Researchers at the University of Maryland School of Medicine have identified a common gene variant that appears to influence people’s risk of developing high blood pressure, according to the results of a study being published online Dec. 29, 2008 in the Proceedings of the National Academy of Sciences (PNAS).

The STK39 gene is the first hypertension susceptibility gene to be uncovered through a new technique called a genome-wide association study and confirmed by data from several independent studies.  Located on chromosome 2, the gene produces a protein that helps to regulate how the kidneys process salt, which plays a key role in determining blood pressure.

“This discovery has great potential for enhancing our ability to tailor treatments to the individual – what we call personalized medicine – and to more effectively manage patients with hypertension.  We hope that it will lead to new therapies to combat this serious public health problem worldwide,” says the senior author, Yen-Pei Christy Chang, Ph.D., an assistant professor of medicine and of epidemiology and preventive medicine at the University of Maryland School of Medicine.

But, Dr. Chang says, more research is needed.  “Hypertension is a very complex condition, with numerous other genetic, environmental and lifestyle factors involved.  The STK39 gene is only one important piece of the puzzle,” she says.  “We want to determine how people with different variations of this gene respond to diuretics and other medications, or to lifestyle changes, such as reducing the amount of salt in their diet.  This information might help us discover the most effective way to control an individual patient’s blood pressure.”

One in four Americans has elevated blood pressure, or hypertension, which can lead to death or result in complications, such as cardiovascular disease, stroke and end-stage kidney disease.  Doctors consider the ideal systolic and diastolic blood pressure to be less than 120/80.  (The numbers reflect the pressure of the blood against the arteries when the heart beats and is at rest.)  When blood pressure is elevated, doctors recommend lifestyle changes or prescribe medications, such as diuretics, which force the kidneys to remove water from the body, in order to treat the condition.

However, patients respond differently to treatments and finding the best treatment among all the possible ones for specific patients is still a “try and see” process, according to Dr. Chang.

Scientists believe multiple genes are involved in the most common form of high blood pressure called essential hypertension.  But, because so many factors affect blood pressure, including diet, exercise and stress levels, it has been difficult to pinpoint a specific gene or group of genes, says the lead author, Ying Wang, Ph.D., a researcher at the University of Maryland School of Medicine.

The University of Maryland researchers identified the link between the STK39 gene and blood pressure by analyzing the DNA of 542 members of the Old Order Amish community in Lancaster County, Pa., scanning approximately 100,000 genetic markers across the entire genome for variants known as single nucleotide polymorphisms, or SNPs, associated with systolic and diastolic blood pressure.  The researchers found strong association “signals” with common variants of the serine/threonine kinase gene, or STK39, and confirmed their findings in another group of Amish people and in four other groups of Caucasians in the United States and Europe.

People with one particular variant showed slight increases in blood pressure compared to those with a more common form of the gene and were more likely to develop hypertension, researchers found.  The researchers estimate that about 20 percent of Caucasians in the general population have this variant of the STK39 gene.

“With this new ’scanning’ approach – the genome-wide association study – we are able to uncover genes that have previously eluded us.  The field of complex disease genetics has undergone a revolution in terms of discovering new genes and understanding the genetic basis of common adult-onset diseases,” says co-author Alan R. Shuldiner, M.D., professor of medicine; head of the Division of Endocrinology, Diabetes and Nutrition; and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine.

The study being published online in PNAS is titled, “Whole-genome association study identifies STK39 as a novel hypertension susceptibility gene.”  It will appear in the print edition of PNAS early next month.

The Amish are ideal for such studies because they are a genetically homogeneous people whose forefathers came to Pennsylvania from Europe in the mid-1700s and share a similar diet and rural lifestyle.  Because many in the Amish community don’t have regular medical check-ups, they often don’t know they have high blood pressure or take medications for it, according to Dr. Chang.  The Amish appear to have as much hypertension as other Caucasians.  As a result of the study, some of the participants learned that they had hypertension and were able to start treatment.

The research, which was funded by the National Institutes of Health, is a spin-off project of another University of Maryland study – the Amish Family Diabetes study – looking for genes that may cause type 2 diabetes.  Researchers at the School of Medicine already have identified a number of genes that may play a role in the development of this type of diabetes.

Facial expressions of emotion are hardwired into our genes, according to a study published today in the Journal of Personality and Social Psychology.  The research suggests that facial expressions of emotion are innate rather than a product of cultural learning.  The study is the first of its kind to demonstrate that sighted and blind individuals use the same facial expressions, producing the same facial muscle movements in response to specific emotional stimuli.

The study also provides new insight into how humans manage emotional displays according to social context, suggesting that the ability to regulate emotional expressions is not learned through observation.

San Francisco State University Psychology Professor David Matsumoto compared the facial expressions of sighted and blind judo athletes at the 2004 Summer Olympics and Paralympic Games.  More than 4,800 photographs were captured and analyzed, including images of athletes from 23 countries.

“The statistical correlation between the facial expressions of sighted and blind individuals was almost perfect,” Matsumoto said.  “This suggests something genetically resident within us is the source of facial expressions of emotion.”

Matsumoto found that sighted and blind individuals manage their expressions of emotion in the same way according to social context.  For example, because of the social nature of the Olympic medal ceremonies, 85 percent of silver medalists who lost their medal matches produced “social smiles” during the ceremony.  Social smiles use only the mouth muscles whereas true smiles, known as Duchenne smiles, cause the eyes to twinkle and narrow and the cheeks to rise.

“Losers pushed their lower lip up as if to control the emotion on their face and many produced social smiles,” Matsumoto said.  “Individuals blind from birth could not have learned to control their emotions in this way through visual learning so there must be another mechanism.  It could be that our emotions, and the systems to regulate them, are vestiges of our evolutionary ancestry.  It’s possible that in response to negative emotions, humans have developed a system that closes the mouth so that they are prevented from yelling, biting or throwing insults.”

New research in an animal model suggests that a diet high in inorganic phosphates, which are found in a variety of processed foods including meats, cheeses, beverages, and bakery products, might speed growth of lung cancer tumors and may even contribute to the development of those tumors in individuals predisposed to the disease.

The study also suggests that dietary regulation of inorganic phosphates may play an important role in lung cancer treatment.  The research, using a mouse model, was conducted by Myung-Haing Cho, D.V.M., Ph.D., and his colleagues at Seoul National University, appears in the first issue for January of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

“Our study indicates that increased intake of inorganic phosphates strongly stimulates lung cancer development in mice, and suggests that dietary regulation of inorganic phosphates may be critical for lung cancer treatment as well as prevention,” said Dr. Cho.

Lung cancer is the number one cause of cancer deaths in the world and is also the most frequently diagnosed solid tumor.  Non–small cell lung cancer (NSCLC) constitutes over 75 percent of lung cancers and has an average overall 35-year survival rate of 14 percent.  Earlier studies have indicated that approximately 90 percent of NSCLC cases were associated with activation of certain signaling pathways in lung tissue.  This study revealed that high levels of inorganic phosphates can stimulate those same pathways.

“Lung cancer is a disease of uncontrolled cell proliferation in lung tissue, and disruption of signaling pathways in those tissues can confer a normal cell with malignant properties,” Dr. Cho explained.  “Deregulation of only a small set of pathways can confer a normal cell with malignant properties, and these pathways are regulated in response to nutrient availability and, consequently, cell proliferation and growth.

“Phosphate is an essential nutrient to living organisms, and can activate some signals,” he added.  “This study demonstrates that high intake of inorganic phosphates may strongly stimulate lung cancer development by altering those (signaling) pathways.”

In the study, lung cancer-model mice were studied for four weeks and were randomly assigned to receive a diet of either 0.5 or 1.0 percent phosphate, a range roughly equivalent to modern human diets.  At the end of the four-week period, the lung tissue was analyzed to determine the effects of the inorganic phosphates on tumors.

“Our results clearly demonstrated that the diet higher in inorganic phosphates caused an increase in the size of the tumors and stimulated growth of the tumors,” Dr. Cho said.

Dr. Cho noted that while a moderate level of phosphate plays an essential role in living organisms, the rapidly increasing use of phosphates as a food additive has resulted in significantly higher levels in average daily diets.  Phosphates are added to many food products to increase water retention and improve food texture.

“In the 1990s, phosphorous-containing food additives contributed an estimated 470 mg per day to the average daily adult diet,” he said.  “However, phosphates are currently being added much more frequently to a large number of processed foods, including meats, cheeses, beverages, and bakery products.  As a result, depending on individual food choices, phosphorous intake could be increased by as much as 1000 mg per day.”

“Although the 0.5 percent was defined as close to ‘normal,’ the average diet today is actually closer to the one percent diet and may actually exceed it,” Dr. Cho noted.  “Therefore, the 0.5 percent intake level is actually a reduced phosphate diet by today’s scale.”

Dr. Cho said future studies will help refine what constitutes a “safe” level of dietary inorganic phosphate, with recommendations that will be easily achievable in the average population.

“The results of this study suggest that dietary regulation of inorganic phosphates has a place in lung cancer treatment, and our eventual goal is to collect sufficient information to accurately assess the risk of these phosphates,” he said.

John Heffner, M.D., past president of the ATS, stated that this line of investigation in animals addresses the complex interactions between host factors and the environment that underlie cancer in man.  “We know that only some patients who smoke develop lung cancer but the reasons for this varying risk are unknown.  This study now provides a rationale for funding case-control studies in humans to determine the potential role of dietary phosphates in promoting cancer.”

Shredded extracellular matrix (ECM) is toxic to neurons. Chen et al. Reveal a new mechanism for how ECM demolition causes brain damage. The study will appear in the December 29, 2008 issue of The Journal of Cell Biology (www.jcb.org).

A stroke or head injury kills large numbers of neurons through a process called excitotoxicity. A surge of the neurotransmitter glutamate jolts receptors such as the kainate receptor and stimulates cell death. Enzymes add to the death toll by chopping up ECM near the injury site. How ECM breakdown takes out neurons was mysterious. The standard view was that neurons perished because they got separated from the ECM as it dissolved.

Chen et al. Found otherwise when they engineered mice to lack the ECM component laminin in the hippocampus, a brain region often damaged by stroke or injury. If cells languished after parting from the ECM, the researchers reasoned that mice missing laminin would suffer more damage from excitotoxicity. But when excitotoxicity was spurred with an injection of kainate—a molecule that, like glutamate, activates the kainate receptor—the laminin-lacking mice showed less brain damage. After a dose of diced laminin, however, the mutant mice were vulnerable to kainate, indicating that the fragments are the culprit in cell death.

The researchers discovered that chopped-up ECM kills cells by ramping up production of one subunit of the kainate receptor, known as KA1. They speculate that hiking the amount of KA1 subunits might make the receptor more sensitive and thus more likely to trigger an overreaction by the cell.

Although drugs that obstruct the glutamate receptor slow brain cell death, they can lead to serious cognitive impairment and even coma. The study suggests that drugs that block KA1 might provide an alternative way to save brain cells after stroke or head trauma.

Wind, water, and waves erode billions of tons of soil from the earth’s surface.  As a result, many rivers are plagued with excessive amounts of suspended sediment.  According to the U.S. Environmental Protection Agency, such eroded sediment is the largest nonpoint source pollution in the environment.

While the mechanism responsible for soil erosion may seem obvious –wind, water and wave forces breaking apart particles – in fact, the precise conditions or criterion that sets a particle free from its mates has not been identified.  For 72 years, scientists and engineers have been working with a time-averaged force criterion, originally proposed by A. Shields, an American engineer, to describe threshold conditions for sediment to become mobile.

Now, a team of Virginia Tech College of Engineering faculty members and graduate students have demonstrated that sustained spikes in turbulence are responsible for dislodging particles, whether on land or in the water.  They report their research results in the October 31 issue of Science in the article, “The Role of Impulse on the Initiation of Particle Movement Under Turbulent Flow Conditions.”*

Scientists and engineers have long suspected that turbulence, an ubiquitous feature of natural fluid flow phenomena, was part of the equation.  Anyone who has flown has experienced turbulence.  So a guess that turbulence is the culprit was still not sufficiently informative.

“There has been a need to develop a method that accounts for the role of turbulence on soil erosion in a quantitative way,” said civil and environmental engineering Professor Panos Diplas, lead author on the research.”If you measured the velocity of the air flowing across a fixed place in the middle of Virginia Tech’s drill field, you would see that velocity fluctuates wildly,” Diplas said.

“Wildly and randomly,” said mechanical engineering Associate Professor Clint Dancey, co-author.

“When a weather report includes a high wind warning, it will go something like, ‘30 mph gusting to 70.’  Yet the present system for determining erosion potential in a flow only measures a single, time-averaged value.  “It does not account for the spikes or their duration,” said Diplas.

Diplas, Dancey, and their students began to do experiments to determine the influence of the spikes.  What they discovered is that not all spikes are created equal.

Using a metal ball slightly nested among Teflon balls, they introduced electromagnetic pulses of known magnitude and of different millisecond durations.  The magnetic field simulated the drag of water in a river.  “I had an ‘aha moment’ when I saw the video of that controlled experiment,” said Dancey.

“We saw that, in addition to their amplitude, it was the duration of the ‘gusts’ that caused the metal ball to be dislodged or eroded from its resting pocket” said Diplas.

Using electromagnetic pulses, the team was able to establish a range of combinations of magnitude and duration that result in particle dislodgement.  They call this product of magnitude and duration ‘impulse’.

Next, the team moved their investigation to a two-foot-wide, 65-foot-long flume with actual water in the Baker Environmental Hydraulics Laboratory (www.hydraulicslab.cee.vt.edu) at Virginia Tech.  The flume is used to simulated phenomena encountered in natural streams.  A half-inch diameter ball was slightly nested on a bed of immobile ‘pebbles’.  Laser Doppler velocimetry (LDV) measured the instantaneous flow velocity of the water, which was allowed to move with the typical random turbulence of channel flows.  Laser beams shining through the flume from outside recorded when the mobile grain moved.  Thus the conditions of drag that caused erosion were captured.  The results agreed with the findings of the electromagnetic study, the Science article reports.

“It is fundamental physics with broad applications to water or air flows,” said Dancey.  “The goal is to produce criteria that are more broadly applicable and have more predictive power.”

And not only for the thresholds that result in soil erosion, but for the movement of contaminants.  “A lot of particles have chemicals attached to them.  At what point does pollution occur?”  Said Diplas.  “That is, if pollutants are resting in a river bed, and there is a flood, at some point the turbulence is going to move the pollutants downstream.  We need to know when this will happen!”

Another force capable of mobilizing particles is lift, the force that moves a buried particle out of its bed?.  “We have employed a theoretical approach to explain what is happening when lift is the prevailing force experienced by a soil particle.  The results in this case agree with those obtained from the electromagnet experiments when drag was the dominant force.  Impulse, not just force, represents the more general criterion for identifying the critical conditions for particle dislodgement.”  Dancey said.

“We anticipate that this same mechanism will be responsible for particle dislodgement under the more general condition when both drag and lift forces contribute to particle movement,” added Diplas.

A fungus called microsporidia that causes chronic diarrhea in AIDS patients, organ transplant recipients and travelers has been identified as a member of the family of fungi that have been discovered to reproduce sexually.  A team at Duke University Medical Center has proven that microsporidia are true fungi and that this species most likely undergoes a form of sexual reproduction during infection of humans and other host animals.

The findings could help develop effective treatments against these common global pathogens and may help explain their most virulent attacks.

“Microsporidian infections are hard to treat because until now we haven’t known a lot about this common pathogen,” says Soo Chan Lee, Ph.D., lead author and a postdoctoral researcher in the Duke Department of Molecular Genetics and Microbiology.  “Up to 50 percent of AIDS patients have microsporidial infections and develop chronic diarrhea.  These infections are also detected in patients with traveler’s diarrhea, and also in children, organ transplant recipients and the elderly.”

Of the 1200 species of microsporidia, more than a dozen infect humans.  Their identity had been obscured because these tiny fungi cannot live outside of an infected host cell and they have a small number of genes which are rapidly evolving.

The Duke scientists used two genetic studies to show that microsporidia apparently evolved from sexual fungi and are closely related to the zygomycete fungus in particular.

They found that microsporidia share 33 genes out of 2,000 with zygomycetes.  Which the microsporidia did not share with other fungi.  This genomic signature also shows that microsporidia and zygomycetes likely shared a common ancestor and are more distantly related to other known fungal lineages.

In addition, these two types of fungi have the same sex-locus genes – and in the same order – in their DNA.  Other genes involved in sexual reproduction are also present.  The findings suggest that microsporidia may have a genetically controlled sexual cycle, and may be undergoing sexual reproduction while they infect the host, Lee said.

Lee said the next step is to explore the sexual reproduction of these species, which may cause more severe (more virulent) infections because they use the host’s cellular environment and machinery as a safe haven in which to reproduce.

“These studies resolve the enigma of the evolutionary origins and proper placement of this highly successful group of pathogens, and provide better approaches to their experimental study,” said senior author Joseph Heitman, M.D., Ph.D., director of the Center for Microbial Pathogenesis and director of the Duke University Program in Genetics and Genomics.

The team will pursue further studies with Duke genetic researchers Raphael Valdivia, Ph.D., and Alejandro Aballay, Ph.D., using cultured cells and C. elegans, a worm that researchers recently found is a natural host for microsporidia.  “Using this roundworm may prove to be a useful way to study microsporidia genetics in a living creature,” Heitman said.

New research by the University of East Anglia (UEA) has demonstrated for the first time that human activity is responsible for significant warming in both polar regions.

The findings by a team of scientists led by UEA’s Climatic Research Unit will be published online by the Nature Geoscience this week.

Previous studies have observed rises in both Arctic and Antarctic temperatures over recent decades but have not formally attributed the changes to human influence due to poor observation data and large natural variability.  Moreover, the International Panel on Climate Change (IPCC) had concluded that Antarctica was the only continent where human-induced temperature changes had yet to be detected.

Now, a newly updated data-set of land surface temperatures and simulations from four new climate models show that temperature rises in both polar regions are not consistent with natural climate variability alone and are directly attributable to human influence.

The results demonstrate that human activity has already caused significant warming, with impacts on polar biology, indigenous communities, ice-sheet mass balance and global sea level.

“This is an important work indeed,” said Dr Alexey Karpechko of UEA’s Climatic Research Unit.

“Arctic warming has previously been emphasized in several publications, although not formally attributed to human activity.  However in Antarctica, such detection was so far precluded by insufficient data available.  Moreover circulation changes caused by stratospheric ozone depletion opposed warming over most of Antarctica and made the detection even more difficult.

“Since the ozone layer is expected to recover in the future we may expect amplifying Antarctic warming in the coming years.”

When it comes to the decision to wake up and grow, bacterial spores “listen in” to find out what their neighbors are doing and then they follow the crowd, according to a new report in the October 31st issue of the journal Cell, a Cell Press publication.  Although there is still a lot to learn about how this process works, the discovery could lead to a new kind of antimicrobial agent that works not by killing active bacteria, but by keeping dormant bacteria—which typically resist traditional antibiotics—inactive.

The researchers show that the spores of a soil-dwelling bacteria can sense the presence of so-called muropeptide fragments released from the cell walls of other growing bacteria.  Those muropeptides act as powerful germinants, stimulating the spores to exit the safety of their dormant state and make a go of it.

As other bacteria, including those responsible for diseases like tuberculosis and staph infection, harbor a version of the receptor responsible for this ability in the bacteria under study, the researchers said they think the mechanism they’ve uncovered will prove to be universal.

“[From the bacteria’s perspective,] dormancy is a great state,” said Jonathan Dworkin of Columbia University.  “They are invulnerable to antibiotics.  If you keep them in that state, you can’t kill them but they don’t grow either.  Antibiotics usually kill bacteria by preventing some essential process, but if an antibiotic instead kept dormant bacteria from emerging, it would be essentially like killing them.”  They’d be stuck in a state of suspended animation.

In the new study, the researchers found that muropeptides derived from cultures of growing cells stimulate the germination of dormant Bacillus subtilis spores.  Diverse bacteria can serve as the source for those muropeptide molecules, but the key is a single amino acid ingredient, they found.

The spores ability to receive the signal depends on a eukaryotic-like Ser/Thr membrane kinase receptor (PrkC).  Indeed, a small molecule known to stimulate related kinases is sufficient to spark the activity of the sleeping spores.  Another small molecule called staurosporine, which inhibits related kinases, also prevents spores from activating in the presence of muropeptide.

Dworkin noted that the immune systems of animals recognize the presence of foreign invaders in a similar way, by detecting chains of muropeptide (called peptidoglycans).

” The recognition of peptidoglycans is central to innate immunity,” he said.  “This shows that bacteria do a similar thing, but for different reasons.”  His team is anxious to understand the details better to make the comparison to the immune system as “there may be deep similarities.”

In addition to the promise for a new type of antibiotic medication, the news may stand to benefit the food industry.

Bacterial spores are also a significant problem for food preservation, Dworkin said, because they can withstand heat sterilization.  “If the food industry could find ways to control spore germination, that may be just as good as killing them,” he said.

A new study in the October 31st issue of Cell, a Cell Press journal, has revealed the molecular and cellular underpinnings of one of the most common, single gene causes for learning disability in humans.  The findings made in learning disabled mice offer new insight into what happens in the brain when we learn and remember.

While most previous studies have focused on the role of brain cells that excite other brain cells in the process of learning, the current results suggest that inhibitory neurons and a careful balance between excitatory and inhibitory signals may be just as essential, according to the researchers.  They liken the role of those inhibitory and excitatory signals in the brain to the role of red and green stoplights in directing traffic.

” The significance of these findings is two-fold,” said Alcino Silva of the University of California, Los Angeles.  “First, we have in great detail the exact mechanism for one of the most common single gene causes for learning disability known.  It’s also a beachhead in our understanding of the balance between excitation and inhibition critical for learning.”

Learning disabilities are estimated to affect one in five people worldwide.  “It’s a huge problem and there is little known about their causes,” Silva said.

To begin to chip away at those underlying causes for conditions that often have complex causes, Silva’s team began a hunt several years ago to unravel the mechanisms responsible for a couple of single gene disorders that lead to learning disability.

In the new study, they examined mice with learning disabilities resulting from a condition called neurofibromatosis type 1.  The condition stems from a defect in the Nf1 gene encoding a protein called neurofibromin.  Earlier studies showed that neurofibromin controls a “Ras/Erk” signal that is involved in long-term potentiation (LTP) and learning in mice.  LTP is a process that strengthens the connections between neurons in the brain–the cellular basis for learning and memory.

Now, the researchers have found that the deficits in spatial learning experienced by mice with an abnormal version of the Nf1 gene stem from an increased release by inhibitory neurons of a chemical nerve messenger (or neurotransmitter) called GABA.  GABA is the chief inhibitory neurotransmitter in the central nervous systems of mammals.

That rise in GABA leads to deficits in the plasticity of neurons required for learning and memory.  Importantly, they also show that the learning deficits in the mice can be reversed with treatments that reign GABA levels back in.  They also show that GABA levels normally swell when mice learn, suggesting that a balance of GABA is the key.

Silva’s team notes another recent study implicating changes in GABA inhibition in the learning deficits exhibited by an animal model of Down’s syndrome.  Although learning disability—characterized by profound changes in one part of brain function—differs widely from mental retardation, that finding together with the new study suggest there may nevertheless be a common thread, Silva said.

Ultimately, these insights could lead to new ways to treat learning disabilities, although reaching that goal won’t be a simple proposition.

” It won’t be a single step from the mechanism to finding a drug,” Silva said.  As with other complex disorders like cancer, he said, it will likely take years of exploration to turn scientific advances into medical applications.  Nevertheless, “the more insight we have into the mechanisms responsible, the more likely it is that our treatment efforts will be effective.  ”

The new study is also representative of the exciting advances in the study of neuroscience more broadly.

” We are at the beginning of a wonderful journey into how the human mind works,” Silva said.  “We are developing a highly detailed view of what goes on in the brain when we learn and remember.  There is nothing more inspiring; it’s what makes us who we are.”

Two biologists at the University of California, San Diego have discovered the first of a new class of cellular motor proteins that “rewind” sections of the double-stranded DNA molecule that become unwound, like the tangled ribbons from a cassette tape, in “bubbles” that prevent critical genes from being expressed.

“When your DNA gets stuck in the unwound position, your cells are in big trouble, and in humans, that ultimately leads to death” said Jim Kadonaga, a professor of biology at UCSD who headed the study.  “What we discovered is the enzyme that fixes this problem.”

The discovery represents the first time scientists have identified a motor protein specifically designed to prevent the accumulation of bubbles of unwound DNA, which occurs when DNA strands become improperly unwound in certain locations along the molecule.

The UCSD researchers’ findings, detailed in the October 31 issue of Science, are also important because they provide biomedical scientists with a greater understanding of the molecular mechanisms that lead to a rare genetic disorder called Schimke immuno-osseous dysplasia.  The discovery will eventually allow medical researchers to design future treatments for this devastating genetic disorder, which causes strokes, congestive heart failure, kidney failure and death in young children.

“We knew this particular protein caused this disease before we started the study,” said Kadonaga.  “That’s why we investigated it.  We just didn’t know what it did.”

What this protein, called HARP for HepA-related protein, did astounded Kadonaga and Timur Yusufzai, a postdoctoral fellow working in his laboratory.  The two molecular biologists initially discovered that this motor protein burns energy in the same way as enzymes called helicases and, like helicases, attached to the dividing sections of DNA.  But while helicases use their energy to separate two annealed nucleic acid strands—such as two strands of DNA, two strands of RNA or the strands of a RNA-DNA hybrid— the scientists found to their surprise that this protein did the opposite; that is, it rewinds sections of defective DNA and thus seals the two strands together again.

As a consequence, the UCSD biologists termed their new enzyme activity an “annealing helicase.”

“We didn’t even consider the idea of annealing helicases before this study started,” said Kadonaga.  “It didn’t occur to us that such enzymes even existed.  In fact, we never knew until now what happened to DNA when it got stuck in the unwound position.”

Now scientists who study the action of helicases on DNA and RNA have an entirely new class of proteins to investigate.

“This will open up a whole new area of study,” said Kadonaga.  “There are very few enzymes known that alter DNA structure.  And we’ve discovered an entirely new one.  This was not expected to happen in the year 2008.  We should have found them all by now.”

“I believe it’s going to go beyond DNA.  Just as there are DNA-DNA helicases, there are RNA-DNA helicases and RNA-RNA helicases.  So it doesn’t take a lot of imagination to foresee that there are probably going to be RNA-DNA annealing helicases and RNA-RNA annealing helicases.  The field potentially can be fairly large.  And as more and more people discover additional annealing helicases, this field will expand.”

Kadonaga and Yusufzai are already searching for more annealing helicases, but they also plan to continue their studies of HARP.

“First, what we want to do is find more of these proteins, so we’re looking for more right now,” said Kadonaga.  “We also want to see what other specific processes are affected by this particular protein, HARP, in the cell.”

A new study uses a sophisticated genetic strategy to reveal new roads past an apparent dead end in the historical record of a distinctive civilization that dominated the Mediterranean Sea during the first millennium BC.  The research from National Geographic and IBM’s Genographic Project, published by Cell Press in the November 14th issue of the American Journal of Human Genetics, describes a methodology that may prove to be useful for discovering previously undetected signals left by migrations for any historically documented expansion.

Although extensive documentation by writers and archeologists has provided detailed insight into the origins and early expansion of the Phoenician people, their genetic contributions to the current population are unknown.  “The Phoenicians were the dominant traders in the Mediterranean Sea two to three thousand years ago, and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then disappeared from history.  We wished to identify their male genetic traces in modern populations,” explains senior study author Dr. Chris Tyler-Smith from The Wellcome Trust Sanger Institute.

Drs.  Zalloua, Platt, Tyler-Smith and colleagues developed a strategy to identify a genetic pattern associated not with an overall geographical gradient, but with the specific historical expansion of the Phoenician people.  They chose Phoenician-influenced sites based on well-documented historical records and collected new Y chromosomal data from 1330 men in these sites as well as comparative data from the literature.  “We chose the Y chromosome because its male-specificity means that it would have been carried by the predominantly male Phoenician traders, and is high level of geographical differentiation provides the best chance of recognizing colonization events,” offers Dr. Tyler-Smith.  The researchers developed an analytical strategy to distinguish between lineages linked with Phoenicians and those associated with geographically similar but historically distinct events.

This technique allowed them to identify weak but systematic genetic signatures shared by the Phoenician sites that could not be explained by chance or by other expansions.  Specifically, the Phoenician signature contributed at least 6% to the modern Phoenician-influenced populations that were examined.  “Our work underscores the effectiveness of Y-chromosomal variability when combined with appropriate computational analysis for studying complex patterns of human migration, and the utility of wide geographical sampling using a uniform marker set.  This method is applicable to any type of genetic information from which descent could be inferred,” concludes Dr. Tyler-Smith.

A major puzzle for neurobiologists is how the brain can modify one microscopic connection, or synapse, at a time in a brain cell and not affect the thousands of other connections nearby.  Plasticity, the ability of the brain to precisely rearrange the connections between its nerve cells, is the framework for learning and forming memories.

Duke University Medical Center researchers have identified a missing-link molecule that helps to explain the process of plasticity and could lead to targeted therapies.

The discovery of a molecule that moves new receptors to the synapse so that the neuron (nerve cell) can respond more strongly helps to explain several observations about plasticity, said Michael Ehlers, M.D., Ph.D., a Duke professor of neurobiology and senior author of the study published in the Oct. 31 issue of Cell.  “This may be a general delivery system in the brain and in other types of cells, and could have significance for all cell signaling.”

Ehlers said this could be a general way for all cells to locally modify their membranes with receptors, a process critical for many activities -cell signaling, tumor formation and tissue development.

“Part of plasticity involves getting receptors to the synaptic connections of nerve cells,” Ehlers said.  “The movement of neurotransmitter (chemical) receptors occurs through little packages that deliver molecules to the synapse when new memories form.  What we have discovered is the molecular motor that moves these packages when synapses are active.”

When neurons fire at the same time, their connections strengthen and a person can associate certain features.  “Once you have heard someone’s name, seen his face, where he was standing, all these features can be bound into a unified packet of information – a percept – and at a very cellular level this occurs by strengthening synaptic connections between co-active neurons,” said Ehlers, who is also a Howard Hughes Medical Investigator.

To learn and make new associations, the brain alters the strengths of the synapses’ electrical inputs onto cells that compute these features.  Scientists studied the hippocampus, where memories form, but this machinery could operate in other brain areas.

“One of earliest changes in Alzheimer’s disease is synapse dysfunction, so this molecule might be a new target for that disease,” he said.  “Abnormal movement of receptors may be implicated in brain development, in autism.”  He said the molecule potentially is involved “in the abnormal electrical activity of epilepsy and the overactive brain pathways of addiction.”

In a series of biochemistry and microscopic imaging experiments, Ehlers and colleagues found that the myosin Vb (five-b) molecule in hippocampal neurons responded to a flow of calcium ions from the synaptic space by popping up and into action.  One end of the myosin is attached the meshlike actin filaments so it can “walk” to the end of the nerve cells where receptors are.  On its other end, it tows an endosome, a packet that contains new receptors.

“These endosomes are like little memories waiting to happen,” Ehlers said.  “They are reservoirs of neurotransmitter receptors that brain cells deploy to add more receptors to a particular synapse.  More receptors equals stronger synapses.”

Electrical impulses cause one nerve cell to dump its neurotransmitter, in this case, glutamate, into the small space between neurons (the synapse), which activates neurotransmitter receptors on the receiving side.  These are ion channels that open in response to neurotransmitter and generate the electrical impulse.

When the scientists blocked myosin in single cells, this stopped the addition of new receptors and prevented electrical impulses from getting stronger, showing that myosin is essential to enhancing nerve cell connections.

“This is a very basic cellular mechanism of brain plasticity.  It is likely fundamental to brain development and disease,” Ehlers said.  “The myosin Vb molecule gives us a new way to think about designing therapies for treating memory loss, psychiatric disease and brain development.”

A previously undescribed, cold-loving fungus has been linked to white-nose syndrome, a condition associated with the deaths of over 100,000 hibernating bats in the northeastern United States.  The findings are published in this week’s issue of Science.

The probable cause of these bat deaths has puzzled researchers and resource managers urgently trying to understand why the bats were dying in such unprecedented numbers.  Since the winter of 2006-07, bat declines at many surveyed hibernation caves exceeded 75 percent.

The fungus – a white, powdery-looking organism – is commonly found on the muzzles, ears and wings of afflicted dead and dying bats, though researchers have not yet determined that it is the only factor causing bats to die.  Most of the bats are also emaciated, and some of them leave their hibernacula – winter caves where they hibernate – to seek food that they will not find in winter.

USGS microbiologist and lead author David Blehert isolated the fungus in April 2008, and identified it as a member of the group Geomyces.  The research was conducted by U.S. Geological Survey scientists in collaboration with the New York State Department of Environmental Conservation, the New York State Department of Health, and others.

Geomyces are a group of fungi that live in soil, water and air and are capable of growing and reproducing at refrigerator-level temperatures.  Although the new fungus is a close genetic relative of known Geomyces, it does not look like a typical member of this group under the microscope.  “We found that this fungus had colonized the skin of 90 percent of the bats we analyzed from all the states affected by white-nose syndrome,” Blehert said.

Researchers don’t know yet if white-nose syndrome emerged because this newly identified fungus was introduced into caves or whether the fungus already existed in caves and began infecting bats after they were already weakened from some other cause.  “This fungus may have been recently introduced to bat hibernation caves and, if so, human and animal movements among these caves are causes that need to be considered,”says Blehert.  “Data show the occurrence of white-nose syndrome radiating outward from the site of its first appearance, and genetic identity among fungal isolates from distant caves argues for a recent introduction of this microbe.  Before the identification of white-nose syndrome, mass mortality events in bats as a result of disease were very rare.”

WNS was first seen in New York during the winter of 2006.  Since then, populations of cave-hibernating bats have been drastically declining in Connecticut, Maine, New York and Vermont.  Affected species include little brown bats, northern bats, tricolored bats, Indiana bats, small-footed myotis and big brown bats.

Worldwide, bats play critical ecological roles in insect control, plant pollination and seed dissemination, and the decline of North American bat populations would likely have far-reaching ecological consequences, the researchers wrote.  They noted that parallels can be drawn between the threat posed by WNS and chytridiomycosis, a lethal fungal skin infection that has recently caused precipitous global amphibian population declines.

“Right now,” said Blehert, “we are uncertain about the long-term effects of white-nose syndrome on North American bats, but we are quite concerned about future effects on bat populations wherever environmental conditions are conducive to growth of the fungus.  To manage and perhaps halt this disease, we have to first better understand it.”

Researchers have revealed the complete mitochondrial genome of one of the world’s most celebrated mummies, known as the Tyrolean Iceman or Ötzi.  The sequence represents the oldest complete DNA sequence of modern humans’ mitochondria, according to the report published online on October 30th in Current Biology, a Cell Press publication.

Mitochondria are subcellular organelles that generate all of the body’s energy and house their own DNA, which is passed down from mother to child each generation.  Mitochondrial DNA thus offers a window into our evolutionary past.

“Through the analysis of a complete mitochondrial genome in a particularly well-preserved human, we have obtained evidence of a significant genetic difference between present-day Europeans and a representative prehistoric human—despite the fact that the Iceman is not so old—just about 5,000 years,” said Franco Rollo of the University of Camerino in Italy.

The Tyrolean Iceman witnessed the Neolithic-Copper Age transition in Central Europe more than 5,000 years ago.  His mummified corpse was recovered from an Alpine glacier on the Austro-Italian border in 1991.  In 2000, scientists defrosted the Iceman’s body for the first time and sampled DNA from his intestines.

Earlier study of the DNA showed that he belonged to the lineage, or “subhaplogroup,” known as K1.  About 8% of modern Europeans belong to the K haplogroup, meaning that they share a common ancestor, and that group is divided into two “subhaplogroups,” K1 and K2.  The K1 haplogroup, in turn, can be divided into three clusters.

In the new study, the researchers took advantage of advanced genome-sequencing technologies to shed more light on the Iceman’s genetics.  They sequenced his entire mitochondrial genome and compared that sequence to other published human mitochondrial DNA sequences to construct his evolutionary (or phylogenetic) family tree.

“The surprise came when we found that the lineage of the Iceman did not fit any of the three known K1 clusters,” Rollo said.  His team has informally named the newly discovered branch on the human family tree “Ötzi’s branch.”

“This doesn’t simply mean that Ötzi had some ‘personal’ mutations making him different from the others but that, in the past, there was a group—a branch of the phylogenetic tree—of men and women sharing the same mitochondrial DNA,” Rollo said.  “Apparently, this genetic group is no longer present.  We don’t know whether it is extinct or it has become extremely rare.”

At least for the moment, he said, that means no one can claim to be “the issue of Ötzi.”

Molecular targets identified by a Spanish research team may hold the key to freedom for some sufferers of kidney disease. A new study published in Disease Models & Mechanisms (DMM), reveals the cellular signals which cause one treatment for kidney failure to lose its usefulness over time.

One of the most devastating aspects of kidney failure is the strict, time-consuming treatment regimen. Normally, healthy kidneys take on the role of filtering and cleaning the blood. Therefore patients with diseased kidneys traditionally need to attend a dialysis clinic to have their blood cleaned through a special filter. This treatment requires three regular clinic visits per week, with each session lasting three to five hours.

An alternative to this treatment involves creation of an “artificial kidney” in a process known as peritoneal dialysis (PD). Fluid is inserted into the abdominal cavity, and the blood vessel-rich cavity lining, the peritoneum, acts as a filter for the blood. Exchanges of dialysis fluid can take place at home, thus freeing patients of a rigid schedule of clinic visits.

However, the filtration ability of the peritoneum can lose efficiency over time, requiring patients to discontinue PD. In order to understand this change in the peritoneum, scientists Raffaele Strippoli, Miguel del Pozo and colleagues examined the dialysis fluid from PD patients, and identified molecular signals that cause abnormal changes in the peritoneum. They also found that pharmacologically disrupting these signals causes these abnormal cells to revert back to their original state, as they normally existed in the abdominal cavity lining.

These findings support further research on maintaining the effectiveness of PD, and indicate that perhaps even former PD patients could once again have an option to use PD rather than traditional hemodialysis. Additionally, the cellular changes studied in the peritoneum are similar to cell transformations in tumor formation and inflammation. Their findings may aid in greater understanding of cell change in these situations, as well.