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Science study shows ‘promiscuous’ enzymes still prevalent in metabolism

 

Open an undergraduate biochemistry textbook and you will learn that enzymes are highly efficient and specific in catalyzing chemical reactions in living organisms, and that they evolved to this state from their “sloppy” and “promiscuous” ancestors to allow cells to grow more efficiently. This fundamental paradigm is being challenged in a new study by bioengineers at the University of California, San Diego, who reported in the journal Science what a few enzymologists have suspected for years: many enzymes are still pretty sloppy and promiscuous, catalyzing multiple chemical reactions in living cells, for reasons that were previously not well understood.

 


 

In this study, the research team, led by Bernhard Palsson, Galetti Professor of Bioengineering at the UC San Diego Jacobs School of Engineering, brought together decades of work on the behavior of individual enzymes to produce a genome-scale model of E. coli metabolism and report that at least 37 percent of its enzymes catalyze multiple metabolic reactions that occur in an actively growing cell.

 

“We’ve been able to stitch all of the enzymes together into one giant model, giving us a holistic view of what has been driving the evolution of enzymes and found that it isn’t quite what we’ve thought it to be,” said Palsson.

 

When organisms evolve, it is the genes or proteins that change. Therefore, gene and protein evolution has classically been studied one gene at a time. However in this work, Palsson and his colleagues, introduce an important paradigm shift by demonstrating that the evolution of individual proteins and enzymes is influenced by the function of all of the other enzymes in an organism, and how they all work together to support the growth rate of the cell.

 

Using a whole-cell model of metabolism, the research team found that the more essential an enzyme is to the growth of the cell, the more efficient it needs to be; meanwhile, enzymes that only weakly contribute to cell growth can remain ‘sloppy.’ The study found three major reasons why some enzymes have evolved to be so efficient, while others have not:

 

Enzymes that are used more extensively by the organism need to be more efficient to avoid waste. To increase efficiency, they evolve to catalyze one specific metabolic reaction.

When enzymes are responsible for catalyzing reactions that are necessary for cell growth and survival, they are specific in order to avoid interference from molecules that are not needed for cell growth and survival.

Since organisms have to adapt to dynamic and noisy environments, they sometimes need to have careful control of certain enzyme activities in order to avoid wasting energy and prepare for anticipated nutrient changes. Evolving higher specificity makes these enzymes easier to control.

 

“Our study found that the functions of promiscuous enzymes are still used in growing cells, but the sloppiness of these enzymes is not detrimental to growth. They are much less sensitive to changes in the environment and not as necessary for efficient cell growth,” said Nathan Lewis, who earned a Ph.D. in bioengineering at the Jacobs School in March and is now a postdoctoral fellow at Harvard Medical School.

 

This study is also a triumph in the emerging field of systems biology, which leverages the power of high-performance computing and an enormous amount of available data from the life sciences to simulate activities such as the rates of reactions that break down nutrients to make energy and new cell parts. “This study sheds light on the vast number of promiscuous enzymes in living organisms and shifts the paradigm of research in biochemistry to a holistic level,” said Lewis. “The insights found in our work also clearly show that fine-grained knowledge can be obtained about individual proteins while using large-scale models.” This concept will yield immediate and more distant results.

 

“Our team’s findings could also inform other research efforts into which enzymes require further study for overlooked promiscuous activities,” said Hojung Nam, a postdoctoral researcher in Palsson’s lab. “Besides testing and characterizing more enzymes for potential promiscuous activities, enzyme promiscuity could have far-reaching impacts as scientists try to understand how unexpected promiscuous activities of enzymes contribute to diseases such as leukemia and brain tumors,” said Nam.

Source: University of California, San Diego


Published on 1st   September  2012

 

Aspirin may help men with prostate cancer live longer, study suggests

 

Men who have been treated for prostate cancer, either with surgery or radiation, could benefit from taking aspirin regularly, says a new study that includes a researcher at UT Southwestern Medical Center.

Taking aspirin is associated with a lower risk of death from prostate cancer, especially in men with high risk disease, according to a multicenter study published in today’s issue of the Journal of Clinical Oncology. Dr. Kevin Choe, assistant professor of radiation oncology at UT Southwestern, is first author of the paper.

 


 

Preclinical studies have shown that aspirin and other anticoagulation medications may inhibit cancer growth and metastasis, but clinical data have been limited previously. The study looked at almost 6,000 men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database who had prostate cancer treated with surgery or radiotherapy.

 

About 2,200 of the men involved – 37 percent – were receiving anticoagulants (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of death from prostate cancer was compared between those taking anticoagulants and those who were not.

 

The findings demonstrated that 10-year mortality from prostate cancer was significantly lower in the group taking anticoagulants, compared to the non-anticoagulant group – 3 percent versus 8 percent, respectively. The risks of cancer recurrence and bone metastasis also were significantly lower. Further analysis suggested that this benefit was primarily derived from taking aspirin, as opposed to other types of anticoagulants.

 

The suggestion that aspirin, a frequently prescribed and relatively well-tolerated medication, may improve outcomes in prostate cancer is of particular interest, Dr. Choe said, since prostate cancer is the most common non-skin cancer among men and the second-leading cancer killer in the U.S.

 

“The results from this study suggest that aspirin prevents the growth of tumor cells in prostate cancer, especially in high-risk prostate cancer, for which we do not have a very good treatment currently,” Dr. Choe said. “But we need to better understand the optimal use of aspirin before routinely recommending it to all prostate cancer patients.”

 

Other scientists involved with the study include Janet Cowan, Drs. June Chan, and Peter Carroll of the University of California, San Francisco; Dr. Anthony D’Amico of Harvard University; and senior author Dr. Stanley Liauw of the University of Chicago.

 

 

Source: UT Southwestern Medical Center

 

 

Published on 30th August 2012

 

 

 

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Midlife fitness staves off chronic disease at end of life

 

Being physically fit during your 30s, 40s, and 50s not only helps extend lifespan, but it also increases the chances of aging healthily, free from chronic illness, investigators at UT Southwestern Medical Center and The Cooper Institute have found.

 


 

For decades, research has shown that higher cardiorespiratory fitness levels lessen the risk of death, but it previously had been unknown just how much fitness might affect the burden of chronic disease in the most senior years – a concept known as morbidity compression.

 

“We’ve determined that being fit is not just delaying the inevitable, but it is actually lowering the onset of chronic disease in the final years of life,” said Dr. Jarett Berry, assistant professor of internal medicine and senior author of the study available online in the Archives of Internal Medicine.

 

Researchers examined the patient data of 18,670 participants in the Cooper Center Longitudinal Study, research that contains more than 250,000 medical records maintained over a 40-year span. These data were linked with the patients’ Medicare claims filed later in life from ages 70 to 85. Analyses during the latest study showed that when patients increased fitness levels by 20 percent in their midlife years, they decreased their chances of developing chronic diseases – congestive heart failure, Alzheimer’s disease, and colon cancer – decades later by 20 percent.

 

“What sets this study apart is that it focuses on the relationship between midlife fitness and quality of life in later years. Fitter individuals aged well with fewer chronic illnesses to impact their quality of life,” said Dr. Benjamin Willis of The Cooper Institute, first author on the study.

 

This positive effect continued until the end of life, with more-fit individuals living their final five years of life with fewer chronic diseases. The effects were the same in both men and women.

 

These data suggest that aerobic activities such as walking, jogging, or running translates not only into more years of life but also into higher quality years, compressing the burden of chronic illness into a shorter amount of time at the end of life, Dr. Berry said.

 

According to the National Heart, Lung, and Blood Institute (NHLBI), adults should get at least 2 ½ hours of moderate to intense aerobic activity each week to ensure major heart and overall health benefits.

 

UT Southwestern has a partnership with The Cooper Institute, the preventive medicine research and educational nonprofit located at the Cooper Aerobics Center, to develop a joint scientific medical research program aimed at improving health and preventing a wide range of chronic diseases. One of the world’s most extensive databases, the Cooper Center Longitudinal Study includes detailed information from clinic visits that has been collected since Dr. Kenneth Cooper founded the institute and clinic in 1970.

 

Other UT Southwestern researchers involved in the study include Dr. David Leonard, assistant professor of clinical sciences, and Ang Gao, a biostatistical consultant in internal medicine.

 

The study was funded with support from the NHLBI and the American Heart Association.

 

 

Source: UT Southwestern Medical Center

 

 

Published on 30th August 2012

 

 

GEORGIA TECH ADVANCES POTENTIAL COMMERCIAL SPACE FLIGHT SYSTEM

 

Last spring private industry successfully sent a spacecraft carrying cargo to the International Space Station. Now the race is on to see which company will be the first to make commercial human spaceflight a reality.

 


 

Sierra Nevada Corporation (SNC) is one of three companies that will receive hundreds of millions of dollars to further develop its commercial human spacecraft system, NASA announced earlier this month.

 

SNC has turned to Georgia Tech for expertise on how to ensure the smoothest possible re-entry for its spacecraft, the Dream Chaser, which is reminiscent of NASA’s space shuttle.

 

Robert Braun, Georgia Tech professor of space technology, and his research team – Research Engineer Jenny Kelly and engineering graduate students Zach Putnam and Mike Grant – are working with SNC on the design of an advanced guidance algorithm that will make the most of the Dream Chaser’s superior aerodynamic performance during re-entry and landing.

 

Of the three companies selected by NASA to develop spaceships to taxi astronauts to and from the International Space Station, Sierra Nevada Corporation is the only one with a winged vehicle. It is designed to launch vertically and land on a runway, similar to the Space Shuttle. Boeing and SpaceX are developing capsules that would land in a body of water.

 

Because the Dream Chaser is similar to the Space Shuttle, it could land using the same guidance algorithm the shuttle used. However, that algorithm, like the shuttle, is based on technology that is more than 40 years old; it does not take advantage of the onboard computing available for today’s space systems.

 

“The shuttle was built in the 1970s, and its designers didn’t have the onboard computing capabilities we have today,” Braun said. “The Dream Chaser can capitalize on an advanced entry guidance algorithm matched to its aerodynamic and onboard computing capability.”

 

Braun and his team took the Dream Chaser’s aerodynamic configuration, control surfaces and mass properties into account when developing the algorithm. To date, the algorithm runs a computer simulation that allows SNC engineers to tweak aspects of the spacecraft design based on scenarios such as variable atmospheric conditions to perfect the landing process.

 

The result is an algorithm that “allows the vehicle to fly how it was meant to fly,” Putnam said.

 

Georgia Tech engineers delivered an early prototype of the software to the SNC team this month for detailed evaluation and testing.

 

Zachary Krevor, a Georgia Tech graduate who is SNC’s principal systems engineer with the flight dynamic and performance group, was eager to see the results.

 

“This is important for us because we feel the algorithm could have performance benefits for our vehicle and make it robust to atmospheric disturbances while ensuring we have a ‘low g’ re-entry,” he said. “Capsules do not have the ‘low g’ re-entry that is so important for both astronauts and sensitive science payloads.”

 

For the students, the project provides real-world experience in the nascent commercial space industry.

 

“To be able to participate in the new era of commercial flight is very exciting,” Grant said. “It has been a great learning experience to see how commercial space companies work and a real thrill to contribute in a meaningful way to the potential flight of this new space flight system.”

 

Sierra Nevada Corporation’s Dream Chaser received an award of $212.5 million from NASA’s Commercial Crew Integrated Capability Program on August 3 that will allow the company to complete development of the system and transport crews to space as early as 2016. An approach and landing test for the Dream Chaser is scheduled for later this year.

 

 

 

Source: Georgia Institute of Technology

 

Published on 19th August  2012

 

CATHEPSIN CANNIBALISM: ENZYMES ATTACK ONE ANOTHER INSTEAD OF HARMING PROTEINS

Manu Platt - Cathepsin Cannibalism

 


 

 

Research led by Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, has shown for the first time that members of the cathepsin family of proteases can attack one another – instead of the protein substrates they normally degrade. (Credit: Georgia Tech Photo by  Gary Meek)


 

 

Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed “cathepsin cannibalism,” the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.

 

Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.

 

Using a combination of modeling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.

 

“These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,” said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.”

 

The research was supported by the National Institutes of Health, the National Science Foundation and the Georgia Cancer Coalition. Details of the study were reported August 10 in the Journal of Biological Chemistry.

 

Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.

 

When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.

 

Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specializes in modeling – to examine what possible conditions could account for the experimental result. Barry’s modeling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.

 

That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.

 

“We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,” said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. “We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.”

 

The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.

 

Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.

 

“The effect of the cathepsins on one another complicates the system,” said Platt. “If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-target binding and side effects that were not anticipated.”

 

Platt’s long-term research has focused on cathepsins, including the development of sensitive tools and assays to quantify their activity in cells and tissue, as well as potential diagnostic applications for breast, lung and cervical cancer. Cathepsins normally operate within cells to carry out housekeeping tasks such as breaking down proteins that are no longer needed.

 

“These enzymes are very powerful, but they have been overlooked because they are difficult to study,” said Platt. “We are changing the way that people view them.”

 

For the future, Platt plans to study interactions of additional cathepsins – as many as three or four are released during certain disease processes – and to develop a comprehensive model of how these proteases interact while they degrade collagen and elastin. That model could be useful to the designers of future drugs.

 

“As we build toward a comprehensive model of how these enzymes work, we can begin to understand how they behave in the extracellular matrix around these cells,” said Platt. “That will help us be smarter about how we go about treating diseases and designing new drugs.”

 

 

Source: Georgia Institute of Technology

 

Published on 19th August  2012

 

 

 

 

WET MAMMALS SHAKE DRY IN MILLISECONDS

 

If you’ve ever bathed a dog, you know firsthand how quickly a drenched pup can shake water off.

 

Now researchers at the Georgia Institute of Technology have found that furry mammals can shake themselves 70 percent dry in just a fraction of a second.

 


 

David Hu, assistant professor of mechanical engineering and biology at Georgia Tech, and mechanical engineering graduate student Andrew Dickerson, who led the project, used high-speed videography and fur particle tracking to characterize the shakes of 33 different animals – 16 species and five dog breeds – at Zoo Atlanta. The research was published in the Journal of Royal Society Interface.

 

Understanding the physics of the wet dog shake could help engineers recreate the optimal oscillation frequency and use it to improve the efficiency of washing machines, dryers, painting devices, spin coaters and other machines.

 

“We hope the findings from our research will contribute to technology that can harness these efficient and quick capabilities of drying seen in nature,” Dickerson said.

 

It may even lead to improved functioning for robotics, such as the Mars Rover, which suffered reduced power from the accumulation of dust on its solar panels.

 

“In the future, self-cleaning and self-drying may arise as an important capability for cameras and other equipment subject to wet or dusty conditions,” Hu said.

 

Over millions of years, animals have perfected the mechanism to dry quickly to avoid hypothermia. Wet fur, being a poor insulator, causes the animal to lose heat quickly and the evaporation of the entrapped water may zap an animal’s energy reserves, making it a matter of life or death to remain dry in cold weather, Hu said.

 

Small animals may trap substantial volumes of water in their fur for their size. For example, when emerging for a bath, a person carries one pound of water. A rat, however, carries five percent of its mass and an ant three times its mass.

 

Georgia Tech researchers found that animals oscillate at frequencies sufficient to lose water droplets and that shaking frequency is a function of animal size.

 

The larger the animal, the more slowly it shakes dry, Hu and Dickerson said. For example, a mouse moves its body back and forth 27 times per second, but a grizzly bear shakes four times per second. The tinier mammals can experience more than 20 g’s of acceleration.

 

Mammals with fur, unlike humans, tend to have loose skin that whips around as the animal changes direction, increasing the acceleration. This is crucial to shaking success, and subsequently, body heat regulation, Dickerson said.

 

“What would you do on a cold day if you were wet and could not towel off or change clothes? Every warm-blooded furry creature faces this dilemma often,” Dickerson said. “It turns out that oscillatory shaking exhibited by mammals is a quite efficient way to dry.”

 

In addition to observing live animals, the engineers also built a robotic wet-dog-shake simulator to further study how drops were ejected.

 

Hu and Dickerson will continue to look at how animals interact with water in the natural world. Specifically, the researchers want to investigate how animals such as beavers and otters have adapted to life in the water and how water droplets interact with hair.

 

 

Source: Georgia Institute of Technology

 

Published on 19th August  2012

 

Probing Question: Is it possible to save coral reefs?

 

It’s one thing for consumers to know intellectually that our gas-guzzling, polluting ways are taking their toll on the planet. It’s another thing to connect all the dots in terms of actions and consequences. Yet, even as we continue to drive SUVs and convert wilderness areas into housing developments, we hold out hope that the environment will rebound.

 


 

Unfortunately, for coral reefs, it’s going to take a lot more than hope, says Todd LaJeunesse, assistant professor of biology at Penn State.

Coral reefs are suffering from overfishing and other types of resource exploitation, LaJeunesse explains. In addition, they are being degraded by pollution from sewage and agricultural runoff, and by increasing sea-surface temperatures and acidification as a result of global warming.

“Coral reefs are important not only for the beauty they provide to snorkeling tourists, but for the ecosystem services they provide to us all,” says LaJeunesse. “They protect coastal areas by buffering the effects of hurricanes; they serve as habitat for food fish and other edible animals; and they are sources of medicines.”

According to the National Oceanic and Atmospheric Administration, reef-supported tourism alone generates an estimated $30 billion annually, with additional environmental and economic benefits valued at ten times that amount.

LaJeunesse’s own research focuses on the relationship between corals — which are animals — and the symbiotic algae, known as zooxanthellae, that live inside their cells. The photosynthetic algae provide food and energy to the corals, while the corals, in turn, provide a safe home for the algae.

“Heat disrupts the association between corals and their symbionts,” explains LaJeunesse, “and this causes the algae to be expelled from the corals, leaving behind a dead, bleached skeleton.”

Because of the barrage of human-induced pressures on corals, most places in the world have seen significant declines in coral cover over the last couple of decades, he adds. “Our own Florida Keys has been among the hardest hit. The area used to be covered with corals of all shapes, sizes, and colors; now there is just a whole lot of dead coral.”

Many of the reefs in the Caribbean Ocean have taken a turn for the worse, adds LaJeunesse. “Elsewhere on the planet, they seem to be doing a little better — in the Indo-Pacific, for example — but scientists think those reefs are just a couple decades behind the Caribbean in their decline.”

“Not only is coral cover declining, but coral species diversity also is dropping,” says LaJeunesse.

He uses genetic techniques to identify the species of zooxanthellae that associate with certain species of coral. Knowing exactly what species you’re working with is the first step in really understanding the organisms, he says.

“No doubt in the future, some species of coral that are better adapted to heat and pollution and that associate with thermally tolerant species of zooxanthellae will survive,” says LaJeunesse. But, he cautions, these species likely won’t be robust enough to withstand the constant wave action and animal predation that, over time, breaks reefs down. And species-poor reefs won’t, in any way, resemble the healthy reefs that we have seen historically and still see in a few places today.

“We don’t want to underestimate life’s ability to persist, but life needs a chance,” he adds. “Whether you view it from a spiritual or an analytical perspective, life is remarkable and it should be cherished. It seems people are looking to scientists to tell them that everything is going to be okay, that technology will save our beloved ecosystems. But that’s not going to happen.

“What I can tell people,” concludes LaJeunesse, “is that, as a functioning ecosystem, coral reefs are in critical danger. “They likely won’t exist in the future in any state resembling what they do now, and if we want to save even some of them, it is going to take major socio-political action that changes the way we exploit nature and use energy.”

“To save what is left of the reefs,” he says with conviction, “we need to drastically change the way we consume — that’s the bottom line.”

 

 

 

Source: Pennsylvania State University

 

Published on 13th  August 2012

 

New model synapse could shed light on disorders like anxiety, epilepsy

Model synapses revealed that, when a GABA-A receptor had Alpha 2 subunits, the receptor tended move toward and form at the synaptic region. However, when a GABA-A receptor had Alpha 6 subunits, the receptor tended to move toward the extrasynaptic region.

 


 

 

Model synapses revealed that, when a GABA-A receptor had Alpha 2 subunits, the receptor tended to move toward and form at the synaptic region. However, when a GABA-A receptor had Alpha 6 subunits, the receptor tended to move toward the extrasynaptic region. (Credi: Gong Chen lab. Penn State)


 

 

A new way to study the role of a critical neurotransmitter in disorders such as epilepsy, anxiety, insomnia, depression, schizophrenia, and alcohol addiction has been developed by a group of scientists led by Gong Chen, an associate professor of biology at Penn State University. The new method involves molecularly engineering a model synapse — a structure through which a nerve cell send signals to another cell. This model synapse can precisely control a variety of receptors for the neurotransmitter called GABA, which is important in brain chemistry. The research, which will be published in the Journal of Biological Chemistry on Aug. 10 opens the door to the possibility of creating safer and more-efficient drugs that target GABA receptors and that cause fewer side effects.

Neurotransmitters — chemicals sent by nerves to trigger other cells to change their electrical responses — interact with special receptors located on the cell’s outer membrane. These receptors form inside the cell, and then are transported to different locations on the membrane to await the arrival of neurotransmitters. Chen explained that understanding how these receptors work and how they move to various locations on a cell’s membrane is a critical step toward the development of new drugs targeting diseases that affect brain chemistry.

In their study, Chen and his team focused on a particular receptor — called the GABA-A receptor– that responds to the neurotransmitter GABA. “The GABA-A receptors are associated with various disorders in which nerve-cell excitability is altered, such as epilepsy and anxiety, and these receptors mediate major inhibition in the brain,” Chen explained. “Each GABA-A receptor protein is made up of five subunits and there are 19 possible subunits that can combine in various ways to form any single receptor. We focused on a particular group of subunits called Alpha, and how changing these tiny subunits might affect the GABA-A receptor’s location on the cell membrane.”

First, Chen and his team used molecular engineering techniques to develop a model synapse between a nerve cell and a special kind of kidney cell used widely in cell-biology research — called an HEK cell — in order to study how specific receptors behaved. They then altered the Alpha subunits in the GABA-A receptors expressed in the kidney cell in order to test how a single variation might affect the behavior of the receptor. They found that the receptors behaved very differently in response to the GABA neurotransmitter, depending on whether they had an Alpha 2 or an Alpha 6 subunit. “Not only do the Alpha subunits play an important role in determining how the GABA-A receptor responds to the neurotransmitter, but the Alpha 2 and Alpha 6 subunits also guide the receptors to very different regions on the cell membrane,” Chen said.

Specifically, Chen and his collaborators found that when a GABA-A receptor had an Alpha 2 subunit, the receptor tended to cluster at the synaptic region on the cell membrane. However, when a GABA-A receptor had an Alpha 6 subunit, the receptor tended to migrate to a different area on the cell membrane called the extrasynaptic region.

Chen explained that understanding such a difference in receptor behavior can be especially important in predicting what side effects a drug might cause. For example, many GABA-receptor-targeting drugs such as Valium and Xanax, which are used to treat anxiety, appear to directly change the GABA neurotransmitter’s synaptic transmission, significantly altering nerve-cell activity and causing side effects such as confusion, agitation, and memory loss.

“If we imagine that a cell represents a big city, then the synaptic regions are major highways leading to the city,” Chen said. “There are serious side effects of disrupting those ‘major highways’ because brain function relies upon a delicate excitation-inhibition balance and breaking that balance will affect the output of neural circuits.” Chen added that, in the same analogy, the extrasynaptic regions could be thought of as the less-trafficked, but numerous smaller roads. “The idea is that if drugs could be developed that manipulate only the extrasynaptic receptors rather than the synaptic receptors, the ‘major highways’ would remain undisturbed and the heavy traffic could continue with less interruption. That is, targeting extrasynaptic receptors by modulating the Alpha 6 subunit represents a step toward creating new drugs with fewer side effects.”

In addition to Chen, other researchers who contributed to this study include Xia Wu, Zheng Wu, Gang Ning, Yao Guo, and Bernhard Luscher from Penn State; Rashid Ali and Angel L. De Blas from the University of Connecticut; and Robert L. Macdonald from Vanderbilt University.

The research is supported by two organizations of the U.S. National Institutes of Health: the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.

 

 

 

Source: Pennsylvania State University

 

Published on 13th  August 2012

 

Tale of Two Scientific Fields–Ecology and Phylogenetics–Offers New Views of Earth’s Biodiversity

 

Patterns in nature are in everything from ocean currents to a flower’s petal.


Scientists are taking a new look at Earth patterns, studying the biodiversity of yard plants in the U.S. and that of desert mammals in Israel, studying where flowers and bees live on the Tibetan plateau and how willow trees in America’s Midwest make use of water.

 

They’re finding that ecology, the study of relationships between living organisms and their environment, and phylogenetics, research on evolutionary relationships among groups of organisms, are inextricably intertwined.

 

Results of this tale of two fields are highlighted in a special, August 2012 issue of the journal Ecology, published by the Ecological Society of America (ESA). Most of the results reported are funded by the National Science Foundation (NSF).

 

The issue will be released at the annual ESA meeting, held this year from August 5-10 in Portland, Ore.

 

Melding information from ecology and phylogenetics allows scientists to understand why plants and animals are distributed in certain patterns across landscapes, how these species adapt to changing environments across evolutionary time–and where their populations may be faltering.

 

“To understand the here and now, ecologists need more knowledge of the past,” says Saran Twombly, program director in NSF’s Division of Environmental Biology.  “Incorporating evolutionary history and phylogenies into studies of community ecology is revealing complex feedbacks between ecological and evolutionary processes.”

 

Maureen Kearney, also a program director in NSF’s Division of Environmental Biology adds, “Recent studies have demonstrated that species’ evolutionary histories can have profound effects on the contemporary structure and composition of ecological communities.”

 

In the face of rapid changes in Earth’s biota, understanding the evolutionary processes that drive patterns of species diversity and coexistence in ecosystems has never been more pressing, write co-editors Jeannine Cavender-Bares of the University of Minnesota, David Ackerly of the University of California at Berkeley and Kenneth Kozak of the University of Minnesota.

 

“As human domination of our planet accelerates,” says Cavender-Bares, “our best hope for restoring and sustaining the ‘environmental services’ of the biological world is to understand how organisms assemble, persist and coexist in ecosystems across the globe.”

 

Papers in the volume address subjects such as the vanishingly rare oak savanna ecosystem of U.S. northern tier states, revealing an ancient footprint of history on the savanna as well as how it has fared in a 40-year fire experiment.

 

Other results cover the influence of ecological and evolutionary factors on hummingbird populations; habitat specialization in willow tree communities; growth strategies in tropical tree lineages and their implications for biodiversity in the Amazon region; and the characteristics of common urban plants.

 

“The studies in this issue show that knowledge of how organisms evolve reveals new insights into the ecology and persistence of species,” says Cavender-Bares.

 

Plants in urban yards, for example, are more closely related to each other–and live shorter lives–than do plants in rural areas, found Cavender-Bares and colleagues.

 

Their study compared plant diversity in private urban yards in the U.S. Midwest with that in the rural NSF Cedar Creek Long-Term Ecological Research site in Minnesota.

 

Cities are growing faster and faster, with unexpected effects, says Sonja Knapp of the Hemholtz Center for Environmental Research in Germany, lead author of the paper reporting the results.

 

“Understanding how urban gardening affects biodiversity is increasingly important,” says Cavender-Bares.  “Urbanites should consider maintaining yards with a higher number of species.”

 

In the special issue, researchers also look at topics such as what determines the number of coexisting species in local and regional communities of salamanders. Kenneth Kozak of the University of Minnesota and John Wiens of Stony Brook University report that variation in the amount of time salamanders occupy different climate zones is the primary factor.

 

Evolution of an herbaceous flower called goldfields, and how that led to the plant’s affinity for certain habitats, is the subject of a paper by David Ackerly, Nancy Emery of Purdue University and colleagues. Emery is the paper’s lead author.

 

In all, 17 papers combine ecology and phylogenetics to offer new answers to long-standing questions about the patterns and processes of biodiversity on Planet Earth.

 

 

 

Source: National Science Foundation

 

Published on 7th August  2012

 

Scientists Define New Limits of Microbial Life in Undersea Volcanoes

Photo of Alvin extending its mechanical arm to a high-temperature black smoker.

 


 

Alvin extends its mechanical arm to a high-temperature black smoker at Endeavor Segment.

(Photo Credit: Bruce Strickrott/WHOI)

 

 

By some estimates, a third of Earth’s organisms live in our planet’s rocks and sediments, yet their lives are almost a complete mystery.

 

This week, the work of microbiologist James Holden of the University of Massachusetts-Amherst and colleagues shines a light into this dark world.

 

In the journal Proceedings of the National Academy of Sciences (PNAS), they report the first detailed data on methane-exhaling microbes that live deep in the cracks of hot undersea volcanoes.

 

“Evidence has built that there’s an incredible amount of biomass in the Earth’s subsurface, in the crust and marine sediments, perhaps as much as all the plants and animals on the surface,” says Holden.

 

“We’re interested in the microbes in the deep rock, and the best place to study them is at hydrothermal vents at undersea volcanoes. Warm water there brings the nutrient and energy sources these microbes need.”

 

Just as biologists studied the habitats and life requirements of giraffes and penguins when they were new to science, Holden says, “for the first time we’re studying these subsurface microorganisms, defining their habitat requirements and determining how they differ among species.”

 

The result will advance scientists’ comprehension of biogeochemical cycles in the deep ocean, he and co-authors believe.

 

“Studies such as this add greatly to our understanding of microbial processes in the still poorly-known deep biosphere,” says David Garrison, program director in the National Science Foundation’s Division of Ocean Sciences, which funded the research.

 

The project also addresses such questions as what metabolic processes may have looked like on Earth three billion years ago, and what alien microbial life might look like on other planets.

 

Because the study involves methanogens–microbes that inhale hydrogen and carbon dioxide to produce methane as waste–it may also shed light on natural gas formation on Earth.

 

One major goal was to test results of predictive computer models and to establish the first environmental hydrogen threshold for hyperthermophilic (super-heat-loving), methanogenic (methane-producing) microbes in hydrothermal vent fluids.

 

“Models have predicted the ‘habitability’ of the rocky environments we’re most interested in, but we wanted to ground-truth these models and refine them,” Holden says.

 

In a two-liter bioreactor at UMass Amherst where the scientists could control hydrogen levels, they grew pure cultures of hyperthermophilic methanogens from their study site alongside a commercially available hyperthermophilic methanogen species.

 

The researchers found that growth measurements for the organisms were about the same. All grew at the same rate when given equal amounts of hydrogen and had the same minimum growth requirements.

 

Holden and Helene Ver Eecke at UMass Amherst used culturing techniques to look for organisms in nature and then study their growth in the lab.

 

Co-investigators Julie Huber at the Marine Biological Laboratory on Cape Cod provided molecular analyses of the microbes, while David Butterfield and Marvin Lilley at the University of Washington contributed geochemical fluid analyses.

 

Using the research submarine Alvin, they collected samples of hydrothermal fluids flowing from black smokers up to 350 degrees C (662 degrees F), and from ocean floor cracks with lower temperatures.

 

Samples were taken from Axial Volcano and the Endeavour Segment, both long-term observatory sites along an undersea mountain range about 200 miles off the coast of Washington and Oregon and more than a mile below the ocean’s surface.

 

“We used specialized sampling instruments to measure both the chemical and microbial composition of hydrothermal fluids,” says Butterfield.

 

“This was an effort to understand the biological and chemical factors that determine microbial community structure and growth rates.”

 

A happy twist awaited the researchers as they pieced together a picture of how the methanogens live and work.

 

At the low-hydrogen Endeavour site, they found that a few hyperthermophilic methanogens eke out a living by feeding on the hydrogen waste produced by other hyperthermophiles.

 

“This was extremely exciting,” says Holden. “We’ve described a methanogen ecosystem that includes a symbiotic relationship between microbes.”

 

 

 

Source: National Science Foundation

 

Published on 7th August  2012

 

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