The Visible EmbryoHome
Google
 
Home---History---Bibliography--Pregnancy Timeline---Prescription Drugs in Pregnancy--- Pregnancy Calculator----Female Reproductive System---News Alerts---Contact

Week Ending FRIDAY May 1, 2009---------------------------News Archive

Inner Workings of Human Embryonic Stem Cells Revealed
Scientists at UC Santa Barbara have made a significant discovery in understanding the way human embryonic stem cells function

They explain nature's way of controlling whether these cells will renew, or will transform to become part of an ear, a liver, or any other part of the human body. The study is reported in the May 1 issue of the journal Cell.

The scientists say the finding bodes well for cancer research, since tumor stem cells are the engines responsible for the growth of tumors. The discovery is also expected to help with other diseases and injuries. The study describes nature's negative feedback loop in cell biology.

"We have found an element in the cell that controls ‘pluripotency,' that is the ability of the human embryonic stem cell to differentiate or become almost any cell in the body," said senior author Kenneth S. Kosik, professor in the Department of Molecular, Cellular & Developmental Biology. Kosik is also co-director and Harriman Chair in Neuroscience Research of UCSB's Neuroscience Research Institute.

"The beauty and elegance of stem cells is that they have these dual properties," said Kosik. "On the one hand, they can proliferate –– they can divide and renew. On the other hand, they can also transform themselves into any tissue in the body, any type of cell in the body."

The research team includes James Thomson, who provided an important proof to the research effort. Thomson, an adjunct professor at UCSB, is considered the "father of stem cell biology." Thomson pioneered work in the isolation and culture of non-human primate and human embryonic stem cells. These cells provide researchers with unprecedented access to the cellular components of the human body, with applications in basic research, drug discovery, and transplantation medicine.

With regard to human embryonic stem cells, Kosik explained that for some time he and his team have been studying a set of control genes called microRNAs. "To really understand microRNAs, the first step is to remember the central dogma of biology ––DNA is the template for RNA and RNA is translated to protein. But microRNAs stop at the RNA step and never go on to make a protein.

"The heart of the matter is that before this paper, we knew that if you want to maintain a pluripotent state and allow self-renewal of embryonic stem cells, you have to sustain levels of transcription factors," said Kosik. "We also knew that stem cells transition to a differentiated state when you decrease those factors. Now we know how that happens a little better."

The new research shows that a microRNA –– a single-stranded RNA whose function is to decrease gene expression –– lowers the activity of three key ingredients in the recipe for embryonic stem cells. This microRNA is known as miR-145. The discovery may have implications for improving the efficiency of methods designed to reprogram differentiated cells into embryonic stem cell-like cells.

As few as three or four genes can make cells pluripotent. "We know what these genes are," Kosik said. That information was used recently for one of the most astounding breakthroughs of biology of the last couple of years –– the discovery of induced pluripotent skin cells.

"You can take a cell, a skin cell, or possibly any cell of the body, and revert it back to a stem cell," Kosik said. "The way it's done, is that you take the transcription factors that are required for the pluripotent state, and you get them to express themselves in the skin cells; that's how you can restore the embryonic stem cell state. You clone a gene, you put it into what's called a vector, which means you put it into a little bit of housing that allows those genes to get into a cell, then you shoot them into a stem cell. Next, when those genes –– those very critical pluripotent cell genes –– get turned on, the skin cell starts to change, it goes back to the embryonic pluripotent stem cell state."

The researchers explained that a rise in miR-145 prevents human embryonic stem cells' self-renewal and lowers the activity of genes that lend stem cells the capacity to produce other cell types. It also sends the cells on a path toward differentiation. In contrast, when miR-145 is lost, the embryonic stem cells are prevented from differentiating as the concentrations of transcription factors rise.

They also show that the control between miR-145 and the "reprogramming factors" goes both ways. The promoter for miR-145 is bound and repressed by a transcription factor known as OCT4, they found.

"It's a beautiful double negative feedback loop," Kosik said. "They control each other. That is the essence of this work."

Because there is typically less "wiggle room" in the levels of microRNA compared to mRNA, further studies are needed to quantify more precisely the copy numbers of miR-145 and its targets, to figure out exactly how this layer of control really works, Kosik said.

People of Higher Socioeconomic Status Choose Better Diets - But Pay More Per Calorie
As people become more educated, studies have demonstrated that they tend to choose foods that are lower in calories but higher in nutrients. They also pay more

In a study published in the May 2009 issue of the Journal of the American Dietetic Association, researchers from the University of Washington compared the eating habits and food costs of a sample of 164 adults in the Seattle, Washington area.

The energy density of the diet (i.e. available energy per unit weight) is one indicator of diet quality. Lean meats, fish, low-fat dairy products and fresh vegetables and fruit provide fewer calories per unit weight than do fast foods, sweets, candy and desserts. Energy dense foods provide more calories per unit weight but tend to be nutrient-poor.

Diets of low energy density and high nutrient content have been associated with less weight gain and with lower rates of obesity, type 2 diabetes, cardiovascular disease and some forms of cancer. In contrast, energy-dense diets have been linked to higher obesity rates and higher disease risk. Improving diet quality by lowering its energy density is standard advice for weight control, cancer prevention and better health.

The 164 participants (103 women and 61 men) recorded their usual frequency of consumption of 152 foods and 22 beverages and indicated portion size. They also provided four-day dietary records and completed demographic and behavioral questionnaires.

For both men and women, higher dietary energy density was associated with higher intakes of total fat and saturated fat and with lower intakes of dietary fiber, potassium and vitamins A and C. Daily diet cost ($/day) was slightly higher for men ($6.72/day) than women ($6.21/day), reflecting the fact that men ate more than women. However, the difference reversed after adjusting for energy. For each 2,000 kcal of dietary energy, men spent $7.43 compared to $8.12 spent by women. Diets that were more costly in terms of $/2000 kcal were also lower in energy density and contained higher levels of nutrients.

Higher quality diets were not only more costly per 2000 kcal but were associated with higher household incomes and education of study participants. Education, rather than incomes was the dominant factor. More highly educated respondents reported higher quality and therefore more costly diets, independent of household income level.

Writing in the article, Pablo Monsivais, PhD MPH, and Adam Drewnowski, PhD, both of the University of Washington, Seattle, conclude, "The finding that higher-quality diets were consumed by women of higher (socioeconomic status) and more costly per 2000 kcal has implications for epidemiologic studies of diet and chronic disease. Nutritional epidemiology has historically been based on the premise that nutrient exposures are directly linked to health outcomes. However, nutritional status is also intimately linked to socioeconomic status, and the findings reported here raise the possibility that the higher monetary cost of nutritious diets may provide one explanation for these observations. Future studies, based on more representative samples, will be needed to elucidate the connections between diet quality and diet cost across socioeconomic strata."

White Tea - The Solution to the Obesity Epidemic?
Possible anti-obesity effects of white tea have been demonstrated in a series of experiments on human fat cells (adipocytes)

Researchers writing in BioMed Central's open access journal Nutrition and Metabolism have shown that an extract of the herbal brew effectively inhibits the generation of new adipocytes and stimulates fat mobilization from mature fat cells.

Marc Winnefeld led a team of researchers from Beiersdorf AG, Germany, who studied the biological effects of an extract of white tea – the least processed version of the tea plant Camellia sinensis. He said, "In the industrialized countries, the rising incidence of obesity-associated disorders including cardiovascular diseases and diabetes constitutes a growing problem. We've shown that white tea may be an ideal natural source of slimming substances."

After treating lab-cultured human pre-adipocytes with the tea extract, the authors found that fat incorporation during the genesis of new adipocytes was reduced. According to Winnefeld, "The extract solution induced a decrease in the expression of genes associated with the growth of new fat cells, while also prompting existing adipocytes to break down the fat they contain."

White tea is made from the buds and first leaves of the plant used to make green tea and the black tea most commonly drunk in Western countries. It is less processed than the other teas and contains more of the ingredients thought to be active on human cells, such as methylxanthines (like caffeine) and epigallocatechin-3-gallate (EGCG) – which the authors believe to be responsible for many of the anti-adipogenic effects demonstrated in their study.

1918 Spanish Flu Is Current H1N1 Swine Influenza
In 1918 a human influenza virus known as the Spanish flu spread through the central United States while a swine respiratory disease occurred concurrently

A Kansas State University researcher has found that the virus causing the pandemic was able to infect and replicate in pigs, but did not kill them, unlike in other mammalian hosts like monkeys, mice and ferrets where the infection has been lethal.

Juergen A. Richt, Regents Distinguished Professor of Diagnostic Medicine and Pathobiology at K-State's College of Veterinary Medicine, studied the 1918 Spanish flu pandemic with colleagues from the Canadian Food Inspection Agency, U.S. Department of Agriculture and Mount Sinai School of Medicine.

Their research supports the hypothesis that the 1918 pandemic influenza virus and the virus causing the swine flu were the same. Richt said the virus was able to infect and replicate in swine and cause mild respiratory disease. The 1918 virus spread through the pig population, adapted to the swine and resulted in the current lineage of the H1N1 swine influenza viruses. The researchers' study is published in the May 2009 Journal of Virology.

"This study emphasizes that an influenza virus, which is known to induce a lethal infection in ferrets and macaques, is not highly virulent in pigs, indicating a potential resistance of swine to highly virulent influenza viruses," Richt said. "It also suggests that pigs could have played a role in maintaining and spreading the 1918 human pandemic influenza virus."

Swine flu is a respiratory disease of pigs caused by type A influenza that regularly causes outbreaks of influenza among the animals and can be transmitted to humans. It is a typical zoonotic agent. While swine flu was first recognized as a disease in 1918, there also were reports of the influenza occurring in the Midwest in 1930.

For the study, the researchers used the 1918 pandemic virus and a 1930 H1N1 influenza virus for experimental infections in swine. The 1930 virus was chosen as a virus because it is thought to be a descendent of the 1918 virus, Richt said.

The researchers did not find a significant difference in effects from the 1918 and 1930 viruses in infected pigs. This was surprising, since the 1918 virus killed more than 20 million people and was lethal to ferrets, mice and macaques. Another surprising finding from the study was the rapid antibody response in the animals infected with the 1918 virus, which is not typically reported for the swine influenza virus.

Richt said he plans to conduct a follow-up project that will study what makes a swine flu virus a pandemic flu virus.

The researchers conducted the study in the biosafety-level 4 laboratory and animal cubicle at the National Centre for Foreign Animal Disease in Canada.

Pinpointing the Mechanisms of Self-Control in the Brain
Study of dieters shows how two brain areas interact in people with the willpower to say no to unhealthy foods

When you're on a diet, deciding to skip your favorite calorie-laden foods and eat something healthier takes a whole lot of self-control--an ability that seems to come easier to some of us than others. Now, scientists from the California Institute of Technology (Caltech) have uncovered differences in the brains of people who are able to exercise self-control versus those who find it almost impossible.

The key? While everyone uses the same single area of the brain to make these sorts of value-laden decisions, a second brain region modulates the activity of the first region in people with good self-control, allowing them to weigh more abstract factors--healthiness, for example--in addition to basic desires such as taste to make a better overall choice.

These findings, which are being published in the May 1 issue of the journal Science, not only provide insight into the interplay between self-control and decisionmaking in dieters, but may explain how we make any number of decisions that require some degree of willpower.

"A very basic question in economics, psychology, and even religion, is why some people can exercise self-control but others cannot," notes Antonio Rangel, a Caltech associate professor of economics and the paper's principal investigator. "From the perspective of modern neuroscience, the question becomes, 'What is special about the circuitry of brains that can exercise good behavioral self-control?' This paper studies this question in the context of dieting decisions and provides an important insight."

That insight was the result of an innovative experiment: A group of volunteers--all self-reported dieters--were shown photos of 50 foods, including everything from Snickers bars to Jello to cauliflower. The participants were asked to rate each of the foods based on how good they thought that food would taste. Afterwards, they were shown the same slides again and asked to rate each of the foods based on its supposed health benefits.

From those ratings, the researchers selected an "index food" for each volunteer--a food that fell about in the middle of the pack in terms of tastiness and supposed health benefits.

The participant was then shown the 50 items one final time and was asked to choose between it and the index item. (To keep the choosers "honest" without forcing them to eat 50 different foods in one sitting, the researchers would randomly select a number corresponding to one of the slides, and the participant would have to eat whichever food had been chosen at that point.)

All three viewings of the slides were done with the participant inside an MRI scanner, so that the blood-oxygen level dependent signal (a proxy for neuronal activity) in specific areas of the brain could be measured.

After all the choices had been made, the researchers were able to pick out 19 volunteers who showed a significant amount of dietary self-control in their choices, picking mostly healthy foods, regardless of taste. They were also able to identify 18 additional volunteers who showed very little self-control, picking what they believed to be the tastier food most of the time, regardless of its nutritional value.

When they looked at the brain scans of the participants, they found significant differences in the brain activity of the self-control group as compared to the non-self-controllers.

In the non-self-controllers, Rangel notes, the vmPFC seemed to only take the taste of the food into consideration in making a decision. "In the case of good self-controllers, however, another area of the brain--called the dorsolateral prefrontal cortex [DLPFC]--becomes active, and modulates the basic value signals so that the self-controllers can also incorporate health considerations into their decisions," he explains. In other words, the DLPFC allows the vmPFC to weigh both taste and health benefits at the same time.

"The vmPFC works during every decision," says Hare. "The DLPFC, on the other hand, is more active when you're employing self-control."
"This, ultimately, is one reason why self-controllers can make better choices," Rangel adds.

Still, the DLPFC can only do so much. For instance, it can't override a truly negative reaction to a food, notes Hare. "We rarely got people to say they'd eat cauliflower if they didn't like cauliflower," he says. "But they would choose not to eat ice cream or candy bars, knowing they could eat the healthier index food instead."

"After centuries of debate in social sciences we are finally making big strides in understanding self-control from watching the brain resist temptation directly," says Colin Camerer, the Robert Kirby Professor of Behavioral Economics in Caltech's Division of Humanities and Social Sciences and another of the paper's coauthors. "This study, and many more to come, will eventually lead to much better theories about how self-control develops and how it works for different kinds of temptations."

The next step, the researchers say, is to come up with ways to engage the DLPFC in the decisions made by people with poor self-control under normal conditions. For instance, Hare says, it might be possible to kick the DLPFC into gear by making the health qualities of foods more salient for people, rather than asking them to make the effort to judge a food's health benefits on their own. "If we highlight the fact that ice cream is unhealthy just before we offer it," he notes, "maybe we can reduce its value in advance, give the person a head start to making a better decision."

Whether this is indeed feasible remains to be tested. But clearly, the possibilities are tantalizing, since these same sorts of value-based choices are at the root of everything from addictions like smoking to risky financial decisions.

"Imagine how much better life could be if we knew how to flex the willpower muscles in the brain and strengthen them with exercises," says Camerer.

The work described in the Science paper, "Self-Control in Decision-Making Involves Modulation of the vmPFC Valuation System," was funded by the Moore Foundation and the Economic Research Service of the U.S. Department of Agriculture on Behavioral Health Economics Research on Dietary Choice and Obesity.



THURSDAY April 30, 2009---------------------------News Archive

Poor Nutrition in Womb = Permanent Offspring Gene Changes
New research study in The FASEB Journal explains how poor maternal nutrition passes health risk across generations

The new science of epigenetics explains how genes can be modified by the environment, and a prime result of epigenetic inquiry has just been published online in The FASEB Journal (http://www.fasebj.org): You are what your mother did not eat during pregnancy.

In the research report, scientists from the University of Utah show that rat fetuses receiving poor nutrition in the womb become genetically primed to be born into an environment lacking proper nutrition.

As a result of this genetic adaptation, the rats were likely to grow to smaller sizes than their normal counterparts. At the same time, they were also at higher risk for a host of health problems throughout their lives, such as diabetes, growth retardation, cardiovascular disease, obesity, and neurodevelopmental delays, among others. Although the study involved rats, the genes and cellular mechanisms involved are the same as those in humans.

“Our study emphasizes that maternal–fetal health influences multiple healthcare issues across generations,” said Robert Lane, professor of pediatric neonatology at the University of Utah, and one of the senior researchers involved in the study. “To reduce adult diseases such as diabetes, obesity, and cardiovascular disease, we need to understand how the maternal–fetal environment influences the health of offspring.”

The scientists made this discovery through experiments involving two groups of rats. The first group was normal. The second group had the delivery of nutrients from their mothers' placentas restricted in a way that is equivalent to preeclampsia. The rats were examined right after birth and again at 21 days (21 days is essentially a preadolescent rat) to measure the amount of a protein, called IGF-1, that promotes normal development and growth in rats and humans. They found that the lack of nutrients caused the gene responsible for IGF-1 to significantly reduce the amount of IGF-1 produced in the body before and after birth.

“The new ‘epigenetics’ has taught us how nature is changed by nurture,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “The jury's in and, yes, expectant moms really are eating for two. This study shows not only that we need to address problems such as preeclampsia during pregnancy, but also that prenatal care is far more important than anyone could have imagined a decade ago.”


Drugs Given for Egg Preservation Need to be Given in Stages
Cryoprotectants needed to preserve eggs for reproduction need to be given in stages, albeit rapid ones, say scientists who have developed a mathematical model that predicts optimal time for loading and unloading these drugs

Their studies in Rhesus monkey eggs, which are very similar to human eggs, show that a two-step process of easing into and out of the drugs needed to help protect eggs at subzero temperatures dramatically reduces the amount eggs contract and expand in the process.

These dramatic size shifts can literally rip an egg apart or, at the very least, reduce the chances it can be fertilized, says Dr. Ali Eroglu, reproductive biologist and cryobiologist in the Medical College of Georgia Schools of Medicine and Graduate Studies.

Scientists first looked at how fast the three most commonly used cryoprotectants – dimethylsulfoxide, ethylene glycol and propylene glycol – permeate monkey eggs. Faster permeability is better with these drugs which must be given at room temperature when their toxicity levels are high. With permeability rates in hand, MCG scientists used a mathematical model, developed in collaboration with Villanova University in Pennsylvania, to successfully predict optimal loading and removal times.

They found propylene glycol works best in monkeys. The drug penetrated the egg membrane faster and got out faster, Dr. Eroglu and his colleagues report in the April issue of Molecular Reproduction & Development.

All of the drugs worked best when used incrementally: putting some in the medium around the egg and a few minutes later adding a little more when it was time for cryopreservation and, conversely, transferring them to increasingly lower concentrations of the drugs when it was time for thawing.

While still less than 10 percent, success rates for egg preservation to help protect an endangered species or enable a cancer patient to retain fertility have improved in recent years as scientists learn more about how best to give and remove the drugs – including using more than one at a time – with the idea that they may work synergistically and hopefully with reduced toxicity.

Scientists also are taking important cues from critters with an innate ability to preserve themselves. Increasingly added to the mix of manmade cryoprotectants are sugars, which are used by a variety of species, such as brine shrimp and eight-legged tardigrades, a microscopic water-dweller also known as “water bears," to survive drought conditions. Scientists like Dr. Eroglu, are showing that these sugars, such as trehalose used by tardigrades, also can help humans, monkeys and other species that don't naturally produce them.

With human egg preservation, the sugars currently are placed in the medium along with the cryoprotectants, where it appears to work some magic. Sugar can't permeate a cell membrane so high concentrations in the medium reduce the amount of fluid that moves inside the egg. Too much fluid causes the egg to swell and potentially burst. Almost paradoxically, because sugar thickens the medium, it helps put pressure on the cell to move cryoprotectants out when it's time.

Animals likely use sugars this way and to transform to a glasslike state. Those that naturally produce sugars have transporters that enable it to be outside and inside their cells, where it appears to afford additional protection. Dr. Eroglu has given mice eggs that added protection by injecting sugar in a process similar to how sperm can be injected for fertilization. He's found it dramatically reduces the temperature needed to reach the glasslike preserved state. In fact, he's shown trehalose can enable eggs to move into a glasslike state at -30 degrees Celsius compared to -80 C, -100 C or even colder temperatures required with only conventional cryoprotectants.

That means eggs can be stored and transported much more easily. "With conventional cryoprotectants, you have to store them in liquid nitrogen. With this, you can just put them in a freezer or transport them on dry ice," Dr. Eroglu says. Additionally, the more dramatic temperature shifts put additional stress on already stressed eggs.

Improved transportability could be a big plus if/when these preservation techniques are applied to organs, he says. About 40 percent of organs intended for transplantation are damaged before and during transportation and Dr. Eroglu theorizes the glasslike state that can preserve an egg for years could go a long way in reducing that.

One of his many goals is to make the protective powers of sugar more widely available by designing ones that can penetrate a cell or egg membrane.

Researchers at Mercer University School of Medicine in Macon, Ga., Yerkes National Primate Research Center in Atlanta and Emory University School of Medicine in Atlanta also contributed to the study.

Tufted Bacteria Cause Infection in Premature Babies
Bacteria that normally reside on the skin of healthy people can cause serious infections in premature babies

A group of researchers at Karolinska Institutet have now found an explanation for why a certain kind of staphylococcus can attach itself to the skin and quickly develop dynamic ecosystems: the bacteria are like tufted, self-adhesive hairballs.

The scientists believe that the hair-like protrusions on the surface of the bacteria that have now been identified serve to adhere the bacteria to the host's cells, whereupon they cause infection. They also found that the antimicrobial substance LL37, which is found on the skin (amongst other places) can inhibit the growth of the bacteria, and probably plays an important part in keeping the bacteria flora stable and inhibiting their uncontrolled proliferation.

"We wanted to conduct this research not only to learn more about the pathogenic potential of the bacteria, but also to understand how the child can protect itself from attack by, for instance, enhancing the body's own defences," says Giovanna Marchini, associate professor at Karolinska Institutet and senior physician at the Astrid Lindgren Children's Hospital neonatal section.

"It's thought that the past decades' hunt for disease-causing bacteria means that we now live too cleanly, which has contributed to the sharp rise in allergies and other 'luxury diseases'," continues Dr Marchini. "Other than wanting to prevent infection in babies, we also think it's an exciting challenge to understand the conceivable health aspects of these tiny, round and tufted skin dwellers."

Tiny Differences in Genes Shed Light on Human History
Report published in the journal GENETICS describes new tool for population studies by examining single molecule changes in DNA fragments

By examining very small differences in people's genes, scientists from Cornell University have developed a new tool for identifying big events in human history and pinpointing the origins of specific gene mutations. This research, published in the May issue of the journal GENETICS (http://www.genetics.org), helps shed light on times when the human population moved close to extinction and helps scientists close in on gene mutations that make some demographic groups more likely to develop diseases such as cancer, heart disease, diabetes, among others.

"We know that many diseases are caused by a combination of genetic and environmental factors," said Kirk E. Lohmueller, one of the researchers involved in the work from Cornell University. "To find the genes that contribute to disease, it's very helpful to know the demographic history of the population being studied. Accurate estimates of population events help inform the search for mutations that might have been helpful and necessary for survival at the time, but no longer necessary and potentially harmful today."

In their work, Lohmueller and colleagues confirmed the existence of a major decline in European populations (called a "bottleneck") 32,500-47,500 years ago. They used computer simulations to model the expected correlation among segments of DNA containing very small genetic mutations that only involve a single letter of the genetic code (called "single nucleotide polymorphisms" or SNPs). Prior to this development, methods used to identify major population events relied on the frequency patterns of individual SNPs, while ignoring the patterns of specific groups of SNPs. This work shows that looking at groups of SNPs helps us better understand what happened long before there was a human historical record.

"When we think of the past, we often think in terms of the historical or geological records," said Mark Johnston, Editor-in-Chief of the journal GENETICS. "What makes this development so amazing is that it helps align these records with an emerging biological record based on our DNA. This technique can be applied to any species, making it possible for us to learn and compare the biological histories of all living creatures."


Oral Delivery System for RNAi Therapeutics Developed
Paper in scientific journal Nature describes proof of concept for oral delivery of therapeutic short interfering RNA molecules

Researchers at the University of Massachusetts Medical School (UMMS) report today on a novel approach to the delivery of small bits of genetic material in order to silence genes using "RNA interference"—and in the process, discovered a potent method of suppressing inflammation in mice similar to what occurs in a range of human diseases.

In the April 30, 2009 issue of the journal Nature, Professor Michael P. Czech, PhD, and colleagues in the Program in Molecular Medicine at UMMS describe the engineering of small encapsulating particles containing short pieces of RNA that dramatically silenced genes in mice following oral administration in small doses. The paper, "Orally delivered siRNA targeting macrophage MAP4K4 suppresses systemic inflammation," provides a possible pathway to address the most common—and daunting—challenge in the new field of RNA therapeutics: how to deliver the short strands of RNA used in gene silencing to specific tissues and cell types.

"We are very encouraged by these results, which show that oral delivery of a therapeutic dose of small, interfering RNA (siRNA) to a specific cell type in an animal model is possible, and that evidence of gene silencing using this delivery system is measurable," said Dr. Czech.

The discovery in 1998 that short strands of RNA can silence the action of a given gene changed the scientific world's understanding of how genes are regulated. Highly specific and highly potent, "RNA interference" or "RNAi" has become both a crucial laboratory technique and widely studied for potential therapeutic applications; the explanation of the mechanism of RNAi was recognized with the 2006 Nobel Prize in Medicine, awarded to UMMS Professor Craig C. Mello, PhD, and collaborator Andrew Z. Fire, PhD, of Stanford University; since the discovery, laboratories around the world have focused on the potential of RNAi to silence genes with high specificity, low toxicity and minimal immune system response.

But how to deliver tiny strands of genetic material into cells in a living organism has been a formidable obstacle. In this paper, Czech and colleagues chose to target a particular type of cell in the immune system called a "macrophage," a type of white blood cell that engulfs and digests cellular debris and responds to invading organisms by stimulating the immune response. Because macrophages control the inflammatory response in diseases such as rheumatoid arthritis and atherosclerosis (a precursor to heart disease), they represent an attractive target for drug delivery.

To move short strands of RNA into the macrophages, the researchers exploited a distinctive characteristic of yeast particles: the ability to be engulfed and digested by macrophages. By using these yeast particles as a delivery shell, they were able to deliver siRNAs targeting a gene known for its key role in the inflammatory response—and turn it off. The macrophages carrying the RNAi moved throughout the organism as they circulated from the digestive system (where they first encountered the particles and engulfed them) with the result that over time, a large portion of the organism's macrophages exhibited gene silencing.

The method of treating yeast particles to remove components that would cause an immune response and generate oral delivery vehicles composed of "beta1,3-D glucan" was developed by UMMS research professor and paper co-author Gary R. Ostroff, PhD. The method of using glucan particles as a drug delivery system has been tested in a number of animal models. In December 2008, the Massachusetts Life Sciences Center awarded a three-year, $750,000 cooperative research grant to UMMS and biotech startup RXi Pharmaceuticals to investigate the development of a range of orally delivered RNAi therapeutics using the glucan particle model. (RXi was co-founded by Nobel Laureate Mello, who serves on its Scientific Advisory Board, and Czech.)

In the series of experiments, the researchers were able to silence gene expression both in vitro and in vivo, in a mouse model, at a range of doses and concentrations; oral delivery of as little as 20 micrograms per kilogram of body weight of siRNA silenced a signaling protein called MAP4K4, a key player in the inflammatory response in disease processes like arthritis. (By contrast, research studies evaluating intravenous injections of siRNAs often used concentrations from 12 to 500 times higher.)

"In the future, this paper will be viewed as a landmark in the process of translating RNAi into effective new therapies for human diseases," said Terence R. Flotte, MD, dean of the school of medicine at UMMS. "It addresses one of the most fundamental problems in the field, that of delivery of the RNAi molecule to the cells affected by the disease process."

Motor Execution in Children With Autism Reveals Brain Activation Differences
In the first neuroimaging study to examine motor execution in children with autism, researchers at the Kennedy Krieger Institute have uncovered important new insight into the neurological basis of autism

The study, published online in the journal Brain’s April 23 Brain Advanced Access, compared the brain activity of children with high functioning autism and their typically developing peers while performing a simple motor task—tapping their fingers in sequence.

The researchers found that children with autism relied more heavily on a region of the brain responsible for conscious, effortful movement, while their typically developing peers utilized a region of the brain important for automating motor tasks. Children with autism also showed less connectivity between different regions of the brain involved in coordinating and executing movement, supporting the theory that a decreased ability of distant regions of the brain to communicate with each other forms the neurological basis of autism.

Researchers used fMRI scans to examine the brain activity of 13 children with high functioning autism and 13 typically developing children while performing sequential finger tapping. The typically developing children had increased activity in the cerebellum, a region of the brain important for automating motor tasks, while children with autism had increased activity in the supplementary motor area (SMA), a region of the brain important for conscious movement. This suggests children with autism have to recruit and rely on more conscious, effortful motor planning because they are not able to rely on the cerebellum to automate tasks.

Researchers also examined the functional connectivity of the brain regions involved in motor planning and execution in order to compare the activity between different brain regions involved in the same task. The children with autism showed substantially decreased connectivity between the different brain regions involved in motor planning and execution. These results add to increasing evidence that autism is related to abnormalities in structural and functional brain connectivity, which makes it difficult for distant regions of the brain to learn skills and coordinate activities.

“Tapping your fingers is a simple action, but it involves communication and coordination between several regions of the brain,” said Dr. Stewart H. Mostofsky, senior study author and a pediatric neurologist in the Department of Developmental Cognitive Neurology at the Kennedy Krieger Institute. “These results suggest that in children with autism, fairly close regions of the brains involved in motor tasks have difficulty coordinating activity. If decreased connectivity is at the heart of autism, it makes sense social and communication skills are greatly impaired, as they involve even more complex coordination between more distant areas of the brain.”

While autism is characterized by impaired communication and social skills, these abilities are hard for scientists to measure and quantify. In contrast, the neurological processes behind motor skills are well understood, and motor tasks can be objectively observed and measured. Examining motor execution provides researchers a way to study the basic brain systems important for learning and guiding actions, which has important implications for all learned behavior, including complex communication and social skills. Researchers at the Kennedy Krieger Institute have been using the study of motor skills as an important window into the neurobiological basis of autism.

“When we learn to interact with the world around us, we acquire many skills,” said Dr. Mostofsky. “Whether they are complex social skills or simple motor skills, they all begin with the brain responding to a stimulus and learning the appropriate response. In this way, studying motor skills provides important information about how the brain of a child with autism learns differently, and how autism affects the basic neural systems important for acquiring all skills, from tapping your toes in rhythm to recognizing emotions in the facial expressions of others.”

Funding support for this study was provided through grants from the National Alliance for Autism Research/Autism Speaks, the National Institutes of Health and the Johns Hopkins General Clinical Research Center.


WEDNESDAY April 29, 2009---------------------------News Archive

Obesity, Reproduction and Pregnancy Outcomes
Diet and nutrition counseling for virtually all overweight and obese women of childbearing age can reduce health risks associated with excess weight for mothers and children alike, according to a newly released position paper from the American Dietetic Association and the American Society of Nutrition

The position, published in the May issue of the Journal of the American Dietetic Association, represents the associations’ official stance on obesity, reproduction and pregnancy outcomes:

Given the detrimental influence of maternal overweight and obesity on reproductive and pregnancy outcomes for the mother and child, it is the position of the American Dietetic Association and the American Society for Nutrition that all overweight and obese women of reproductive age should receive counseling prior to pregnancy, during pregnancy and in the interconceptional period on the roles of diet and physical activity in reproductive health, in order to ameliorate these adverse outcomes.

The joint ADA/ASN position and accompanying paper were written by Anna Maria Siega-Riz, PhD, RD, LDN, assistant professor of maternal and child health at the University of North Carolina; and Janet C. King, PhD, senior scientist at Children’s Hospital and Research Center, Oakland, Calif.

An estimated 33 percent of U.S. women are obese, according to the authors, who write that a long-term goal of health professionals must be to reduce the number of women who become pregnant while obese. They add that the effect of a woman’s nutritional status prior to pregnancy is an issue of great public health importance.

“Among obese women, who already have aberrations in glucose and lipid metabolism, the further adjustments induced by hormonal changes in pregnancy create a metabolic milieu that enhances the risk for metabolic disorders such as gestational diabetes mellitus and preeclampsia,” according to the position paper.

Infants born to obese mothers have “a higher prevalence of congenital anomalies than do offspring of normal-weight women, suggesting that maternal (obesity) alters development in the sensitive embryonic period.” The authors note neural tube defects such as spina bifida and anencephaly are about twice as common among children of obese women. “Other birth defects more frequent in offspring of obese women include oral clefts, heart anomalies, hydrocephaly and abdominal wall abnormalities.”

Objectives of the new ADA/ASN position are to provide guidance to nutrition professionals in becoming aware of risks and possible complications of excess weight and obesity for fertility, course of pregnancy, birth outcomes and short and long-term maternal and child health; and to commit ADA and ASN to identifying gaps in scientific research needed to improve knowledge of risks and complications and develop effective strategies “that can be implemented before and during pregnancy as well as during the interconceptional period,” the authors write.

The American Dietetic Association is the world’s largest organization of food and nutrition professionals. ADA is committed to improving the nation’s health and advancing the profession of dietetics through research, education and advocacy. Visit the American Dietetic Association at www.eatright.org/.

The Neural Basis of Reading
Most people are expert readers, but it is something of an enigma that our brain can achieve expertise in such a recent cultural invention, which lies at the interface between vision and language

Given that the first alphabetic scripts are thought to have been invented only around four to five thousand years it is unlikely that enough time has elapsed to allow the evolution of specialized parts of the brain for reading. While neuroimaging techniques have made some progress in understanding the neural underpinning of this essentially cultural skill, the exact unfolding of brain activity has remained elusive.

Now, a better understanding of the brain basis of reading has been reported in research published in the open-access, peer-reviewed journal PLoS ONE. The research was led by Piers Cornelissen, Morten Kringelbach, Ian Holliday and Peter Hansen from the Universities of York, Oxford, Aston, and Birmingham UK, and was funded by the Wellcome Trust. The authors showed very early interactions between the vision and language domains during reading, with the speech motor areas of the brain (inferior frontal gyrus) being active at the same time (after a seventh of a second) as the orthographic word-form is being resolved within a brain region called the fusiform gyrus. This finding challenges the conventional view of a temporally serial processing sequence for reading in which letter forms are initially decoded, interact with their phonological and semantic representations, and only then gain access to a speech code.

This finding has a potentially important clinical application in relation to developmental dyslexia (affecting between 15-30 million people in the US alone) and those with acquired reading disabilities through injury or disease. A better understanding of normal reading processes could potentially help these individuals.

The research team used a neuroimaging method called magnetoencephalography (MEG) at Aston University, UK. This is an advanced neuroscientific tool, which offers both excellent temporal (in milliseconds) and spatial (in millimetres) resolution of whole brain activity. Because the researchers were primarily interested in the highly automatized processing of words, they used an implicit task that required participants to monitor the colour of a small red cross and to press a button as soon as the colour changed. This was interspersed with words, consonant strings and faces that were shown for 300 ms, but which were not important to solve the task.

The authors found key differences in the early brain activity of normal adults when they were reading words compared to reading consonant strings and seeing faces. Time-frequency analyses showed a left-lateralized inferior frontal gyrus (pars opercularis) response to words between 100-250 ms in the beta frequency band that was significantly stronger than the response to consonant strings or faces. The left inferior frontal gyrus response to words peaked at ~130 ms. This response was significantly later in time than the left middle occipital gyrus, which peaked at ~115 ms, but not significantly different from the peak response in the left mid fusiform gyrus, which peaked at ~140 ms, at a location coincident with the fMRI-defined visual word form area (VWFA).

Significant responses were also detected to words in other parts of the reading network, including the anterior middle temporal gyrus, the left posterior middle temporal gyrus, the angular and supramarginal gyri, and the left superior temporal gyrus.

The left inferior frontal gyrus is located in the front of the brain. This is a key region of the language brain and lesions can lead to the inability to articulate words. In the context of the experiment, the inferior frontal gyrus appears to play a key role integrating the visual and language aspects of reading.

Reading problems are common. Further research could identify whether the present finding of early and specific activity in inferior frontal gyrus are affected in individuals with developmental dyslexia. The present paradigm could eventually provide opportunities for early identification of those at risk.

Overturning Orthodoxy on How Macrophages Kill Bacteria
For decades, microbiologists assumed that macrophages, immune cells that can engulf and poison bacteria and other pathogens, killed microbes by damaging their DNA. A new study from the University of Illinois disproves that

The study, published in the journal PLoS One, shows that macrophages focus their most potent poisons, known as reactive oxygen species (ROS), on targets outside the cytoplasm.

Macrophages are voracious eaters that “swallow” cellular debris and invading organisms. They kill microbes with ROS. All aerobic cells inadvertently produce ROS that can, if left unchecked, damage DNA and other cellular components and cause cell death. Bacteria and animal cells contain special enzymes, called superoxide dismutases, which neutralize an important ROS, called superoxide. Macrophages have harnessed these lethal compounds, dumping large quantities of superoxide onto engulfed bacteria to kill them.

Although macrophages direct ROS against invading bacteria, Salmonella typhimurium, the microbe used in the study, is adept at evading these defenses. The most virulent strains of S. typhimurium can survive and even propagate inside macrophages, eventually emerging to infect more cells.

“It’s been assumed that reactive oxygen species kill the bacteria by going into the cytoplasm and causing DNA damage,” said medical microbiology professor James Slauch, who led the study. “You can find this idea over and over again in review articles and many immunological textbooks, but with no real data to back it up.”

To test this hypothesis, Slauch and graduate student Maureen Craig looked at the superoxide dismutases that are part of the bacterial defense against ROS. There are two such enzymes in the cytoplasm of S. typhimurium, called SodA and SodB, and another, SodC, in the periplasm, the space between the bacteria’s inner and outer membranes.

One way to understand the role of an enzyme is to see what happens when it is absent, so the researchers looked at mutant S. typhimurium that had the genes for SodA, SodB, or both enzymes, deleted. Deleting the gene for SodA seemed to make no difference, but the SodB mutants were less able to survive and cause disease in a mouse. The double mutants were even more impaired. They were much, much less likely to survive in the mouse than bacteria with only the SodB gene missing. These findings “offer genetic proof” that both enzymes “are involved in the same process,” Slauch said.

The fact that the bacterial mutants were less likely to survive in a mouse did not prove, however, that the missing enzymes were protecting the bacteria from ROS generated in the mouse macrophages, Slauch said.

“You get the same result if you grow these mutants in the laboratory in aerobic conditions,” he said.


Furthermore, the SodA/SodB mutant bacteria were profoundly weakened – even in a mouse that was unable to produce the potent ROS superoxide in its macrophages. These results suggest that the superoxide dismutases in the bacterial cytoplasm are most likely protecting the bacterium from its own, naturally occurring ROS, Slauch said.

In contrast, deleting the gene encoding the periplasmic superoxide dismutase, SodC, conferred the same defect regardless of whether the cytoplasmic SodA/SodB were present or absent, showing that its function is independent of the cytoplasm.

Moreover, strains lacking SodC were impaired only in the presence of superoxide produced in macrophages; there was no impairment in laboratory media or in mice lacking the ability to make superoxide.

This suggests that the superoxide and other reactive oxygen species are not making it from the macrophage into the bacterial cytoplasm, Slauch said.

“We conclude from all this data that the most sensitive target of ROS in the macrophages lies outside the cytoplasm,” Slauch said. “We don’t know what that target is, but it’s clearly not in the cytoplasm.”

For Your Health, Pick a Mate Who is Conscientious and Neurotic
Conscientiousness is a good thing in a mate, researchers report, not just because it’s easier to live with someone who washes the dishes without being asked, but also because having a conscientious partner may actually be good for one’s health

Their study, of adults over age 50, also found that women, but not men, get an added health benefit when paired with someone who is conscientious and neurotic.

This is the first large-scale analysis of what the authors call the “compensatory conscientiousness effect,” the boost in health reported by those with conscientious spouses or romantic partners. The study appears this month in Psychological Science.

“Highly conscientious people are more organized and responsible and tend to follow through with their obligations, to be more impulse controlled and to follow rules,” said University of Illinois psychology professor Brent Roberts, who led the study. Highly neurotic people tend to be more moody and anxious, and to worry, he said.

Researchers have known since the early 1990s that people who are more conscientious tend to live longer than those who are less so. They are more likely to exercise, eat nutritious foods and adhere to vitamin or drug regimens, and are less likely to smoke, abuse drugs or take unwarranted risks, all of which may explain their better health. They also tend to have more stable relationships than people with low conscientiousness.

Most studies have found a very different outcome for people who are highly neurotic. They tend to report poorer health and less satisfying relationships.

Many studies focus on how specific personality traits may affect one’s own health, Roberts said, but few have considered how one’s personality can influence the health of another.

“There’s been kind of an individualistic bias in personality research,” he said. “But human beings are not islands. We are an incredibly interdependent species.”

Roberts and his colleagues at the U. of I. and the University of Michigan looked at the association of personality and self-reported health among more than 2,000 couples taking part in the Health and Retirement Study, a representative study of the U.S. population over age 50. The study asked participants to rate their own levels of neuroticism and conscientiousness and to answer questions about the quality of their health. Participants also filled out a questionnaire that asked them whether or not a health problem limited their ability to engage in a range of activities such as jogging one block, climbing a flight of stairs, shopping, dressing or bathing.

As other studies have found, the researchers found that those who described themselves as highly conscientious also reported better health and said they were more able to engage in a variety of physical activities than those who reported low conscientiousness.

For the first time, however, the researchers also found a significant, self-reported health benefit that accompanied marriage to a conscientious person, even among those who described themselves as highly conscientious.

“It appears that even if you are really highly conscientious, you can still benefit from a spouse’s conscientiousness,” Roberts said. “It makes sense that regardless of what your attributes are, if you have people in your social network that have resources, such as conscientiousness, that can always help.”

A more unusual finding involved an added health benefit reported by women who were paired with highly conscientious men who were also highly neurotic, Roberts said. The same benefit was not seen in men with highly conscientious and neurotic female partners. While both men and women benefit from being paired with a conscientious mate, Roberts said, only the women saw a modest boost in their health from being with a man who was also neurotic.

“The effect here is not much larger than the effect of aspirin on cardiovascular health, which is a well-known small effect,” he said.

Asked whether women looking for long-term mates should choose a man who is conscientious and neurotic over one who is simply conscientious, Roberts said, “I wouldn’t recommend it.”

Save Yourself, Cancer Cell
Some neuroblastoma tumors are addicts

The tumor cells need a steady supply of a molecule called netrin-1, and they get their fix by making the compound themselves. Forcing the cells to go cold turkey could provide a new treatment for neuroblastoma, one of the most common childhood cancers.

Even healthy cells are often poised on the verge of death. Unless so-called dependence receptors receive continual stimulation, the cells kill themselves [apoptosis].

One molecule that activates these receptors is netrin-1, a protein that is needed for normal neural development. Previous studies showed that certain breast and lung tumors pump out large amounts of netrin-1, suggesting that they rely on the molecule for survival.

Delloye-Bourgeois et al. now show that netrin-1 is also necessary for neuroblastoma. The most aggressive tumors manufactured extra netrin-1, the researchers found, and production of the molecule affected patients’ prognosis. Ninety percent of infants with tumors that made little netrin-1 were alive after five years, but only 48% of infants with tumors that produced copious netrin-1 survived that long.

These findings suggest that blocking netrin-1 curbs tumor growth. Indeed, eliminating netrin-1 in tumor cell lines led to their demise. And when the team implanted neuroblastoma tumors into chicken embryos and then neutralized netrin-1, the tumors shrank and were less likely to metastasize.

Cancers sometimes break their dependence on receptor stimulation by jettisoning the receptors. But neuroblastoma tumors didn't do that. Instead, some neuroblastomas feed their own addiction by manufacturing more netrin-1, thus preventing apoptosis [cell death]. The researchers have recently begun preclinical studies on two netrin-1–blocking compounds that might provide an alternative to chemotherapy and radiation.

What Goes In - Must Come Out, the Lymphatic Drainage System
Our bodies' tissues need continuous irrigation and drainage

Blood vessels feeding the tissues bring in the fluids, and drainage occurs via the lymphatic system. While much is known about how blood vessels are built, the same was not true for lymph vessels. Now though, Norrmén et al. have identified two of the lead engineers that direct drainage construction in the mouse embryo.

The engineers are the transcription factors, Foxc2 and NFATc1. Foxc2 had been implicated in lymph vessel development already, but Norrmén and colleagues have now found that the factor specifically regulates a late stage of lymph development when large, valve-containing vessels arise from more primitive capillaries. The study will be published online April 27 (www.jcb.org) and will appear in the May 4 print issue of the Journal of Cell Biology.

Foxc2 built the lymph vessel valves with the help of NFATc1, which was a known heart valve engineer. Norrmén and colleagues also showed that Foxc2 and NFATc1 physically interact and that many DNA binding sites for the two transcription factors are closely linked. This latter finding generated a long list of target genes that might be controlled by the two factors.

The team now plans to investigate these targets as well as to work out the upstream molecular pathways controlling Foxc2 and NFATc1. Whatever the mechanisms, if the team can show that Foxc2 and NFATc1 also prompt lymph vessel regeneration in adults, boosting these factors could help patients with lymph drainage problems – including those that have suffered extensive tissue injuries, or have had lymph nodes removed as part of cancer treatment.

Founded in 1955, the Journal of Cell Biology (JCB) is published by the Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editors. JCB content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit www.jcb.org or visit the JCB press release archive at http://www.eurekalert.org/jrnls/rupress.


TUESDAY April 28, 2009---------------------------News Archive

Key Factors In Heart Cell Creation Identified
Scientists at the Gladstone Institute of Cardiovascular Disease have identified for the first time key genetic factors that drive the process of generating new heart cells

The discovery, reported in the current issue of the journal Nature, provides important new directions on how stem cells may be used to repair damaged hearts.

For decades, scientists were unable to identify a single factor that could turn nonmuscle cells into beating heart cells. Using a clever approach, the research team led by Benoit Bruneau, Ph.D., found that a combination of three genes could do the trick. This is the first time any combination of factors has been found to activate cardiac differentiation in mammalian cells or tissues.

"The heart has very little regenerative capacity after it has been damaged," said Dr. Bruneau. "With heart disease the leading cause of death in the Western world, this is a significant first step in understanding how we might create new cells to repair a damaged heart."

Two of the three genes encode proteins called transcription factors, which are master regulators that bind to DNA and determine which genes get activated or shut off. The two transcription factors, GATA4 and TBX5, cause human heart disease when mutated and also cooperate with each other to control other genes. When Dr. Bruneau and postdoctoral fellow Jun K. Takeuchi added different combinations of transcription factors to mouse cells, these two seemed important for pushing cells into heart cells—but they were not enough.

"When we finally identified the key factor that could work with GATA4 and TBX5 to turn cells into beating heart cells, it was somewhat of a surprise to us," said Dr. Bruneau.

The surprising factor was a cardiac-specific protein called BAF60c, which helps determine whether transcription factors like GATA4 and TBX5 can even gain access to the DNA regions they were supposed to turn on or off. "Our previous studies had shown that chromatin remodeling complexes were important," said Dr. Bruneau. "Mice with lower levels of these complexes have severe heart defects and defective cardiac differentiation. These observations prompted us to look at Baf60c in heart differentiation."

The effect was dramatic. Addition of the three factors directed differentiation of mouse mesoderm, which normally has the potential to make bone, blood, muscle, heart, and other tissues, specifically into cardiac muscle cells (cardiomyocytes) that beat rhythmically, just like normal heart cells. In fact, even cells that normally contribute to the placenta could be induced to transform into beating cardiomyocytes.

"Together, these factors give us a potent mechanism to control cellular differentiation," said Dr. Bruneau. "This knowledge may help us to understand how to reprogram new cardiomyocytes for therapeutic purposes."

The research was supported by the Human Frontiers Science Program, MEXT, Mitsubishi Foundation, the National Institutes of Health, and William H. Younger, Jr.

Addition of Dasatinib to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers
The addition of a chemotherapeutic drug for leukemia to a standard regimen of two other chemotherapy drugs appears to enhance the response of certain ovarian cancers to treatment, according to a pre-clinical study led by researchers in the Duke Comprehensive Cancer Center

"We know that a pathway called SRC is involved in cell proliferation in certain types of cancers, including some ovarian cancers," said Deanna Teoh, MD, a fellow in gynecologic oncology at Duke and lead investigator on this study.

"By examining gene expression data, we determined that the combination of the leukemia drug dasatinib (Sprycel) made carboplatin and paclitaxel more effective in cell lines with higher levels of SRC expression and SRC pathway deregulation."

That synergistic effect, in which drugs used in combination strengthen each other's efficacy, was absent when low SRC expression and low SRC pathway deregulation were present, Teoh said.

"These findings indicate that we may be able to direct the use of a targeted therapy like dasatinib based on gene expression pathways in select ovarian cancers," she said.

The results of the study are being presented on a poster at the 100th annual American Association for Cancer Research meeting in Denver on April 19, 2009. The study was funded by the Prudent Fund and the National Institutes of Health.

"Our ultimate goal is to offer personalized therapy for women with ovarian cancer," said Angeles Secord, MD, a gynecologic oncologist at Duke and senior investigator on this study.

"Hopefully in the future we will apply targeted therapies to individual patients and their cancers in order to augment response to treatment while minimizing toxic side effects."

For this study, researchers examined four ovarian cancer cell lines, known as IGROV1, SKOV3, OVCAR3 and A2780. Three of the cell lines demonstrated high activation of SRC and one demonstrated lower SRC expression.

All were treated in lab dishes with various combinations of the chemotherapeutic agents dasatinib, carboplatin and paclitaxel.

"We found that the addition of dasatinib to standard therapy in the three cell lines with significant SRC pathway deregulation - IGROV1, OVCAR3 and A2780 - enhanced the response of the cancer cells to therapy," Teoh said.

"Conversely, in SKOV3, which has minimal SRC protein expression and pathway deregulation, we saw the least amount of anti-cancer activity when we added dasatinib."

It's possible that by blocking the SRC activity with the dasatinib, we are enhancing the effect of the other chemotherapeutic agents, Teoh said.

The results of this study support the further investigation of targeted biologic therapy using a SRC inhibitor in some ovarian cancers, she said. Currently a phase I trial of a a combination of dasatinib, paclitaxel and carboplatin is available for women with advanced or recurrent ovarian, tubal and peritoneal cancers.

Dasatinib is a chemotherapeutic that is currently FDA-approved for use in leukemia. It is manufactured by Bristol-Myers Squibb and is sold under the brand name Sprycel. Bristol-Myers Squibb provided the dasatinib used in this study.

Other researchers involved in this study include Tina Ayeni, Jennifer Rubatt, Regina Whitaker, Holly Dressman and Andrew Berchuck.

The Structure of a Giant Virus
The mimivirus is the largest virus known to scientists, about half of a micrometre (0.0005 millimeter) in diameter. It is more than 10 times larger than the virus that causes the common cold and – unlike other viruses – is large enough to be seen with a light microscope

In this week's issue of PLoS Biology, an international team of researchers have determined key structural features of the mimivirus, findings that could help scientists study how the simplest life forms evolved and whether this unusual virus causes any human diseases.

Mimivirus infects amoebas, but it is also thought that it may act as a human pathogen, because antibodies to the virus have been discovered in people with pneumonia. However, many details about the virus remain unknown, said Michael Rossmann, Purdue University's Hanley Distinguished Professor of Biological Sciences.

Now, Rossmann and a team of researchers from Purdue, the University of California at Irvine, and the University of the Mediterranean in Marseilles, France, have determined the basic design of the virus's outer shell, or capsid, and also of the hundreds of smaller units - called capsomeres - making up this outer shell. Their findings confirmed the existence of a starfish-shaped structure that covers a 'special vertex' - an opening in the capsid where the genetic material leaves the virus to infect its host; an indentation in the virus's genetic material itself is positioned opposite this opening.

"The findings are important in terms of studying the evolution of cells, bacteria and viruses," said Siyang Sun, a postdoctoral research associate working in Rossmann's lab. "The mimivirus is like an intermediate between a cell and a virus. We usually think of cells as being alive and a virus is thought of as being non-living because it needs a host cell to complete its life cycle. The mimivirus straddles a middle ground between viruses and living cells, perhaps redefining what a virus is."

Researchers had previously been unable to determine the virus's structure because they had assumed that, like many other viruses, it's capsid had a design known as icosahedral symmetry. The paper's lead author, Chuan Xiao, discovered the true structure when he decided to try reconstructing the virus, assuming it had not the standard icosahedral symmetry but another configuration called five-fold symmetry.

"If you start out thinking the object has icosahedral symmetry, then you assume there are 60 identical pieces, and that influences how you reconstruct the virus's structure," Rossmann said.

The researchers took images of the virus using an atomic force microscope, revealing a pattern of holes regularly spaced throughout the virus's outer shell.

"The capsids of most other large, pseudo-icosahedral viruses do not contain such holes, and their function is unknown," Rossmann said.

The researchers used cryo-electron microscopy reconstruction to determine the structural details. This reconstruction method enabled them to reassemble three-dimensional images from two-dimensional pictures, much as a complete architectural drawing of a house can be assembled with two-dimensional drawings of the sides, the roof and other elements. An icosahedron has a roughly spherical shape containing 20 triangular facets and 60 identical subunits. Like an icosahedron, the mimivirus capsid also has 20 facets.

However, unlike an icosohedron, five facets of the capsid are slightly different than the others and surround the special vertex. Icosohedra contain 12 similar vertices, whereas the mimivirus contains eleven such vertices, with the 12th being different than the others.

The research, which is funded by the National Institutes of Health, is ongoing, with future work intended to study additional properties of the virus, particularly the structure of the starfish-shaped feature and how it functions.

Building the Lymphatic Drainage System
Our bodies' tissues need continuous irrigation and drainage

Blood vessels feeding the tissues bring in the fluids, and drainage occurs via the lymphatic system. While much is known about how blood vessels are built, the same was not true for lymph vessels. Now though, Norrmén et al. have identified two of the lead engineers that direct drainage construction in the mouse embryo.

The engineers are the transcription factors, Foxc2 and NFATc1. Foxc2 had been implicated in lymph vessel development already, but Norrmén and colleagues have now found that the factor specifically regulates a late stage of lymph development when large, valve-containing vessels arise from more primitive capillaries. The study will be published online April 27 (www.jcb.org) and will appear in the May 4 print issue of the Journal of Cell Biology.

Foxc2 built the lymph vessel valves with the help of NFATc1, which was a known heart valve engineer. Norrmén and colleagues also showed that Foxc2 and NFATc1 physically interact and that many DNA binding sites for the two transcription factors are closely linked. This latter finding generated a long list of target genes that might be controlled by the two factors.

The team now plans to investigate these targets as well as to work out the upstream molecular pathways controlling Foxc2 and NFATc1. Whatever the mechanisms, if the team can show that Foxc2 and NFATc1 also prompt lymph vessel regeneration in adults, boosting these factors could help patients with lymph drainage problems – including those that have suffered extensive tissue injuries, or have had lymph nodes removed as part of cancer treatment.

Founded in 1955, the Journal of Cell Biology (JCB) is published by the Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editors. JCB content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit www.jcb.org or visit the JCB press release archive at http://www.eurekalert.org/jrnls/rupress.

Upside-Down World: DNA Protecting Protein Helps Cancer Drug Kill Cells
Some DNA repair enzymes can become double-edged swords – if they work too slowly, they can block necessary cell maintenance and contribute to cell death

This could explain the somewhat mysterious success of the widely used cancer drug 5-Fluorouracil (5FU) and help clinicians to predict patient's response to chemotherapy, according to new findings from the University of Basel, Switzerland. The work, published in this week's issue of PLoS Biology, reports that 5FU keeps the DNA-repair enzyme TDG too busy to perform properly in cancer cells, thereby promoting tumor death.

5FU has been used in cancer therapy for more than four decades and remains a mainstay in the treatment of colorectal cancer. But precisely how the drug kills cancerous cells was not well understood. It was generally thought that as an inhibitor of thymidylate synthase the compound worked by starving cells of the thymidine needed to make DNA.

First author on the paper Christophe Kunz and his colleagues inactivated the TDG enzyme in different human and mouse cells and found that the cells became resistant to the cancer drug. They wondered how a DNA repair enzyme could change the tolerance of cells to chemotherapy. They found that, in addition to other effects, 5FU is incorporated into DNA, in the place of the normal DNA base Thymidine.

TDG identifies these 5FU insertions, and is tasked with removing the 5FU from the DNA. TDG depends on a chemical modification to leave DNA after doing its job, and its turnover is very slow. When large amounts of 5FU are present in DNA the slow turnover can overload the entire repair system. Under those circumstances, an abasic site (a site where a base is missing) is left unrepaired, and so the DNA damage response kicks in, and kills the cell. So TDG may cause the death of cells flooded with 5FU – a desirable goal in tumour therapy.

"These findings provide a better understanding of how 5-Fluorouracil kills cancer cells," says Dr. Kunz, "in the future this knowledge could provide clinicians with a prognostic tool to decide which chemotherapeutic treatment to use based on the patient's level of TDG expression in the tumor cells." To this end, future research should focus on determining whether TDG expression correlates with 5FU response rates in cancer patients.


Funding - This study was funded by grants from the Swiss Cancer League (http://www.oncosuisse.ch/) and the Swiss National Science Foundation (http://www.snf.ch/E/Pages/default.aspx).

Pandemic Flu Vaccine 6-Month Time Lag
Study is first to show pre-pandemic vaccine approach

New research published today (Monday April 27) from the University of Leicester and University Hospitals of Leicester NHS Trust warns of a six-month time lag before effective vaccines can be manufactured in the event of a pandemic flu outbreak.

By that time, the first wave of pandemic flu may be over before people are vaccinated, says Dr Iain Stephenson, Consultant in Infectious Diseases at the Leicester Royal Infirmary and a Clinical Senior Lecturer at the University of Leicester.

In his paper published in PNAS- Proceedings of the National Academy of Sciences of the USA- Dr Stephenson makes the first case for a pre-pandemic vaccine to mitigate the worst effects of pandemic flu.

He said: "This study is the first to show an effective pre-pandemic vaccine approach. This means that we could vaccinate people potentially many years before a pandemic, to generate memory cells that are long lasting and can be rapidly boosted by a single dose of vaccine when needed."

Dr Stephenson, of the Department of Infection, Immunity and Inflammation at the University of Leicester, said: "If an influenza pandemic occurs, vaccination will to be the main way to protect the population. The major current threat seems to be from avian influenza H5N1 (bird flu) which has spread rapidly around the world and causes human infections and deaths.

"Unfortunately, if a pandemic occurs, it will take up to six months to manufacture effective vaccine, so the first waves of the pandemic may be over before people are vaccinated. Furthermore, most people need two doses of H5 pandemic vaccine to get protection- so this adds a further delay.

"To reduce any delay, we could consider stockpiling vaccine or immunizing people with vaccine prepared in advance -(a so called 'pre-pandemic vaccine' - to protect them before a future pandemic.

"However, we don't know which strain of influenza will cause the pandemic. There are several strains of H5N1 virus, so we can't be sure of which virus strain to make pre-pandemic vaccine from. Therefore a 'pre-pandemic' vaccine needs to give cross protection to as many H5 strains as possible."

Dr Stephenson and his team conducted a study comparing the effect of a single H5 bird flu vaccine dose to people who had been vaccinated with an H5 vaccine previously with people who had not previously received vaccine. The aim was the test out the idea of a pre-pandemic vaccination approach.

He said: "We found that those people who received H5 vaccine between 1999 and 2001 responded very well to a single dose of a newer H5 vaccine. They had memory cells that gave a rapid protective response within 7 days of the repeat vaccine. Also the response was very broad and able to protect against all known strains of H5N1 virus.

"In contrast, those people who had not been previously vaccinated with H5 vaccine, behaved as we had expected. They required 2 doses of vaccine and got good antibody responses up to 6 weeks after the first dose."

Dr Stephenson added that this was the first study to show an effective pre-pandemic vaccine approach.

The trial subjects were all recruited at the University of Leicester or University Hospitals of Leicester.


MONDAY April 27, 2009---------------------------News Archive

Bacterial ‘Injection’ System Revealed
Decoded structure of secretion system, essential for infection, could lead to new drugs


STEM image showing isolated needle complexes marked with rectangles for mass analysis. Rods are TMV (tobacco mosaic virus) particles used for reference.

New details of the composition and structure of a needlelike protein complex on the surface of certain bacteria may help scientists develop new strategies to thwart infection. The research, conducted in part at the U.S. Department of Energy’s Brookhaven National Laboratory, will be published April 26, 2009, in the advance online edition of Nature Structural & Molecular Biology.

The scientists were studying a needlelike protein complex known as a “type III secretion system,” or T3SS, on the surface of Shigella bacteria, a cause of dysentery. The secretion system is a complex protein structure that traverses the bacterial cell membrane and acts as a biological syringe to inject deadly proteins into intestinal cells. These proteins rupture the cell’s innards, leading to bloody diarrhea and sometimes death. Similar secretion systems exist in a range of other infectious bacteria, including those that cause typhoid fever, some types of food poisoning, and plague.

“Understanding the 3D structure of these secretion proteins is important for the design of new broad-spectrum strategies to combat bacterial infections,” said study co-author Joseph Wall, a biophysicist at Brookhaven Lab.

Previous studies of the type III secretion system have revealed that it is composed of some 25 different kinds of proteins assembled into three major parts: a “bulb” that lies within the bacterial cell, a region spanning the inner and outer bacterial membranes, and a hollow, largely extracellular “needle.” But to understand how the parts work together to secrete proteins, the scientists required higher-resolution structural information, and knowledge of the chemical makeup and arrangement of the components.

“STEM and the other techniques work in complementary ways,” said Wall, who designed and runs the STEM facility at Brookhaven Lab. By itself, STEM cannot reveal a structure, but it gives very accurate sizes of the molecules making up particular parts, which helps scientists hone in on the structure hinted at by the other techniques. STEM also allows only good, intact molecules to be selected for analysis, which avoids errors inherent in bulk measures of mixtures of intact and broken complexes, a problem that may have affected previous analyses.

“Our reconstruction shows an overall size, shape and major sub-component arrangement consistent with previous studies,” said Wall. “However, the new structure also reveals details of individual subunits and their angular orientation, which changes direction over the structure’s length. We now see 12-fold symmetric features and details of connections between sub-domains both internally and externally throughout the ‘needle’ base.”

The more accurate model therefore shows how the different parts of the injection machine fit together and may fit with other bacterial components that provide the engine to drive injection. These are important steps toward developing a detailed understanding of how the injection machine works, and to developing inhibitors that can prevent bacterial infections.

Although STEM was built more than 25 years ago, it remains a state-of-the-art tool for accurately determining the stoichiometry and homogeneity of biological complexes. It is one of the unique tools that Brookhaven Lab provides to the scientific community.

Co-authors on this study include: Julie L. Hodgkinson of Oxford University and Medical School Hanover, Germany; Ariel J. Blocker of Oxford and University of Bristol, UK; Ashley Horsley, David Stabat, Steven Johnson, and Susan M. Lea, all of Oxford; Joseph S. Wall and Martha Simon of Brookhaven Lab; and Paula C. A. da Fonseca and Edward P. Morris of Chester Beatty Laboratories, UK.

The research was funded by the UK Medical Research Council, and a Guy G. F. Newton Senior Research Fellowship. The STEM laboratory at Brookhaven Lab is supported by the U.S. National Institutes of Health and the Department of Energy’s Office of Science (Office of Biological and Environmental Research) and by fee-for-service support.

Scientists Identify Key Factors in Heart Cell Creation
Sequence of transcription factors may drive proces to repair damaged hearts

Scientists at the Gladstone Institute of Cardiovascular Disease have identified for the first time key genetic factors that drive the process of generating new heart cells. The discovery, reported in the current issue of the journal Nature, provides important new directions on how stem cells may be used to repair damaged hearts.

For decades, scientists were unable to identify a single factor that could turn nonmuscle cells into beating heart cells. Using a clever approach, the research team led by Benoit Bruneau, Ph.D., found that a combination of three genes could do the trick. This is the first time any combination of factors has been found to activate cardiac differentiation in mammalian cells or tissues.

"The heart has very little regenerative capacity after it has been damaged," said Dr. Bruneau. "With heart disease the leading cause of death in the Western world, this is a significant first step in understanding how we might create new cells to repair a damaged heart."

Two of the three genes encode proteins called transcription factors, which are master regulators that bind to DNA and determine which genes get activated or shut off. The two transcription factors, GATA4 and TBX5, cause human heart disease when mutated and also cooperate with each other to control other genes. When Dr. Bruneau and postdoctoral fellow Jun K. Takeuchi added different combinations of transcription factors to mouse cells, these two seemed important for pushing cells into heart cells—but they were not enough.

"When we finally identified the key factor that could work with GATA4 and TBX5 to turn cells into beating heart cells, it was somewhat of a surprise to us," said Dr. Bruneau.

The surprising factor was a cardiac-specific protein called BAF60c, which helps determine whether transcription factors like GATA4 and TBX5 can even gain access to the DNA regions they were supposed to turn on or off. "Our previous studies had shown that chromatin remodeling complexes were important," said Dr. Bruneau. "Mice with lower levels of these complexes have severe heart defects and defective cardiac differentiation. These observations prompted us to look at Baf60c in heart differentiation."

The effect was dramatic. Addition of the three factors directed differentiation of mouse mesoderm, which normally has the potential to make bone, blood, muscle, heart, and other tissues, specifically into cardiac muscle cells (cardiomyocytes) that beat rhythmically, just like normal heart cells. In fact, even cells that normally contribute to the placenta could be induced to transform into beating cardiomyocytes.

"Together, these factors give us a potent mechanism to control cellular differentiation," said Dr. Bruneau. "This knowledge may help us to understand how to reprogram new cardiomyocytes for therapeutic purposes."

The research was supported by the Human Frontiers Science Program, MEXT, Mitsubishi Foundation, the National Institutes of Health, and William H. Younger, Jr.

Study Reveals Protein that Makes Phosphate Chains in Yeast
Phosphate chains store energy and have many more different functions in a cell

It can be found in all life forms, and serves a multitude of purposes, from energy storage to stress response to bone calcification. This molecular jack-of-all trades is polyphosphate, a long chain of phosphate molecules. Researchers at the European Molecular Biology Laboratory [EMBL] in Heidelberg, Germany, are now the first to uncover how this chain is assembled in eukaryotes [organisms whose cells have a nucleus]. The study, published this week in Science, uncovers the function of a single protein with a wide range of potential implications ranging from improving crops to fighting diseases such as sleeping sickness.

Scientists have known for a long time how bacteria make phosphate chains, but how the same process works in eukaryotes has so far remained elusive. EMBL scientists now show that in yeast a protein called Vtc4p is responsible for the production of polyphosphates. Vtc4p is part of a protein complex called vacuolar transporter chaperone complex [VTC] that is usually found in the membranes of vacuoles – pouches in which cells store molecules for later use, transport or destruction.

"This protein is like a factory," says Klaus Scheffzek, whose group carried out the research at EMBL in collaboration with the Département de Biochimie at the Université de Lausanne, Switzerland, and others,"it sits in the vacuolar membrane, generates long chains of polyphosphates and we speculate that it sends them straight to the vacuole for storage."

Vtc4p is partly embedded in the membrane and has a 'tail' hanging into the cell, which removes a phosphate molecule from ATP, an important energy carrier in the cell. Vtc4p uses the energy that is released by that cleavage to add the newly acquired phosphate to a growing chain of phosphates. Since the rest of Vtc4 straddles the membrane, scientists suspect this protein probably transfers the polyphosphate chain to the vacuole as it produces it.

The researchers determined Vtc4p's function by looking at its 3D structure.

"This study emphasises the importance of structural biology not just to show what molecules look like and how they work but also what that function is," says Michael Hothorn from Scheffzek's group at EMBL, who is presently at The Salk Institute for Biological Studies in California.

Since polyphosphate is a ubiquitous, multi-tasking molecule with many different functions, discovering how it is produced could have implications for many different fields. Although Vtc4p is not present in plants, the discovery could have implications for agriculture, for instance in the production of fertilizers and high-yield crops. Polyphosphate is important for plant growth, and the scientists suspect Vtc4p could play an important role in making it available to plants that have fungi living in their roots. Because the VTC can move from the membrane of the vacuole to that of the cell, it could assemble phosphate chains and transfer them to outside the fungus cell, where they would be available to the plant.

The research could also pave the way for new treatments for diseases such as sleeping sickness and Chagas disease, as the parasites that cause them need polyphosphate chains to survive.

Source Article
Hothorn, M., Neumann, H., Lenherr, E.D., Wehner, M., Rybin, V., Hassa, P.O., Uttenweiler, A., Reinhardt, M., Schmidt, A., Seiler, J., Ladurner, A.G., Herrmann, C., Scheffzek, K. & Mayer, A. Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase. Science, 24 April 2009

Making Waves in the Brain
Scientists have studied high-frequency brain waves, known as gamma oscillations, for more than 50 years, believing them crucial to consciousness, attention, learning and memory. Now, for the first time, MIT researchers and colleagues have found a way to induce these waves by shining laser light directly onto the brains of mice.

The work takes advantage of a newly developed technology known as optogenetics, which combines genetic engineering with light to manipulate the activity of individual nerve cells. The research helps explain how the brain produces gamma waves and provides new evidence of the role they play in regulating brain functions -- insights that could someday lead to new treatments for a range of brain-related disorders.

"Gamma waves are known to be [disrupted] in people with schizophrenia and other psychiatric and neurological diseases," says Li-Huei Tsai, Picower Professor of Neuroscience and a Howard Hughes Medical Institute investigator. "This new tool will give us a great chance to probe the function of these circuits."

Tsai co-authored a paper about the work that appears in the April 26 online issue of Nature.

Gamma oscillations reflect the synchronous activity of large interconnected networks of neurons, firing together at frequencies ranging from 20 to 80 cycles per second. "These oscillations are thought to be controlled by a specific class of inhibitory cells known as fast-spiking interneurons," says Jessica Cardin, co-lead author on the study and a postdoctoral fellow at MIT's McGovern Institute for Brain Research. "But until now, a direct test of this idea was not possible."

To determine which neurons are responsible for driving the oscillations, the researchers used a protein called channelrhodopsin-2 (ChR2), which can sensitize neurons to light. "By combining several genetic tricks, we were able to express ChR2 in different classes of neurons, allowing us to manipulate their activity with precise timing via a laser and an optical fiber over the brain," explains co-lead author Marie Carlén, a postdoctoral fellow at the Picower Institute.

The trick for inducing gamma waves was the selective activation of the "fast-spiking" interneurons, named for their characteristic pattern of electrical activity. When these cells were driven with high frequency laser pulses, the illuminated region of cortex started to produce gamma oscillations. "We've shown for the first time that it is possible to induce a specific brain state by activating a specific cell type" says co-author Christopher Moore, associate professor of neuroscience and an investigator in the McGovern Institute. In contrast, no gamma oscillations were induced when the fast-spiking interneurons were activated at low frequencies, or when a different class of neurons was activated.

The authors further showed that these brain rhythms regulate the processing of sensory signals. They found that the brain's response to a tactile stimulus was greater or smaller depending on exactly where the stimulus occurred within the oscillation cycle. "It supports the idea that these synchronous oscillations are important for controlling how we perceive stimuli," says Moore. "Gamma rhythms might serve to make a sound louder, or a visual input brighter, all based on how these patterns regulate brain circuits."

Because this new approach required a merger of expertise from neuroscience and molecular genetics, three different laboratories contributed to its completion. In addition to Tsai, Moore and Carlén of MIT, co-authors include Jessica Cardin, research affiliate at the McGovern Institute and the University of Pennsylvania, and Karl Deisseroth and Feng Zhang at Stanford University. Other co-authors were Konstantinos Meletis, a postdoctoral fellow at the Picower Institute, and Ulf Knoblich, a graduate student in MIT's Department of Brain and Cognitive Sciences.

This work was supported by NARSAD, the National Institutes of Health, the National Science Foundation, the Thomas F. Peterson fund, the Simons Foundation Autism Research Initiative and the Knut and Alice Wallenberg Foundation.

Evolution of Human Sex Roles More Complex Than Described by Universal Theory
A new study challenges long-standing expectations that men are promiscuous and women tend to be more particular when it comes to choosing a mate. The research, published by Cell Press in the April issue of the journal Trends in Ecology and Evolution, suggests that human mating strategies are not likely to conform to a single universal pattern and provides important insights that may impact future investigations of human mating behaviors.

In 1948, Angus J. Bateman's performed some now famous studies in fruit flies that showed that males exhibit greater variance in mating success (the number of sexual partners) and in reproductive success (the number of offspring) when compared to females. In addition, Bateman demonstrated that there was a stronger relationship between reproductive success and mating success in males than females.

Bateman concluded that, because a single egg is more costly to produce than a single sperm, the number of offspring produced by a female fruit fly was mainly limited by her ability to produce eggs, while a male's reproductive success was limited by the number of females he inseminated. These studies supported the conventional assumption that male animals are competitive and promiscuous while female animals are non-competitive and choosy.

"The conventional view of promiscuous, undiscriminating males and coy, choosy females has also been applied to our own species," says lead study author Dr. Gillian R. Brown from the School of Psychology at the University of St. Andrews. "We sought to make a comprehensive review of sexual selection theory and examine data on mating behavior and reproductive success in current human populations in order to further our understanding of human sex roles."

Dr. Brown and colleagues examined the general universal applicability of Bateman's principles. To test one of Bateman's assumptions, they collated data on the variance in male and female reproductive success in 18 human populations. While male reproductive success varied more than female reproductive success overall, huge variability was found between populations; for instance, in monogamous societies, variances in male and female reproductive success were very similar.

The researchers also examined factors that might explain variations across human populations that are not in keeping with the prediction of universal sex roles. "Recent advances in evolutionary theory suggest that factors such as sex-biased mortality, sex-ratio, population density and variation in mate quality, are likely to impact mating behavior in humans," concludes Dr. Brown. "The insights gained from this new perspective will have important implications for how we conceive of male and female sexual behavior."

Brown et al.: "Bateman's principles and human sex roles." Researchers include Gillian R. Brown, University of St Andrews, U.K.; Kevin N. Laland, University of St Andrews, U.K.; and Monique Borgerhoff Mulder, University of California at Davis, CA.

Chromosome Breakpoints Contribute to Genetic Variation

A new study reveals that – contrary to decades of evolutionary thought – chromosome regions that are prone to breakage when new species are formed are a rich source of genetic variation

The functions of genes found in these "breakpoint regions" differ significantly from those occurring elsewhere in the chromosomes. This suggests that chromosomal organization plays an important evolutionary role, the researchers report.

The study, published in the journal Genome Research, is the first to show that different parts of chromosomes can have very different evolutionary histories, said University of Illinois animal sciences professor Harris Lewin, who led the research. Lewin directs the Institute for Genomic Biology and is part of an international team that sequenced the cow genome.

"Our results demonstrate that chromosome breakage in evolution is non-random and that the breakpoint regions and the more stable regions of chromosomes are evolving in distinctly different ways," he said.

When egg or sperm cells form in animals, maternal and paternal chromosomes first pair up and then recombine. The chromosomes literally break and reattach to one another. In most cases, the new chromosomes have the same arrangement of genes as the parent cells, but with new combinations of maternal and paternal genes.

The "crossing over" of segments of maternal and paternal chromosomes to form hybrid chromosomes has long been acknowledged as a driver of genetic variation.

Sometimes, however, the wrong chromosomes recombine, segments of chromosomes become inverted or complete breakages and fissions occur. These rearrangements may lead to genetic diseases or may contribute to the development of new species.

Until now, scientists have been unable to determine how the organization of genes along chromosomes and variation within the breakpoint regions contribute to the evolution of an organism's genome, Lewin said. Breakages sometimes disrupt genes or gene families that are regulated together, for example. Deletions, insertions and inversions can cause subtle or dramatic changes in how the genes function.

Scientists once hypothesized that chromosomal breakage and recombination occurred randomly along the chromosomes during evolution. But in 2003, a team from the University of California at San Diego and the Lewin laboratory reported that the breakpoints occurred more often in specific chromosomal regions than in others.

In 2004, Lewin and his colleagues reported a surprising finding: Breakpoint regions also contain a higher density of genes than other parts of the chromosome. In 2005, Lewin's team showed that breakpoint regions also have higher numbers of segmental duplications, a type of mutation that increases the copy number of genes and the sequences that flank them.

"To me, this was completely counterintuitive. I thought we would have these breakpoints in gene deserts," Lewin said. "We had to rethink the whole evolutionary hypothesis about what was going on in breakpoints."

In the new study, Denis Larkin, a senior scientist on Lewin's team, compared the chromosomes of nine mammals (human, chimp, macaque, rat, mouse, pig, cattle, dog, opossum) and a chicken. He found that the breakpoint regions contained many more copy number variants, insertions and deletions in their sequences than the other parts of the chromosomes. Such variations appear to make these regions more susceptible to breakage, Lewin said. (The chromosome analysis was facilitated by Evolution Highway, a powerful software tool developed in collaboration with Michael Welge and Loretta Auvil at the National Center for Supercomputing Applications at the University of Illinois.)

The researchers also found that different classes of genes appear in the breakpoint and break-resistant regions of chromosomes. Those in the breakpoint regions code for proteins involved in immunity and muscle contraction, for example. Rearrangements may cause copies of such genes to increase or change the way they are regulated. These new sources of variation may then be subject to natural selection, the mechanism of evolution proposed by Charles Darwin.

The genes in more stable parts of the chromosomes are involved in growth and development, particularly embryonic development. Disruptions to these genes would probably be harmful to the organism as a whole, Lewin said.

"If the chromosome rearrangement is really bad for the organism, it will be eliminated. It won't survive," he said. "So if something persists in the genome, it generally has to either be neutral, or it has to be of some benefit."

Evolutionary biologists have historically focused on small changes in the genome – such as point mutations or the insertion of viral genes – that sometimes lead to the development of new forms, Lewin said.

"But by overlooking the importance of chromosome rearrangements, these earthquakes in the genome, they may have missed a key component of the mechanism for generating the variation used by natural selection," he said.















Care.com
Learn to Read with Hooked on Phonics
Diapers.com_Free Shipping_ (100x100) Animated
Target
HBC
Kohl's
Sears
Home---History- --Bibliography- -Pregnancy Timeline---Prescription Drugs in Pregnancy--- Pregnancy Calculator----Female Reproductive System---News Alerts---Contact-
Creative Commons LicenseContent protected under a Creative Commons License. No dirivative works may be made or used for commercial purposes.