicine and physiology in the VCU Pauley Heart Center.

This study was supported by a grant from the American Heart Association.

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E. Mezzaroma, S. Toldo, D. Farkas, I. M. Seropian, B. W. Van Tassell, F. N. Salloum, H. R. Kannan, A. C. Menna, N. F. Voelkel, A. Abbate. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108586108

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Serendipitous news reading online is gaining prominence, study shows

ScienceDaily (Dec. 1, 2011) — Traditional media, such as newspapers and television news, require readers and viewers to intentionally seek out news by picking up a newspaper or turning on the television. The Internet and new technologies now are changing the way readers consume online news. New research from the University of Missouri shows that Internet users often do not make the conscious decision to read news online, but they come across news when they are searching for other information or doing non-news related activities online, such as shopping or visiting social networking sites.

Borchuluun Yadamsuren, a post-doctoral fellow at the Reynolds Journalism Institute (RJI) in the University of Missouri School of Journalism, found a shift in the way people have begun to perceive online news. She says that while some people still have the perception of news as tied to traditional media, others now hold a much broader perception of news that goes beyond what is reported by professional journalists. Yadamsuren attributes this to the wide array of information available online.

"Incidental exposure to online news is becoming a major way for many people to receive information about news events," Yadamsuren said. "However, many people don't realize how their news reading behavior is shifting to more serendipitous discovery."

Using mixed method approach, Yadamsuren surveyed nearly 150 respondents with further interviews of 20 of those respondents to understand their incidental exposure to online news. She found that respondents experience incidental exposure to online news in three different contexts. The first group of respondents reported that they come across interesting news stories while they visit online news sites. Others report incidental exposure to online news in the context of non-news related activities such as checking email and visiting Facebook and other social networking sites. The third group of respondents reported that they stumble upon "unusual," "weird," "interesting," "bizarre," unexpected," "outrageous," or "off the wall" news stories while they are conducting their normal Internet searches.

Currently, Yadamsuren is studying the relationship between incidental exposure to online news and different demographic and technology-access related factors. Yadamsuren believes it is important for media organizations to place links to their news stories on different sites throughout the Internet to take advantage of serendipitious news consuming behavior to expand their readership.

Yadamsuren's study was presented at the Association for Education in Journalism and Mass Communication (AEJMC) 2011 and American Society for Information Science and Technology (ASIST) 2011 Annual Meetings. Her research was also published in Information Research. Her current research at RJI involves developing strategies for news organizations to engage younger generations with online news based on incidental exposure.

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Moral dilemma: Would you kill one person to save five?

ScienceDaily (Dec. 1, 2011) — Imagine a runaway boxcar heading toward five people who can't escape its path. Now imagine you had the power to reroute the boxcar onto different tracks with only one person along that route.

Would you do it?

That's the moral dilemma posed by a team of Michigan State University researchers in a first-of-its-kind study published in the research journal Emotion. Research participants were put in a three dimensional setting and given the power to kill one person (in this case, a realistic digital character) to save five.

The results? About 90 percent of the participants pulled a switch to reroute the boxcar, suggesting people are willing to violate a moral rule if it means minimizing harm.

"What we found is that the rule of 'Thou shalt not kill' can be overcome by considerations of the greater good," said Carlos David Navarrete, lead researcher on the project.

As an evolutionary psychologist, Navarrete explores big-picture topics such as morality -- in other words, how do we come to our moral judgments and does our behavior follow suit?

His latest experiment offers a new twist on the "trolley problem," a moral dilemma that philosophers have contemplated for decades. But this is the first time the dilemma has been posed as a behavioral experiment in a virtual environment, "with the sights, sounds and consequences of our actions thrown into stark relief," the study says.

The research participants were presented with a 3-D simulated version of the classic dilemma though a head-mounted device. Sensors were attached to their fingertips to monitor emotional arousal.

In the virtual world, each participant was stationed at a railroad switch where two sets of tracks veered off. Up ahead and to their right, five people hiked along the tracks in a steep ravine that prevented escape. On the opposite side, a single person hiked along in the same setting.

As the boxcar approached over the horizon, the participants could either do nothing -- letting the coal-filled boxcar go along its route and kill the five hikers -- or pull a switch (in this case a joystick) and reroute it to the tracks occupied by the single hiker.

Of the 147 participants, 133 (or 90.5 percent) pulled the switch to divert the boxcar, resulting in the death of the one hiker. Fourteen participants allowed the boxcar to kill the five hikers (11 participants did not pull the switch, while three pulled the switch but then returned it to its original position).

The findings are consistent with past research that was not virtual-based, Navarrete said.

The study also found that participants who did not pull the switch were more emotionally aroused. The reasons for this are unknown, although it may be because people freeze up during highly anxious moments -- akin to a solider failing to fire his weapon in battle, Navarrete said.

"I think humans have an aversion to harming others that needs to be overridden by something," Navarrete said. "By rational thinking we can sometimes override it -- by thinking about the people we will save, for example. But for some people, that increase in anxiety may be so overpowering that they don't make the utilitarian choice, the choice for the greater good."

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Journal Reference:

Navarrete, C.D., McDonald, M., Mott, M., & Asher, B. Virtual Morality: Emotion and Action in a Simulated 3-D Trolley Problem. Emotion, 2011

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MAKS: Drug-free prevention of dementia decline

ScienceDaily (Nov. 30, 2011) — There are many different causes of dementia and, although its progression can be fast or slow, it is always degenerative. Symptoms of dementia include confusion, loss of memory, and problems with speech and understanding. It can be upsetting for both the affected person and their relatives and carers. New research published in BioMed Central's open access journal BMC Medicine shows that a regime of behavioral and mental exercises was able to halt the progression of dementia.

Researchers led by Prof. Graessel, from Friedrich-Alexander-Universität Erlangen, included in their study patients with dementia from five nursing homes in Bavaria. After random selection, half the patients were included on the year-long MAKS 'intervention' consisting of two hours of group therapy, six days a week. In addition all patients maintained their normal treatment and regular activities provided by the nursing home.

The MAKS system consists of motor stimulation(M), including games such as bowling, croquet, and balancing exercises; cognitive stimulation (K), in the form of individual and group puzzles; and practicing 'daily living' activities (A), including preparing snacks, gardening and crafts. The therapy session began with a ten minute introduction, which the researchers termed a 'spiritual element' (S), where the participants discussed topics like 'happiness', or sang a song or hymn.

After 12 months of therapy the MAKS group maintained their level on the Alzheimer's Disease Assessment Scale (ADAS) and, even more importantly maintained their ability to carry out activities of daily living, while the control group all showed a decrease in cognitive and functional ability.

Prof. Graessel explained, "While we observed a better result for patients with mild to moderate dementia, the result of MAKS therapy on ADAS (cognitive function) was at least as good as treatment with cholinesterase inhibitors. Additionally we found that the effect on the patients' ability to perform daily living tasks (as measured by the Erlanger Test of Daily Living (E-ADL)) was twice as high as achieved by medication. This means that MAKS therapy is able to extend the quality of, and participation in, life for people with dementia within a nursing home environment. We are currently in the process of extending these preliminary results to see if this prevention of dementia decline can be maintained over a longer time period."

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Journal Reference:

Elmar Graessel, Renate Stemmer, Birgit Eichenseer, Sabine Pickel, Carolin Donath, Johannes Kornhuber, Katharina Luttenberger. Non-pharmacological, multicomponent group therapy in patients with degenerative dementia: a 12-month randomised, controlled trial. BMC Medicine, 2011; (in press) [link]

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Setting the stage for life: Scientists make key discovery about the atmosphere of early Earth

ScienceDaily (Nov. 30, 2011) — Scientists in the New York Center for Astrobiology at Rensselaer Polytechnic Institute have used the oldest minerals on Earth to reconstruct the atmospheric conditions present on Earth very soon after its birth. The findings, which appear in the Dec. 1 edition of the journal Nature, are the first direct evidence of what the ancient atmosphere of the planet was like soon after its formation and directly challenge years of research on the type of atmosphere out of which life arose on the planet.

The scientists show that the atmosphere of Earth just 500 million years after its creation was not a methane-filled wasteland as previously proposed, but instead was much closer to the conditions of our current atmosphere. The findings, in a paper titled "The oxidation state of Hadean magmas and implications for early Earth's atmosphere," have implications for our understanding of how and when life began on this planet and could begin elsewhere in the universe.

For decades, scientists believed that the atmosphere of early Earth was highly reduced, meaning that oxygen was greatly limited. Such oxygen-poor conditions would have resulted in an atmosphere filled with noxious methane, carbon monoxide, hydrogen sulfide, and ammonia. To date, there remain widely held theories and studies of how life on Earth may have been built out of this deadly atmosphere cocktail.

Now, scientists at Rensselaer are turning these atmospheric assumptions on their heads with findings that prove the conditions on early Earth were simply not conducive to the formation of this type of atmosphere, but rather to an atmosphere dominated by the more oxygen-rich compounds found within our current atmosphere -- including water, carbon dioxide, and sulfur dioxide.

"We can now say with some certainty that many scientists studying the origins of life on Earth simply picked the wrong atmosphere," said Bruce Watson, Institute Professor of Science at Rensselaer.

The findings rest on the widely held theory that Earth's atmosphere was formed by gases released from volcanic activity on its surface. Today, as during the earliest days of the Earth, magma flowing from deep in the Earth contains dissolved gases. When that magma nears the surface, those gases are released into the surrounding air.

"Most scientists would argue that this outgassing from magma was the main input to the atmosphere," Watson said. "To understand the nature of the atmosphere 'in the beginning,' we needed to determine what gas species were in the magmas supplying the atmosphere."

As magma approaches Earth's surface, it either erupts or stalls in the crust, where it interacts with surrounding rocks, cools, and crystallizes into solid rock. These frozen magmas and the elements they contain can be literal milestones in the history of Earth.

One important milestone is zircon. Unlike other materials that are destroyed over time by erosion and subduction, certain zircons are nearly as old as Earth itself. As such, zircons can literally tell the entire history of the planet -- if you know the right questions to ask.

The scientists sought to determine the oxidation levels of the magmas that formed these ancient zircons to quantify, for the first time ever, how oxidized were the gases being released early in Earth's history. Understanding the level of oxidation could spell the difference between nasty swamp gas and the mixture of water vapor and carbon dioxide we are currently so accustomed to, according to study lead author Dustin Trail, a postdoctoral researcher in the Center for Astrobiology.

"By determining the oxidation state of the magmas that created zircon, we could then determine the types of gases that would eventually make their way into the atmosphere," said Trail.

To do this Trail, Watson, and their colleague, postdoctoral researcher Nicholas Tailby, recreated the formation of zircons in the laboratory at different oxidation levels. They literally created lava in the lab. This procedure led to the creation of an oxidation gauge that could then be compared with the natural zircons.

During this process they looked for concentrations of a rare Earth metal called cerium in the zircons. Cerium is an important oxidation gauge because it can be found in two oxidation states, with one more oxidized than the other. The higher the concentrations of the more oxidized type cerium in zircon, the more oxidized the atmosphere likely was after their formation.

The calibrations reveal an atmosphere with an oxidation state closer to present-day conditions. The findings provide an important starting point for future research on the origins of life on Earth.

"Our planet is the stage on which all of life has played out," Watson said. "We can't even begin to talk about life on Earth until we know what that stage is. And oxygen conditions were vitally important because of how they affect the types of organic molecules that can be formed."

Despite being the atmosphere that life currently breathes, lives, and thrives on, our current oxidized atmosphere is not currently understood to be a great starting point for life. Methane and its oxygen-poor counterparts have much more biologic potential to jump from inorganic compounds to life-supporting amino acids and DNA. As such, Watson thinks the discovery of his group may reinvigorate theories that perhaps those building blocks for life were not created on Earth, but delivered from elsewhere in the galaxy.

The results do not, however, run contrary to existing theories on life's journey from anaerobic to aerobic organisms. The results quantify the nature of gas molecules containing carbon, hydrogen, and sulfur in the earliest atmosphere, but they shed no light on the much later rise of free oxygen in the air. There was still a significant amount of time for oxygen to build up in the atmosphere through biologic mechanisms, according to Trail.

The research was funded by NASA.

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Dustin Trail, E. Bruce Watson, Nicholas D. Tailby. The oxidation state of Hadean magmas and implications for early Earth’s atmosphere. Nature, 2011; 480 (7375): 79 DOI: 10.1038/nature10655

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