Labslink Research News

Target Meeting’s 2nd World Molecular & Cell Biology Online Conference Held on February 5-8, 2013: Join for Free

Tue, 22 Jan 2013 15:34:12 PDT

A Free Virtual Molecular & Cell Biology Conference at Targetmeeting.com featuring 80+ live presentations (17 sessions) from academic and industry experts around the world. Computer and internet connection are required. Do not need any special equipment or software. All the attendees just connect to the online conference's server to participate in real time with their distinguished counterparts from across the globe. They can participate from their home or office depending on their convenience, which will save them the trouble of traveling and in utilizing their time optimally. Furthermore, attendees can earn the free Certificates of Attendance. It is a great opportunity to learn about recent advances in the field of molecular & cell biology without travel and money cost.

Major sessions (17 sessions) include
Cell signaling pathways
Cell death
RNA biology
Stem cells
GPCR structure & function
Protein structure & modification
Animal model
Cancer biology & therapy
Cell adhesion & migration
Neuron biology & neurological diseases
And many more…

Keynote & Featured Speakers (80+) include
Devyn M. Smith, Chief Operating Officer, Neusentis Research Unit at Pfizer, USA.
Richard G. Pestell, Chairman & Associate Dean, Thomas Jefferson University, USA.
Rolf D Hubmayr, Walter and LeonoreAnnenberg Professor, Mayo Clinic, USA.
Rakesh Srivastava, Tyler Endowed Professor, University of Kansas Medical Center, USA.
Min Du, Professor & Chair, University of Wyoming, USA.
Leif Hertz, Professor, University of Saskatchewan, SK, Canada.
David Hecht, Professor, Chemistry, Southwestern College, USA.
Jacek Jawien, Professor & Chair, Jagiellonian University School of Medicine, Poland.
Steven Stacker, Head, PeterMacCallum Cancer Centre, Australia.
Dan Tulpan, Professor, University of Moncton, Canada.
Romano Maria Fiammetta, Professor, Federico II University of Naples, Italy.
Farid Menaa, Director R&D, Fluorotronics, Inc. USA.
Kathleen L. Hefferon, Professor& Director, Cornell University, USA.
Yin-Yuan Mo, Professor, Southern Illinois University School of Medicine, USA.
Ming Pei, Director, West Virginia University, USA.
View all speaker profiles, visit www.targetmeeting.com

Researchers, medical professionals, and other related people can enjoy many benefits by participating in the 2nd World Molecular & Cell Biology Online Conference. They can know, learn and follow up on major developments taking place in the areas of interest. You can have the rare privilege of meeting the best international speakers and world-renowned researchers in real time. You can have that much-needed opportunity of networking and exchanging views with the target audience directly. Participants get a worldwide platform to express their opinions and ideas. With their experience and expertise, they can build a solid reputation and create a tremendous and lasting impact on the community. The 2nd World Molecular & Cell Biology Online Conference can create new opportunities for the leading life science professionals and can help them establish new associations with fellow researchers. According to Target Meeting, all presentations and discussions happen in real time. Importantly, they save the participants the hassle of travel; help them use their valuable time effectively and save money. Participants can ask questions, discuss problems, and exchange their ideas on the online platform. The conference presents them the ultimate opportunity to discuss their proposals and initiatives with global experts, something that perhaps would not have been possible using other methods of communication or correspondence. Target Meeting is a leading online life science conference organizer. Thousands of international speakers and ten thousands of attendees participated in the online symposiums and conferences at Target Meeting. With the persistent efforts, Target Meeting has achieved a well-respected reputation among the attendees and within life science communities, based on the quality of organizers, speakers and scientific programs, as well as excellent attendee experience. They have a solid record of having created outstanding opportunities for scientists and clinicians to share their latest research and in inspiring breakthrough ideas. The conferences are a great way to establish and maintain professional relationships with the best brains in medical science. Sign up early (free) to secure your seat, please visit http://www.targetmeeting.com. Upcoming Free Online Conferences at Target Meeting
• February 5-8, 2013, TM’s 2nd world molecular & cell biology online conference.
• March 19-21, 2013, TM’s 2nd world immunology online conference.
• April 16-18, 2013, TM’s 2nd world virology & microbiology online conference.
• May 21-23, 2013, TM’s 2nd world genetics & genomics online conference.
• June 18-20, 2013, TM’s 2nd world neuroscience online conference.
And many more… Contact: William Smith Target Meeting Williams @ targetmeeting dot com
Address: Belliare, TX, 77401, USA

BESC researchers tap into genetic reservoir of heat-loving bacteria

Mon, 02 Jul 2012 16:29:31 PDT

The identification of key proteins in a group of heat-loving bacteria by researchers at the Department of Energy's BioEnergy Science Center could help light a fire under next-generation biofuel production. Scientists have long been on the hunt for cost-effective ways to break down complex plant material such as switchgrass in order to access sugars........> Full story

Iowa State, Salk researchers make plant protein discovery that could boost bioeconomy

Mon, 14 May 2012 16:27:06 PDT

Research groups from Iowa State University and the Salk Institute for Biological Studies have uncovered the function of three plant proteins, a discovery that could help plant scientists boost seed oil production in crops, thereby benefitting the production of food, biorenewable chemicals and biofuels.......> Full story

Geneticist develops tool to identify genes important in disease, tailoring individual treatment

Tue, 01 May 2012 16:53:47 PDT

Though the human genome has been sequenced, scientists are still trying to figure out how the accomplishment can help people, for example, how it can be used to treat disease. As University of Massachusetts Amherst geneticist Jacob Mayfield notes, "It was easy to think of the human genome as the big prize, but what we realize now is, it’s just a foot in the door."........> Full story

great tool to find conference and courses

Sat, 28 Apr 2012 02:36:59 PDT

Hey guys

Some people working at the NKI (Netherlands Cancer Institute) have setup a
search engine for scientific meetings. check the description and the website
as well, if interested...
This website, called biomeeter (www.biomeeter.com) is really well done as it
gives a nice overview of the upcoming meetings organized, and the search can
be done by field or keyword, or even by location (as it's always possible to
combine business with pleasure ;-)).
Another great characteristic of Biomeeter is that you can add yourself
meetings to the website and share the info. And last but not least: you can
get informed with an email alert about upcoming meetings in your field.
So, check it out and if you like it, spread the word in your lab and
institute!

ORNL, Yale take steps toward fast, low-cost DNA sequencing device

Tue, 24 Apr 2012 16:29:03 PDT

Researchers at Oak Ridge National Laboratory and Yale University have developed a new concept for use in a high-speed genomic sequencing device that may have the potential to substantially drive down costs.......> Full story

Scripps research scientists identify most lethal known species of prion protein

Thu, 09 Feb 2012 17:36:03 PDT

Scientists from the Florida campus of The Scripps Research Institute have identified a single prion protein that causes neuronal death similar to that seen in “mad cow” disease, but is at least 10 times more lethal than larger prion species.......> Full story

Don't put all your eggs in 1 basket -- or all your horses on 1 pasture

Thu, 29 Dec 2011 17:24:04 PDT

In Mongolia, extreme weather conditions – droughts followed by cold and snowy winters – occur at irregular intervals. However, the dzud of 2009/10 was the most extreme winter Mongolia had experienced in the past 50 years. Fifteen out of Mongolia’s twenty-one provinces were declared disaster zones........> Full story

Virgin olive oil & fish fatty acids help prevent acute pancreatitis

Thu, 22 Dec 2011 14:49:01 PDT

Oleic acid and hydroxytyrosol –present in a particularly high concentration in virgin olive oil– and n-3 polyunsaturated fatty acids –found in fish– affect the cellular mechanisms involved in the development of acute pancreatitis.......> Full story

Scientists discover second-oldest gene mutation

Thu, 15 Dec 2011 18:27:54 PDT

A new study has identified a gene mutation that researchers estimate dates back to 11,600 B.C., making it the second oldest human disease mutation yet discovered........> Full story

New study shows promise for preventing preterm births

Thu, 15 Dec 2011 18:26:42 PDT

A new study co-authored by the University of Kentucky's Dr. John O'Brien found that applying vaginal progesterone to women who are at a high risk of preterm birth significantly decreased the odds of a premature delivery........> Full story

Thousand-color sensor reveals contaminants in Earth and sea

Wed, 02 Nov 2011 16:45:32 PDT

The world may seem painted with endless color, but physiologically the human eye sees only three bands of light — red, green, and blue. Now a Tel Aviv University-developed technology is using colors invisible to the naked eye to analyze the world we live in. With the ability to detect more than 1,000 colors, the "hyperspectral" (HSR) camera, like Mr. Spock's sci-fi "Tricorder," is being used to "diagnose" contaminants and other environmental hazards in real time........> Full story

Vitamin D study suggests no mortality benefit for older women

Tue, 01 Nov 2011 16:48:39 PDT

Doctors agree that vitamin D promotes bone health, but a belief that it can also prevent cancer, cardiovascular disease and other causes of death has been a major health controversy. Consistent with advice issued last fall by the Institute of Medicine, a new study finds that vitamin D did not confer benefits against mortality in postmenopausal women after controlling for key health factors such as abdominal obesity.......> Full story

MIT: Bacteria may readily swap beneficial genes

Tue, 01 Nov 2011 16:44:21 PDT

Much as people can exchange information instantaneously in the digital age, bacteria associated with humans and their livestock appear to freely and rapidly exchange genetic material related to human disease and antibiotic resistance through a mechanism called horizontal gene transfer (HGT).......> Full story

Students coax yeast cells to add vitamins to bread

Tue, 25 Oct 2011 17:59:16 PDT

Any way you slice it, bread that contains critical nutrients could help combat severe malnutrition in impoverished regions. That is the goal of a group of Johns Hopkins University undergraduate students who are using synthetic biology to enhance common yeast so that it yields beta carotene, the orange substance that gives carrots their color. When it’s eaten, beta-carotene turns into vitamin A........> Full story

Protecting the brain when energy runs low

Mon, 17 Oct 2011 16:55:51 PDT

Researchers from the Universities of Leeds, Edinburgh and Dundee have shed new light on the way that the brain protects itself from harm when 'running on empty.' The findings could lead to new treatments for patients who are at risk of stroke because their energy supply from blood vessels feeding the brain has become compromised. Many regions of the brain constantly consume as much energy as leg muscles during marathon running. Even when we are sleeping, the brain needs regular fuel. Much of this energy is needed to fire up 'action potentials', tiny electrical impulses that travel along nerve cells in the brain. These electrical impulses trigger the release of chemical messages at nerve endings, allowing the brain to process information and control bodily functions. Normally, the bloodstream supplies enough glucose and oxygen to the brain to generate the large amount of energy required for these action potentials to be fired up. But things can go wrong if the blood vessels feeding the brain become narrowed or blocked, restricting the supply of vital nutrients. A team led jointly by Professors Chris Peers (Leeds), Mark Evans (Edinburgh) and Grahame Hardie (Dundee) has now identified a way for the brain to protect itself when its energy supply is running low. This protective strategy, which is triggered by a protein known as AMPK, reduces the firing frequency of electrical impulses, conserving energy. The energy-sensing protein AMPK was first discovered by Professor Graham Hardie of the University of Dundee. He said: "When we first defined the AMPK system by studying fat metabolism in the liver back in the 1980s, we had no idea that it might regulate completely different functions in other organs, like nervous conduction in the brain." "There are drugs currently on the market that stimulate AMPK, which are used to treat other conditions. In future these and other drugs could be given to at-risk patients to give them a better chance of surviving a stroke." Professor Chris Peers, of the University of Leeds' School of Medicine, said: "Our new findings suggest that if brain cells run short of energy, they start to work more slowly. However, it is better to work slowly than not at all. It is possible that this discovery could, in the long term, lead to new treatments for patients who have problems with circulation to the brain, placing them at higher risk of conditions such as stroke." "This research is a good example of what can happen if you pool the expertise of research groups who work in different areas."

University of Alberta discovery could change the face of cell-biology research

Tue, 11 Oct 2011 16:40:29 PDT

Rewrite the textbooks and revisit old experiments, because there's a new cog in our cellular machinery that has been discovered by researchers from the University of Alberta and the University of Cambridge Institute for Medical Research. Inside every cell that isn't bacterial, there is a "membrane trafficking system." It has long been known to have four protein complexes, called adaptins, which are all involved in moving things in, out and around the cell. Joel Dacks, in the Department of Cell biology in the U of A Faculty of Medicine & Dentistry, along with Cambridge colleague Margaret Robinson, have discovered there is a fifth adaptin. According to their research it has been around for billions of years, but no one has been able to spot it. "What this does for cell biology is open up a whole new avenue of research," said Dacks. "We thought there were four big players in the processes of how things got moved around in the back half of the cell. There's a fifth player on the field; we just couldn't see it." Understanding how trafficking works in cells is vital because when something goes wrong in this system, oftentimes this is when you get disease. Mutations in genes involved in trafficking are implicated in a number of neurodegenerative disorders including Alzheimer's, Huntington's disease and ALS, also known as Lou Gehrig's disease. "We already have one disease where we know where this complex is involved," said Dacks. It is called hereditary spastic paraplegia which causes increasing leg spasms and eventually loss of mobility. "More importantly it goes back to that idea that to understand the diseased cell, we have to know what a healthy one really looks like. You need to understand the basic map of the cell to be able to identify how it has gone wrong. We have discovered a previously unrecognized major feature on that map." Dacks says that this machinery is widespread, not only in human cells but in plants, parasites and algae, meaning it is not only a general feature of our types of cells but it is also ancient. The more they learn about this fifth adaptin, the more insight they'll be able to gain about the earliest events – the building of cells. Dacks thinks this discovery, published Oct. 11 in Public Library of Science Biology, could help many scientists answer questions they may have been left with following their research projects. "Scientists have to build explanations using the pieces that they know exist. This may help to incorporate some observations that didn't fit, because now you can explain things with five guys, not four," said Dacks. Dacks found this extra adaptin protein in a harmless soil amoeba. Realizing that the same protein is also found in human cells, he contacted Robinson, his colleague. Her lab at Cambridge analyzed the biology of the newfound adaptin for three years. They passed it back to Dacks and his lab at the U of A to study the evolutionary genomics. "It was a really nice example of collaboration," said Dacks. "The Robinson lab is a leader in this area and together we can ask questions that neither group could tackle on their own." While this will likely change a lot of cell biologists' research, for Dacks the next step is to integrate his lab's theories and create a better idea of how the cell evolved. "It gives us some new evolutionary hypotheses to test with other proteins that also act at these cellular steps, and see if the data are consistent with our models." His research is funded by the Natural Sciences and Engineering Research Council and he is an Alberta Innovates Technology Futures new investigator.

Jonesing for java: Could caffeine use predict risk for cocaine abuse?

Fri, 07 Oct 2011 17:39:16 PDT

Parents of young caffeine consumers take heed: that high-calorie energy drink or soda might present more than just obesity risk. In fact, according to a double-blind, placebo-controlled study that examined responses to stimulants, an individual’s subjective response to caffeine may predict how he or she will respond to other stimulant drugs, possibly reflecting differences in risk for abuse of other more serious drugs of abuse, such as amphetamine and cocaine......> Full story

Nuclear receptors battle it out during metamorphosis in new fruit fly model

Thu, 06 Oct 2011 16:45:16 PDT

Growing up just got more complicated. Thomas Jefferson University biochemistry researchers have shown for the first time that the receptor for a major insect molting hormone doesn't activate and repress genes as once thought. In fact, it only activates genes, and it is out-competed by a heme-binding receptor to repress the same genes during the larval to pupal transition in the fruit fly. For the last 20 years, the nuclear receptor known as EcR/Usp was thought to solely control gene transcription depending on the presence or absence of the hormone ecdysone, respectively. But it appears, researchers found, that E75A, a heme-binding receptor that represses genes, replaces EcR/Usp during metamorphosis when ecdysone is absent. The findings, which could shed light on new ways to better understand and treat hormone-dependent diseases, such as cancer, were published in the online October 6 issue of Molecular Cell. "This is the first time we've shown that a steroid hormone receptor and heme-binding nuclear receptor are even interacting with each other," said Danika M. Johnston, Ph.D. "We didn't really think the two were competing against each other to bind to the same sequence of DNA and regulate the same genes." More specifically, in the absence of ecdysone, both ecdysone receptor subunits localize to the cytoplasm, and the heme-binding nuclear receptor E75A replaces EcR/Usp at common target sequences in several genes. During the larval-pupal transition, a switch from gene activation by EcR/Usp to gene repression by E75A is triggered by a decrease in ecdysone concentration and by direct repression of the EcR gene by E75A. An important nuance of this system is that the heme-binder E75A is sensitive to the amount of nitric oxide in the cell, and it cannot completely fulfill its repressive potential at high levels of this important molecule. Thus, the uncovered system uses changing amounts of two ligands, a steroid hormone and a gas, to regulate transcription during development. "These were quite unexpected findings, given the longstanding thoughts of this process," said Dr. Johnston, "but we just didn't have the tools in the past to figure out what was going on mechanistically. We're painting a clearer picture now." Knowing how nuclear receptors regulate gene expression in animal models can provide useful information in the development of drugs. Today, the molecular targets of roughly 13 percent of U.S. Food and Drug Administration approved drugs are nuclear receptors. "It's very possible that similar situations exist in the mammalian system. That could ultimately lead to different treatments that regulate hormone levels in hormone-dependent diseases, such as cancer," said Dr. Johnston.

'Alarm clock' gene explains wake-up function of biological clock

Thu, 29 Sep 2011 16:51:57 PDT

Ever wondered why you wake up in the morning ---- even when the alarm clock isn't making jarring noises? Wonder no more. Researchers at the Salk Institute for Biological Studies have identified a new component of the biological clock, a gene responsible for starting the clock from its restful state every morning. The biological clock ramps up our metabolism early each day, initiating important physiological functions that tell our bodies that it's time to rise and shine. Discovery of this new gene and the mechanism by which it starts the clock everyday may help explain the genetic underpinnings of sleeplessness, aging and chronic illnesses, such as cancer and diabetes, and could eventually lead to new therapies for these illnesses. "The body is essentially a collection of clocks," says Satchindananda Panda, an associate professor in Salk's Regulatory Biology Laboratory, who led the research along with Luciano DiTacchio, a post-doctoral research associate. "We roughly knew what mechanism told the clock to wind down at night, but we didn't know what activated us again in the morning. Now that we've found it, we can explore more deeply how our biological clocks malfunction as we get older and develop chronic illness." In a report published today in the journal Science, the Salk researchers and their collaborators at McGill University and Albert Einstein College of Medicine describe how the gene KDM5A encodes a protein, JARID1a, that serves as an activation switch in the biochemical circuit that maintains our circadian rhythm. The discovery fills in a missing link in the molecular mechanisms that control our daily wake-sleep cycle. The central player of our biological clock is a protein called PERIOD (PER). The number of PER proteins in each of our cells rises and falls every 24 hours. Our cells use the level of PER protein as an indicator of the time of the day and tell our body when to sleep or be awake. Scientists knew that two genes, CLOCK and BMAL1, served as the key drivers for raising PER protein levels. As the level of PER protein rises during the daytime, reaching its peak around evening, it somehow puts a break on CLOCK and BMAL, thereby reducing its own level during nighttime. Falling PER protein levels at night causes our biological systems to slow: our blood pressure drops, our heart rate slows and our mental processes wind down. But, until now, the precise nature of the nighttime brake and what let CLOCK and BMAL proteins overcome this brake to raise PER protein levels again each morning was a mystery. In their research, which was primarily funded by Salk's Innovation Fund, Panda and his colleagues identified JARID1a, a type of enzyme, as the molecular bugle call for cells and organs to get back to work each morning. By studying the genetic mechanisms underlying circadian rhythms in human and mouse cells and in fruit flies, the researchers discovered that JARID1a was required for normal cycling, both at the cellular level and in terms of an organisms' daily behavior. In human and mouse cells that were genetically modified to under-produce JARID1a, the PER protein did not rise to its normal peak each day. Fruit flies that were similarly genetically altered also had low levels of PER protein. The flies lost track of time: they did not know when to sleep or wake up and took frequent naps throughout the day and night. Digging deeper into the molecular workings of the clock, Panda and his colleagues found that each morning, JARID1a reactivates CLOCK and BMAL1 by countering the action of a brake protein HDAC1. They suspect PER protein tells HDAC1 to put a brake on its own production at night. "JARID1a tells that break to ease off, which causes CLOCK and BMAL1 drivers to rev back up every morning," Panda says. To support their findings about the clock's workings, the researchers studied genetically altered mice cells and fruit flies that lacked the JARID1a gene. They inserted JARID1a into the flies' DNA, which released the HDAC brake so the flies returned to a normal cycle. They treated mouse cells with a drug that mimics JARID1a, which allowed their biological clocks to operate normally. Now that scientists understand why we wake each day, they can explore the role of JARID1a in sleep disorders and chronic diseases, possibly using it as a target for new drugs. With age, for instance, the biological clock seems to decline, often causing older people to suffer from difficulty sleeping. There is also strong evidence that shift workers, such as nurses and emergency personnel, who work long shifts that break them out of the normal 24-hour cycle of waking and sleeping, are at much higher risk for certain diseases. The biological clock also appears important to the development of disease, most likely due to its daily influence over metabolic cycles. Daily cell cycles are fundamental to normal operation of genetic mechanisms that control how cells grow and divide, both in normal development and in cancer. The cellular mechanisms of diabetes, another chronic disease, are also tied to metabolic cycles controlled by the biological clock. For instance, the conversion of sugars into fat, which normally occurs only at certain times of day, often seems to take place all day long in diabetics' bodies, suggesting the clock has lost control. "So much of what it means to be healthy and youthful comes down to a good night's sleep," Panda says. "Now that we have identified JARID1a in activating our daytime cycle, we have a whole new avenue to explore why some people's circadian rhythms are off and to perhaps find new ways to help them."

New modeling of brain's circuitry may bring better understanding of Parkinson's disease

Tue, 27 Sep 2011 17:35:17 PDT

Researchers from the School of Science at Indiana University-Purdue University Indianapolis have developed a mathematical model of the brain's neural circuitry that may provide a better understanding of how and why information is not transmitted correctly in the brains of Parkinson's disease patients. This knowledge may eventually help scientists and clinicians correct these misfires. Work led by Leonid L. Rubchinsky, Ph.D., associate professor of mathematical sciences in the School of Science at IUPUI, examines the exchange of electric signals within the Parkinson affected brain, demonstrating that repetitious, overlapped firing of neurons can lead to waves of overly synchronized brain activity. A report on the model appears in the September 2011 issue of the journal Chaos: An Interdisciplinary Journal of Nonlinear Science, a publication of the American Institute of Physics. "This mathematical model of the brain's circuitry provides insight that we could not obtain from animal or human brains in experimental or clinical studies. With this new modeling we, and others, can now better study the mechanisms of information transmission in the Parkinsonian brain – both how the mechanisms work and how they fail. We can also learn about the properties of the cells that are responsible. All this knowledge is critical to the eventual development of therapies to correct defective transmissions found in the brains of those with Parkinson's disease," said Rubchinsky, who is affiliated with the Center for Mathematical Modeling and Computational Sciences in the School of Science at IUPUI. Parkinson's disease is a progressive disorder causing degeneration of neurons in the substantia nigra, a region of the brain which produces the chemical dopamine. Symptoms of Parkinson's disease include tremor, rigidity or stiffness, slowness of movement and impaired balance and coordination. Approximately 60,000 new cases are diagnosed annually in the United States according to the National Institutes of Health. Currently there is no cure for Parkinson's disease. "Technically we have the tools needed for deep brain stimulation – stimulators, long lasting batteries and implantable chips – but we don't have the algorithms – the formulas and other mathematical tools necessary to know what we are trying to stimulate and how. Our model, and others that will follow, should make deep brain stimulation a feasible therapy for Parkinson's disease within the next decade," said Rubchinsky, who is also a researcher with the Stark Neurosciences Research Institute at the IU School of Medicine.

Catalyst discovery has potential to revolutionize chemical industry

Mon, 26 Sep 2011 20:09:58 PDT

University of Alberta Chemistry Professor Steve Bergens and his graduate student Jeremy Johns have discovered a catalyst that has the potential to revolutionise the chemical industry by reducing its environmental footprint, improving efficiency and minimizing risks. Their findings were published in a top international chemistry journal Angewandte Chemie this month and provide the chemical industry with a potential solution to issues surrounding economics, efficiency and environmental factors. "Our findings are a game changer that people having been seeking an answer to for decades," said Bergens. Bergen said researchers have been working for more than 50 years to find a "clean" and stable catalyst that produces little to no waste and also has a capacity to provide multiple turnovers. In February of this year his student Jeremy Johns created such a catalyst in his laboratory. "After years of producing disappointing results I was thrilled to see the results that came out of this particular experiment," said Dr Bergens. "The chemical industry is making huge efforts to reduce its environmental footprint and their economists and accountants are also looking to reduce the cost of not just transporting catalyst but improving its efficiency," said Dr Bergens. He said the February 2011 discovery opens numerous doors to make these things happen for industries ranging from pharmaceuticals to agrochemicals. "Catalysts are notoriously unstable and challenging to transport, and the waste products the reactions to produce chemicals produce are equally challenging," Bergens added. John's catalyst only produces hydrogen as a waste, something that is easy to burn off or react to produce water. Bergens says early indications are the catalyst is not just safe but also efficient. The researchers have pushed the experiment to produce 7000 turnovers for one unit of catalyst. "We are hugely excited , and the challenge now is to identify exactly how this catalyst is made up and how we can produce it in amounts to further advance this discovery," said Bergens.

Keeping pets sweet: Treating diabetes in dogs

Fri, 23 Sep 2011 16:58:48 PDT

Diabetes has many severe consequences that can only be prevented by maintaining blood glucose levels at values that are extremely close to those of non-diabetics. There have recently been considerable advances in insulin treatment but these require a precise knowledge of fluctuations in blood glucose levels that is difficult to obtain. Measurements are generally taken while patients are in clinics but the results may be misleading as a result of differences in food intake and exercise, as well as the associated stress, all of which may lead to changes in the normal patterns. Monitoring blood glucose levels while patients – people or animals – are leading their normal lives would give far more meaningful information........> Full story

BGI develops RNA-Seq (Quantification) from as low as 100 Ng total RNA

Tue, 20 Sep 2011 17:11:43 PDT

BGI, the world's largest genomics organization, reported that they have achieved optimization RNA-Seq (Quantification) library construction with total RNA inputs as low as 100 ng. This breakthrough enables the application of RNA-Seq (Quantification) technology to experimental designs utilizing samples derived from small numbers of cells, such as those widely used in pharmaceutical research, cancer research, and immunology. RNA-Seq (Quantification), a version of Next Generation Sequencing (NGS), is used for transcriptome quantification and analyzing the gene expression of certain biological objects in specific conditions. It can be widely applied in biomarker detection, basic medical research, drug discovery, among others. Compared with microarray technology, high-throughput RNA sequencing can provide comprehensive assessment of RNA expression profiles with the advantages of high-throughput data, low background, high sensitivity and repeatability. However, some tissues or cultures from specialized cells involved in clinical and pharmaceutical research make it difficult to obtain sufficient RNA for RNA-Seq (Quantification), which previously required 1 μg or more total RNA. BGI has optimized the procedures to enable RNA-Seq (Quantification) using as little as 100 ng total RNA sample input to generate high-quality data. "The improvement of RNA-Seq (Quantification) not only can simplify sample preparation, but also make this sequencing service more cost-effective and with rapid turnaround time," said Jiong Zhang, Technical Specialist at BGI. To ensure the accuracy and quality of data, many evaluations have been conducted at BGI, including the reads quality, assessments of reads randomness, gene coverage, experimental reproducibility, and data accuracy. Results demonstrated that the data generated from 100 ng sample input library was as high-quality as that from traditional 1 μg RNA input library. "I hope our enhanced technique can contribute more to drug discovery and therapeutic application in the future," added Zhang.

Feared spinal X-ray found to be safe, study shows

Wed, 14 Sep 2011 18:00:49 PDT

Medical imaging experts at Johns Hopkins have reviewed the patient records of 302 men and women who had a much-needed X-ray of the blood vessels near the spinal cord and found that the procedure, often feared for possible complications of stroke and kidney damage, is safe and effective. Reporting in the journal Neurology online Sept. 14, the Johns Hopkins researchers found that none of the study participants, all of whom underwent a spinal digital subtraction angiography, or SpDSA, at The Johns Hopkins Hospital between 2000 and 2010, had suffered either a stroke or any kidney damage as a result of the procedure, considered the "gold standard" test for distinguishing among many types of vascular disorders near the spine. These include strokes, hematomas, aneurysms, fistulas and tumors. "Patients and their physicians can now look with confidence to our study and see for themselves the real as opposed to perceived risks and complications from spinal angiography," says study senior investigator and interventional neuroradiologist Philippe Gailloud, M.D. "Advances in the procedure have made it much safer today than before, and neurologists and patients really should consider this valuable diagnostic tool based on the actual medical evidence and not on whatever unsubstantiated rumors they might hear secondhand or read on the Internet," adds Gailloud, an associate professor at the Johns Hopkins University School of Medicine. Gailloud says reports of stroke and kidney damage had been rather high, in as many as 3 percent of people, in the 1970s when the procedure was first introduced. Then, preparing patients for testing and injecting a dye to make the blood vessels more visible often took hours instead of the routine half-hour it takes today, raising the chances that a clot could dislodge in the blood vessels and cause a stroke. The earlier process also used up more than twice as much of the potentially toxic contrast agent than is needed today. Another key finding in the latest study was that spinal angiography could accurately rule out suspected cases of spinal inflammation, a condition known as transverse myelitis. Fourteen of 45 patients diagnosed and treated with steroids or other immune-suppressing drugs for transverse myelitis were later confirmed by SpDSA to have a vascular malformation instead. All of these patients were successfully treated for their actual spinal problem, and none of them suffered any complications as a result. According to Gailloud, who is also director of interventional neuroradiology at Johns Hopkins, this shows physicians that anyone who is diagnosed with transverse myelitis and who does not show improvement after drug treatment but is still likely suffering from a spinal problem should consider having a SpDSA to either verify the original diagnosis or determine if it is actually a vascular malformation. Both conditions have similar symptoms, he says, with people often complaining of a weakening in the legs, even temporary paralysis, sudden and uncontrolled urination, and back pain. Lead study investigator and Hopkins medical student James Chen, M.Sc., began the study with encouragement from experts at the Johns Hopkins Transverse Myelitis Center after noticing continued reluctance by other specialists and patients to use spinal angiography. They believed the procedure to be too dangerous, despite growing acceptance of its efficacy. "To counter medical rumor and historical perception, we simply had to put some current numbers on its safety and risk," says Chen, who is also a Doris Duke Charitable Foundation research fellow in interventional neuroradiology at Johns Hopkins. Gailloud and Chen have already begun the next phase of their research, a prospective study to monitor people after they have had a SpDSA for any possible complications months or even years after the procedure. Initial results are expected in 2012. In the SpDSA procedure, a catheter tube is inserted into the larger blood vessels near the groin and gently threaded, one by one, into each of the major arteries branching from the aorta to the spine. Dye is released into each artery to help form multiple images of each artery, as taken by X-ray. The test is usually performed to specifically identify the source of the vascular problem after an MRI has ruled out any other physical disorders to the spine.

Breaching the blood-brain barrier

Tue, 13 Sep 2011 17:51:57 PDT

Cornell University researchers may have solved a 100-year puzzle: How to safely open and close the blood-brain barrier so that therapies to treat Alzheimer's disease, multiple sclerosis and cancers of the central nervous system might effectively be delivered. (Journal of Neuroscience, Sept. 14, 2011.) The researchers found that adenosine, a molecule produced by the body, can modulate the entry of large molecules into the brain. For the first time, the researchers discovered that when adenosine receptors are activated on cells that comprise the blood-brain barrier, a gateway into the blood-brain barrier can be established. Although the study was done on mice, the researchers have also found adenosine receptors on these same cells in humans. They also discovered that an existing FDA-approved drug called Lexiscan, an adenosine-based drug used in heart imaging in very ill patients, can also briefly open the gateway across the blood-brain barrier. The blood-brain barrier is composed of the specialized cells that make up the brain's blood vessels. It selectively prevents substances from entering the blood and brain, only allowing such essential molecules as amino acids, oxygen, glucose and water through. The barrier is so restrictive that researchers couldn't find a way to deliver drugs to the brain – until now. "The biggest hurdle for every neurological disease is that we are unable to treat these diseases because we cannot deliver drugs into the brain," said Margaret Bynoe, associate professor of immunology at Cornell's College of Veterinary Medicine and senior author of a paper appearing Sept. 14 in the Journal of Neuroscience. Aaron Carman, a former postdoctoral associate in Bynoe's lab, is the paper's lead author. The study was funded by the National Institutes of Health. "Big pharmaceutical companies have been trying for 100 years to find out how to traverse the blood-brain barrier and still keep patients alive," said Bynoe, who with colleagues have patented the findings and have started a company, Adenios Inc., which will be involved in drug testing and preclinical trials. Researchers have tried to deliver drugs to the brain by modifying them so they would bind to receptors and "piggyback" onto other molecules to get across the barrier, but so far, this modification process leads to lost drug efficacy, Bynoe said. "Utilizing adenosine receptors seems to be a more generalized gateway across the barrier," she added. "We are capitalizing on that mechanism to open and close the gateway when we want to." In the paper, the researchers describe successfully transporting such macromolecules as large dextrans and antibodies into the brain. "We wanted to see the extent to which we could get large molecules in and whether there was a restriction on size," Bynoe said. The researchers also successfully delivered an anti-beta amyloid antibody across the blood-brain barrier and observed it binding to beta-amyloid plaques that cause Alzheimer's in a transgenic mouse model. Similar work has been initiated for treating multiple sclerosis, where researchers hope to tighten the barrier rather than open it, to prevent destructive immune cells from entering and causing disease. Although there are many known antagonists (drugs or proteins that specifically block signaling) for adenosine receptors in mice, future work will try to identify such drugs for humans. The researchers also plan to explore delivering brain cancer drugs and better understand the physiology behind how adenosine receptors modulate the blood-brain barrier.

MU study finds quitting smoking enhances personality change

Mon, 12 Sep 2011 17:27:00 PDT

The data indicate that for some young adults smoking is impulsive,” said Andrew Littlefield, a doctoral student in the Department of Psychology in the College of Arts and Science. “That means that 18-year-olds are acting without a lot of forethought and favor immediate rewards over long term negative consequences. They might say, ‘I know smoking is bad for me, but I’m going to do it anyway.’ However, we find individuals who show the most decreases in impulsivity also are more likely quit smoking. If we can target anti-smoking efforts at that impulsivity, it may help the young people stop smoking........> Full story

First proof in patients of an improved 'magic bullet' for cancer detection and radio-therapy

Mon, 12 Sep 2011 17:22:15 PDT

Oncologists have long sought a powerful "magic bullet" that can find tumors wherever they hide in the body so that they can be imaged and then destroyed. Until recently scientists accepted the notion that such an agent, an agonist, needed to enter and accumulate in the cancerous cells to act. An international research team has now shown in cancer patients that an investigational agent that sticks onto the surface of tumor cells without triggering internalization, an antagonist, may be safer and even more effective than agonists. One of the Salk Institute's leading researchers, Dr. Jean Rivier, professor in The Clayton Foundation Laboratories for Peptide Biology and holder of the Frederik Paulsen Chair in Neurosciences and his Swiss collaborator, Dr. Jean Claude Reubi, University of Berne and Adjunct Professor at Salk, co-authored a pilot study, published in the September issue of the Journal of Nuclear Medicine, of five patients and demonstrated that their "antagonist", 111In-DOTA-BASS, outperformed the "agonist" agent, OctreoScan, that is widely used in the clinic to image neuroendocrine tumors bearing somatostatin receptors. "This is the first proof of principle in humans that labeled peptide antagonists can effectively image tumors. Additional research suggests that we could one day use a different radioactive metal to effectively kill the tumors," said Dr. Rivier. Dr. Reubi, a molecular pathologist, and Dr. Rivier, a chemist, collaborated in the design and selection of natIn-DOTA-BASS for human testing, and Dr. Helmut R. Maecke, a radio chemist, loaded DOTA-BASS with its radioactive marker and tested the compound before use in human. Afterward, the "first in man" study with the radioactive loaded DOTA-BASS was performed at the University Hospital in Freiburgby Drs. Damian Wild, Melpomeni Fani, Martin Behe, Ingo Brink, Helmut R. Maecke, and Wolfgang A. Weber. The genesis of this study goes back to 1973, when a team of Salk researchers, which included Drs. Brazeau, Vale, Burgus, Rivier, and Roger Guillemin, a 1977 Nobel laureate, isolated and characterized somatostatin, a peptide produced by neuroendocrine glands. The scientists found that the normal function of somatostatin is to block the release of growth hormone throughout the body, which includes inhibiting the release of thyroid-stimulating hormone (TSH) from the thyroid. Drs. Rivier, Reubi and their colleagues from Germany showed that 111In-DOTA-BASS bound to a greater number of somatostatin receptors on cancer cells than the agonist OctreoScan, and that it did accumulate in normal tissue (liver and kidney) to a lesser extent. The prototype antagonist therapy has been revamped, and the version studied in the Journal of Nuclear Medicine publication, 111In-DOTA-BASS, detected 25 of 28 metastatic neuroendocrine tumors in the patients, whereas OctreoScan detected only 17. In-DOTA-BASS has been licensed to a pharmaceutical company for clinical trial development, according to Rivier, who adds that other researchers are exploring an antagonist approach for other G-protein coupled receptors that are abundantly expressed on cancer cells.

USC scientists identify key protein linked to acute liver failure

Wed, 07 Sep 2011 17:11:00 PDT

New research from the Keck School of Medicine of the University of Southern California (USC) may help prevent damage to the liver caused by drugs like acetaminophen and other stressors. Acetaminophen, more commonly known as Tylenol, helps relieve pain and reduce fever. The over-the-counter drug is a major ingredient in many cold and flu remedies as well as prescription painkillers like Percocet and Vicodin. However, metabolized by the liver, acetaminophen is the most common cause of drug-induced liver disease and acute liver failure in the United States and United Kingdom. Tylenol's maker announced in July that it was lowering the maximum recommended daily dosage to 3,000 milligrams to help prevent accidental overdoses. Doctors at the Keck School of Medicine of USC have identified a protein on the mitochondria of liver cells in mice that, when silenced, protects against liver toxicity usually associated with excess doses of acetaminophen. They found that the protein Sab, or SH3-domain binding protein 5, binds with the enzyme JNK (c-Jun N-terminal kinase). JNK regulates cellular metabolism and survival in response to stress, protecting cells when activated for brief intervals. However, JNK also kills cells when activated for prolonged periods of time. "Because the short-term activation of JNK is associated with cell survival, Sab is potentially a better target than inhibiting JNK, which could have adverse effects," said Neil Kaplowitz, M.D., the study's lead investigator and professor of medicine at the Keck School. Researchers have long believed that acetaminophen was converted into toxic metabolites that, in excess, overwhelm liver cells, causing them to die. In a 2008 study, Kaplowitz, who holds the Keck School's Thomas H. Brem Chair in Medicine and Veronica P. Budnick Chair in Liver Disease, and other USC colleagues turned that theory around — they found that it was not the metabolite, but rather the sustained activation of JNK that harmed the organ. By inhibiting JNK activation in mice, injury to the liver caused by large doses of acetaminophen was avoided. In the current study, published online by the Journal of Biological Chemistry in August, the scientists silenced Sab in mice, which did not affect the metabolism of acetaminophen but successfully prevented liver injury. They also tested the effect on liver injury caused by apoptosis, or programmed cell death in response to inflammatory proteins that are implicated in many diseases and tissues — silencing Sab protected the liver in that case, too. "We proved that the sustained activation of JNK targets Sab and is a requirement for the subsequent death of liver cells," Kaplowitz said. "We then showed that it is a universal effect. Developing a drug to protect against cell death, one could argue to target JNK — but that's a double-edged sword. This provides a whole new target: Create a drug that inhibits the interaction between JNK and Sab."

TB vaccine candidate shows early promise

Mon, 05 Sep 2011 18:27:54 PDT

Researchers at Albert Einstein College of Medicine of Yeshiva University report in the September 4 online edition of Nature Medicine that they have developed a tuberculosis (TB) vaccine candidate that proved both potent and safe in animal studies. (http://www.who.int/mediacentre/factsheets/fs104/en/) According to the World Health Organization, TB kills an estimated 1.7 million people each year and infects one out of three people around the globe. With drug-resistant strains spreading, a vaccine for preventing TB is urgently needed. "Producing effective TB vaccines requires a better understanding of the mechanisms used by Mycobacterium tuberculosis [the bacterial species that causes TB] to evade the body's immune responses," said senior author William Jacobs, Jr., Ph.D., professor of microbiology & immunology and of genetics at Einstein and a Howard Hughes Medical Institute investigator. He notes that the only currently used vaccine, the Bacille Calmette-Guérin (BCG) vaccine, has been notoriously inconsistent in protecting against TB. To determine how M. tuberculosis outwits the immune response, Dr. Jacobs and his colleagues worked with a closely related species known as Mycobacterium smegmatis that is lethal to mice at high doses but does not harm people. The researchers created a version of M. smegmatis lacking a set of genes, known as ESX-3, considered crucial for evading host immunity. When high doses of the altered bacteria were infused into mice, it became clear that bacteria lacking the ESX-3genes could no longer evade their hosts' immune system: the mice controlled and cleared the infection through a robust T-cell response—the same response a successful TB vaccine would elicit. Unfortunately, Dr. Jacobs found that removing the same set of genes from M. tuberculosis killed the bacterium─which meant M. tuberculosis could not be manipulated in this way to make a vaccine. But Dr. Jacobs and his colleagues found a way around this stumbling block. They took the M. smegmatis bacteria lacking ESX-3 and inserted the analogous set of M. tuberculosis ESX-3 genes. These M. smegmatis bacteria were then infused into mice, which once again fought off the infection. And eight weeks later, when the mice were challenged with high doses of M. tuberculosis—which kills mice as well as people—these "vaccinated" mice lived much longer than control mice: an average survival time of 135 days vs. 54 days. Just as impressive, said Dr. Jacobs, was the markedly reduced level of TB bacteria found in the animals' tissues. "Most notably," he said, "those vaccinated animals that survived for more than 200 days had livers that were completely clear of TB bacteria, and nobody has ever seen that before." Dr. Jacobs cautioned that only about one in five mice showed this robust response—indicating that the vaccine must be improved before it can be considered sufficiently effective. "We don't even know yet if it will work in humans, but it's certainly a significant step in efforts to create a better TB vaccine," he said. Aeras, a Rockville, MD-based non-profit development partnership dedicated to preventing TB, has licensed the technology described in this study and is using it to develop a new TB vaccine. The technology could also provide the basis for vaccines that eliminate leprosy and other virulent mycobacteria from infected tissues. The group's paper is titled "A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against M. tuberculosis." Other Einstein researchers involved in the study were lead author Kari Sweeney, Ph.D.; Dee Dao, Ph.D.; Michael Goldberg, M.S.; Tsungda Hsu, Ph.D.; Manjunatha Venkataswamy, Ph.D.; Rani Sellers, Ph.D., DVM; Paras Jain, Ph.D.; Bing Chen, M.D.; Mei Chen; John Kim, Regy Lukose, John Chan, M.D.; and Steven Porcelli, M.D.. Diane Ordway, Ph.D., and Ian Orme, Ph.D., of Colorado State University, Fort Collins, CO were also co-authors of the study. The research was funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Dr. Jacobs' research is also funded by the Howard Hughes Medical Institute.

McMaster researchers find missing genes may separate coach potato from active cousin

Mon, 05 Sep 2011 18:26:47 PDT

ou may think your lack of resolve to get off the couch to exercise is because you're lazy, but McMaster University researchers have discovered it may be you are missing key genes. The researchers made their unexpected finding while working with healthy, specially-bred mice, some of which had two genes in muscle essential for exercise removed. The genes control the protein AMP-activated protein kinase (AMPK), an enzyme that is switched on when you exercise. "Mice love to run," said Gregory Steinberg, associate professor of medicine in the Michael G. DeGroote School of Medicine and Canada Research Chair in Metabolism and Obesity. "While the normal mice could run for miles, those without the genes in their muscle could only run the same distance as down the hall and back. It was remarkable. The mice looked identical to their brothers or sisters but within seconds we knew which ones had the genes and which one didn't." The researchers found the mice without the muscle AMPK genes had lower levels of mitochondria and an impaired ability for their muscles to take up glucose while they exercise. "When you exercise you get more mitochondria growing in your muscle. If you don't exercise, the number of mitochondria goes down. By removing these genes we identified the key regulator of the mitochondria is the enzyme AMPK," said Steinberg. Thousands of scientists around the world are working on AMPK but the McMaster team is the first to demonstrate its essential role in exercise. Their research appears in the current issue of the Proceedings of the National Academy of Sciences. Steinberg said the findings are important for individuals who find it difficult to exercise, such as the obese, asthmatics and people in wheelchairs. Their inability to exercise may lead to other complications such as diabetes and heart disease. The study, he thinks, has a message for couch potatoes. "As we remove activity from our lives due to emerging technology, the base level of fitness in the population is going down and that is reducing the mitochondria in people's muscles. This in turn makes it so much harder for people to start exercising." Steinberg himself runs or bikes to work. "It is the only way that I can manage to make sure I stay fit."

Dendritic cells in liver protect against acetaminophen toxicity

Fri, 02 Sep 2011 18:47:49 PDT

NYU School of Medicine researchers have discovered that dendritic cells in the liver have a protective role against the toxicity of acetaminophen, the widely used over-the-counter pain reliever and fever reducer for adults and children. The study's findings are published in the September issue of the journal Hepatology. The liver is the organ that plays a central role in transforming and filtering chemicals from the body. High-doses of acetaminophen can cause hepatotoxicity, chemical driven liver damage. In fact, accidental and intentional acetaminophen overdose are the most frequent causes of acute liver failure (ALF) in the United States. Acetaminophen related liver failure by intentional or accidental overdose causes 56,000 emergency room visits, 2,600 hospital visits and 450 deaths annually. As a result, this year the FDA mandated drug manufacturers to start limiting the amount of acetaminophen in combination drug products and is currently exploring adding safer dosing instructions to children's acetaminophen products. In the new study, researchers found an abundance of dendritic cells in the liver can protect the organ from acetaminophen damage while low levels of dendritic cells in the liver are associated with exacerbated liver damage, liver cell and tissue death, known as centrilobular hepatic necrosis, and acute liver failure from acetaminophen. "Our research results confirm a central role for dendritic cells and their powerful regulation of acetaminophen's toxicity," said George Miller, MD, senior author of study and assistant professor, Departments of Surgery and Cell Biology at NYU Langone Medical Center. "High levels of dendritic cells have a novel, critical and innate protective role in acetaminophen hepatotoxicity. We now have greater insight into the liver's tolerance of acetaminophen toxicity and dendritic cell regulation of these toxins." In the study, researchers used acetaminophen-induced hepatic injured mice models to closely examine the protective role of dendritic cells. Dendritic cells are the main antigens in the liver that trigger an immune response and control the liver's tolerance to high doses of invading toxins like acetaminophen. In the experiment all mice were injected with acetaminophen but some mice models were first depleted of dendritic liver cells using a diphtheria toxin while others had their dendritic cell levels bolstered with Flt3L, a protein in the blood previously shown to increase proliferation of dendritic cell levels. Researchers discovered dendritic cell depletion exacerbates acetaminophen's damage to the liver. The acetaminophen treated mice with depleted dendritic cells had more extensive liver cell and tissue death compared to other mice. Also, these mice died within 48 hours of acetaminophen challenge- whereas death was rare in other mice without dendritic cell depletion. In addition, the study shows dendritic cell expansion successfully diminished the hepatotoxic effects of acetaminophen protecting the liver from damage. "Understanding the regulatory role of dendritic cells is an important step in the development of immune-therapy for acetaminophen induced liver injury," said Dr. Miller, a member of the NYU Cancer Institute. "Advanced studies are warranted to investigate further the protective role of dendritic cells in humans and their use as a possible new therapeutic target for liver failure prevention in the future."

NIH research model predicts weight with varying diet, exercise changes

Thu, 25 Aug 2011 18:50:53 PDT

Researchers at the National Institutes of Health have created a mathematical model – and an accompanying online weight simulation tool – of what happens when people of varying weights, diets and exercise habits try to change their weight. The findings challenge the commonly held belief that eating 3,500 fewer calories – or burning them off exercising – will always result in a pound of weight loss. Instead, the researchers' computer simulations indicate that this assumption overestimates weight loss because it fails to account for how metabolism changes. The computer simulations show how these metabolic changes can significantly differ among people. Findings will be published Aug. 26 in a Lancet issue devoted to obesity. However, the computer simulation of metabolism is meant as a research tool and not as a weight-loss guide for the public. The computer program can run simulations for changes in calories or exercise that would never be recommended for healthy weight loss. The researchers hope to use the knowledge gained from developing the model and from clinical trials in people to refine the tool for everyone. "This research helps us understand why one person may lose weight faster or slower than another, even when they eat the same diet and do the same exercise," said Kevin Hall, Ph.D., an obesity researcher and physicist at the NIH's National Institute of Diabetes and Digestive and Kidney Diseases and the paper's first author. "Our computer simulations can then be used to help design personalized weight management programs to address individual needs and goals." The online simulation tool based on the model enables researchers to accurately predict how body weight will change and how long it will likely take to reach weight goals based on a starting weight and estimated physical activity. The tool, at http://bwsimulator.niddk.nih.gov/, simulates how factors such as diet and exercise can alter metabolism over time and thereby lead to changes of weight and body fat. To test the model, the researchers compared predicted weight changes to actual changes in people. "Mathematical modeling lets us make and test predictions about changes in weight and metabolism over time," Hall said. "We're developing research tools to accurately simulate physiological differences between people based on gender, age, height, and weight, as well as body fat and resting metabolic rate." For example, the team found that people's bodies adapt slowly to changes in dietary intake. They also found heavier people can expect greater weight change with the same change in diet, though reaching a stable body weight will take them longer than people with less fat. The model also points to a potential simplified method to approximate weight loss in an average overweight person. An adult who has a body mass index (a measure of a person's weight in relation to his or her height) between 25 and 29.9 is considered overweight. One example: For every pound you want to lose, permanently cut 10 calories from your current intake per day. At that rate, it will take about one year to achieve half of the total weight loss, and almost all of the weight loss will have occurred by three years. This calculation shows how long it takes to achieve a weight-loss goal for a single permanent change of diet or exercise. Researchers can use the web simulation tool to plan for a phase of more-rapid weight loss followed by a weight maintenance phase. People should consult with their physician prior to embarking on a diet plan. "By using our model to track progress, clinicians can help people re-evaluate their goals and ability to achieve them at the pace they want," Hall said. "It's a good reality check for how long weight-loss takes, and what changes in eating and exercise are required to achieve and maintain goal weight." Moving toward that goal, a more comprehensive mathematical model of human metabolism was used recently to design an NIH clinical trial that is comparing the effects of reducing fats versus carbohydrates in obese adults. Hall and collaborators also published findings in the May 11 issue of the American Journal of Clinical Nutrition illustrating a method for precisely measuring how much a person's eating changed when he or she went on a diet. "This research illustrates how the interdisciplinary skills of NIH scientists, like a physicist doing obesity research, can help lead to innovative ways to test, understand and treat a major public health epidemic," said NIDDK Director Griffin P. Rodgers, M.D. "Advancing research from the laboratory to the bedside enables us to make the discoveries that can better people's lives."

Three-part handoff delivers proteins to membrane surface

Wed, 24 Aug 2011 19:22:06 PDT

The delivery system for an important class of proteins in the cell membrane can be fully replicated with a mere three components, according to a new study. Tail-anchored proteins, the molecular machines that make up approximately five percent of the membrane proteins in a cell, are known to have their own special pathway for trafficking to the membrane after construction. New research from the University of Chicago and the National Institutes of Health blending structural and functional experiments finds that these proteins can be delivered to the membrane via a simple three-part system. This deeper understanding of the tail-anchored protein pathway could have significance for the development of new drugs and bioengineering methods. Researchers studying how other types of proteins are delivered to the membrane may also benefit from comparison with this specialized pathway as it is further manipulated and dissected. "What we are really excited about is the prospect of having a completely defined, completely synthetic controlled system," said Robert Keenan, PhD, Assistant Professor of Biochemistry and Molecular Biology at the University of Chicago. "Now we can really start asking detailed mechanistic questions." A team of six scientists from the University of Chicago and the National Institute of Child Health and Human Development, led by Keenan and Ramanujan Hegde, MD, Ph.D., published the findings on Wednesday in the journal Nature. Proteins are put together by ribosomes, which read DNA instructions and link amino acids together into their final form. But many proteins must be delivered from the ribosome to the endoplasmic reticulum (ER), where they are packaged and sent to their final destination. The majority of membrane proteins navigate this route by using the "co-translational pathway," where the ribosome builds the protein directly into the ER membrane. But tail-anchored (TA) proteins, so named because only a single, small stretch at the "tail" end of the protein sits in the membrane, are known to use a different delivery system. "TA proteins play all sort of important roles in a variety of different cellular functions," Keenan said. "If you screw this pathway up, bad things will happen. At that level they are just fundamentally important." The first component from this new system was identified in 2007 by Hegde (now at the MRC Laboratory of Molecular biology in Cambridge, England). That protein, called Get3 in yeast, was subsequently discovered to interact with two proteins called Get1 and Get2. But researchers hadn't yet determined how these components worked, and whether these three alone could account for TA protein targeting. Leading the collaboration between Keenan and Hegde's laboratories, co-first authors Agnieszka Mateja of the University of Chicago and Malaiyalam Mariappan of the National Institute of Child Health and Human Development created a synthetic system containing only Get1, Get2, Get3, and a TA protein substrate. The substrate was successfully delivered to the endoplasmic reticulum membrane, confirming that the three-part system was sufficient for trafficking. The scientists then deleted or modified specific pieces of the Get proteins to see how these elements work together to move a tail-anchored protein to its proper position in the cell membrane. The new model of the pathway includes both Dr. Octopus-like hooks, a handoff between two closely partnered proteins, and an elegant system for recycling. 1. A complex of two Get3's bound to two molecules of ATP form a "groove" of the right size and chemical properties to capture a tail-anchored protein (the "substrate") in the cytosol. 2. Once the substrate is safely nestled in the groove, "hooks" on the end of Get2 grab the complex, and bring it to the membrane. The long, flexible arms of Get2 allow it to function in a way that Keenan jokingly says is "like Dr. Octopus." 3. Next, Get2 executes a football-style handoff to the adjacent Get1 protein. Binding to Get1 causes the two Get3s to partially "unzip," wedging open the groove and releasing the tail-anchored substrate for insertion into the membrane. 4. Finally, new ATP molecules bind to Get3 causing it to zip back up into the closed form. This releases it from Get1 so that it can initiate another round of protein delivery in the cytosol. "We have a minimal system, completely purified, that's only three components plus the substrate," Keenan said. "Now we can basically do whatever we want. We can make mutants or chemical modifications, and then we can reconstitute the system and ask, 'does it work?' And if it doesn't work, we can ask where in this process does it actually fail, and why." Some steps of the pathway remain incomplete, such as how the tail-anchor of the protein is finally inserted into the membrane after it is released by Get3. But with the purified system, researchers can begin exploring these questions, and comparing the TA protein pathway to the more complex co-translational pathway. As the delivery systems for proteins of all types are better understood, scientists can then use these systems to create better drugs and manipulate cells for bioengineering purposes. For example, some viruses are thought to exploit protein delivery pathways, and understanding the details of trafficking may suggest new ways of defending cells against infection. "The more we understand about different targeting pathways, the better our ability to successfully target proteins where we want," Keenan said. "Right now, there's no killer app, but you can imagine a lot of potential uses."

Princeton research: In the early life of an embryo, a monster lurks

Mon, 22 Aug 2011 18:24:18 PDT

Research based at Princeton University has revealed that newly fertilized cells only narrowly avoid degenerating into fatal chaos. At the same time, scientists have discovered that embryos have acquired a mechanism to contain this dangerous instability, a finding that could help biologists unravel other mysteries about the first hours of life........> Full story

Enzyme's structure reveals basis for head, sex organ deformities

Fri, 19 Aug 2011 18:16:24 PDT

Scientists this month reported the molecular structural basis for severe head deformities and ambiguous sex organs in babies born with Antley-Bixler syndrome accompanied by an enzyme deficiency. The team, composed of researchers from The University of Texas Health Science Center San Antonio, the Medical College of Wisconsin and Charles University in Prague, solved the atomic structure of this human enzyme with an impressive name — NADPH-cytochrome P450 reductase, abbreviated CYPOR. The group is the first to visualize and depict the structure of the human version of CYPOR. The scientists also reported the structure of two mutations of human CYPOR that result in congenital deformities. "Human syndromes are caused by the deficiency of this enzyme," said Bettie Sue Masters, Ph.D., D.Sc., M.D. (Hon.), professor of biochemistry and the Robert A. Welch Foundation Distinguished Professor in Chemistry at the UT Health Science Center. "The two mutations that we characterized are responsible for severe craniofacial and steroid-production defects in humans, the latter leading to sexual ambiguities." In the body, steroids are produced for many important functions. In CYPOR deficiency, these steroidal malfunctions are related to deformed sexual organs and other defects. The structural basis for human CYPOR deficiency is described in the Aug. 4 edition of Proceedings of the National Academy of Sciences. In previously published research from Dr. Masters' laboratory, addition of a riboflavin (vitamin B2) derivative reversed the defects in the mutated enzymes; this is because the vitamin makes this particular enzyme work, producing metabolites. Metabolites are the products of enzyme-generated reactions. This reversal of CYPOR defects by a riboflavin derivative is yet to be investigated in animals or humans. Foods such as liver, herbs, almonds, wheat bran, fish and cheese are rich in riboflavin. Knowing the molecular structure of CYPOR has proved that riboflavin therapy is worth attempting, Dr. Masters said. As demonstrated by this structure, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy within the womb, if predicted before birth, or rescued after birth in less severe cases, the authors wrote in the Aug. 4 publication.

Revealed: How sticky egg captures sperm

Thu, 18 Aug 2011 16:29:36 PDT

Researchers have uncovered exactly how a human egg captures an incoming sperm to begin the fertilisation process, in a new study published this week in the journal Science. The research identifies the sugar molecule that makes the outer coat of the egg 'sticky', which is vital for enabling the sperm and egg to bind together. Researchers across the world have been trying to understand what performs this task for over thirty years. The scientists behind this study believe their work could help address some of the previously unexplained causes of human infertility and sub-fertility and be very useful for diagnosing this problem in couples who are unable to have children. It could also provide a new target for the development of natural contraceptive agents. The international team, from the University of Missouri, the University of Hong Kong, Academia Sinica in Taiwan and Imperial College London, discovered that the sugar chain known as the sialyl-lewis-x sequence (SLeX) is highly abundant on the surface of the human egg. After experimenting with a range of synthesised sugars in the laboratory they went on to show that SLeX specifically binds sperm to an egg, and tested their findings using the outer coats of unfertilised 'non-living' human eggs. "This exciting research is providing the first insights into the molecular events occurring at the very beginning of human life. The details we've discovered here fill in a huge gap in our knowledge of fertility and we hope they will ultimately help many of those people who currently cannot conceive," said Professor Anne Dell CBE FRS FMedSci from the Department of Life Sciences at Imperial College London, who led the team that discovered the SLeX sugars on the egg surface. "Unravelling the composition of the sugar coat that shrouds the human egg is the culmination of many years of painstaking research by my mass spectrometry colleagues at Imperial. This endeavour was an enormously difficult task because human eggs are very tiny - about the size of a full stop - so we didn't have much material to work with." The World Health Organization estimates that infertility affects up to 15 percent of reproductive-aged couples worldwide and almost one in every seven couples in the UK have problems conceiving a child for various clinical reasons, many of which are still unexplained by medical science. Lead author, Dr Poh-Choo Pang, also from the Department of Life Sciences at Imperial College London, said: "We hope that our study will open up new possibilities for understanding and addressing the fertility problems that many couples face. Although clinical treatments are still a way off, we are very excited about the new research into fertility that we hope will now be possible, building on our work." "We first proposed a model of human sperm-binding involving SLeX-like molecules on the outer covering of the human egg in 1992. Our recent studies have now confirmed that this longstanding model is correct," said corresponding author and associate professor Gary Clark, from the University of Missouri School of Medicine. "Defining how the sperm initially recognises and then penetrates the egg's sugar coat is important for the design of natural contraceptive agents and for unravelling causes of previously unexplained human infertility or sub-fertility." A sperm 'recognises' an egg when proteins on the head of the sperm meet and match a series of specific sugars in the egg's outer coat. Once a successful match has been made, the outside surfaces of the sperm and egg bind together before they merge and the sperm delivers its DNA to the inside, fertilising the egg. The authors of this new study used ultra-sensitive mass-spectrometric imaging technology to assess which molecules were most likely to be key in the binding process. They discovered that SLeX is abundantly found on the egg's outer coat and that it is expressed at a much higher concentration than any of the other sugars that can be found on the thick transparent shell. From these results, they deduced that SLeX was most likely to be responsible for binding with proteins on the head of the sperm. The research team in Hong Kong tested whether SLeX was the key binding sugar using the outer coats of unfertilised and non-living human eggs, obtained by informed consent from in vitro-fertilisation patients. They carefully bisected the empty coat in a delicate procedure using a tiny knife, carried out under a powerful microscope. The scientists treated one half with a chemical that prevented the SLeX sugar from binding, to see what effect this would have on a sperm's ability to bind to the egg. When they released sperm around the bisected egg, they found that significantly fewer bound to the treated half of the egg coat than the untreated half. "Our knowledge on sperm-egg binding in humans is limited. The identification of SLeX would enable researchers to uncover other molecules involved in this important process of human life," said Professor William Yeung from the Department of Obstetrics and Gyneacology and the Centre for Reproduction, Development and Growth at the University of Hong Kong, who led this phase of the research. The researchers are now keen to use the findings of this study to further investigate the proteins on the head of a sperm that enable it to recognise an egg.

Everyday clairvoyance: How your brain makes near-future predictions

Wed, 17 Aug 2011 17:40:06 PDT

Every day we make thousands of tiny predictions — when the bus will arrive, who is knocking on the door, whether the dropped glass will break. Now, in one of the first studies of its kind, researchers at Washington University in St. Louis are beginning to unravel the process by which the brain makes these everyday prognostications. While this might sound like a boon to day traders, coaches and gypsy fortune tellers, people with early stages of neurological diseases such as schizophrenia, Alzheimer's and Parkinson's diseases could someday benefit from this research. In these maladies, sufferers have difficulty segmenting events in their environment from the normal stream of consciousness that constantly surrounds them. The researchers focused on the mid-brain dopamine system (MDS), an evolutionarily ancient system that provides signals to the rest of the brain when unexpected events occur. Using functional MRI (fMRI), they found that this system encodes prediction error when viewers are forced to choose what will happen next in a video of an everyday event. Predicting the near future is vital in guiding behavior and is a key component of theories of perception, language processing and learning, says Jeffrey M. Zacks, PhD, WUSTL associate professor of psychology in Arts & Sciences and lead author of a paper on the study in a forthcoming issue of the Journal of Cognitive Neuroscience. "It's valuable to be able to run away when the lion lunges at you, but it's super-valuable to be able to hop out of the way before the lion jumps," Zacks says. "It's a big adaptive advantage to look just a little bit over the horizon." Zacks and his colleagues are building a theory of how predictive perception works. At the core of the theory is the belief that a good part of predicting the future is the maintenance of a mental model of what is happening now. Now and then, this model needs updating, especially when the environment changes unpredictably. "When we watch everyday activity unfold around us, we make predictions about what will happen a few seconds out," Zacks says. "Most of the time, our predictions are right. "Successfull predictions are associated with the subjective experience of a smooth stream of consciousness. But a few times a minute, our predictions come out wrong and then we perceive a break in the stream of consciousness, accompanied by an uptick in activity of primitive parts of the brain involved with the MDS that regulate attention and adaptation to unpredicted changes." Zacks tested healthy young volunteers who were shown movies of everyday events such as washing a car, building a LEGO model or washing clothes. The movie would be watched for a while, and then it was stopped. Participants then were asked to predict what would happen five seconds later when the movie was re-started by selecting a picture that showed what would happen, and avoiding similar pictures that did not correspond to what would happen. Half of the time, the movie was stopped just before an event boundary, when a new event was just about to start. The other half of the time, the movie was stopped in the middle of an event. The researchers found that participants were more than 90 percent correct in predicting activity within the event, but less than 80 percent correct in predicting across the event boundary. They were also less confident in their predictions. "This is the point where they are trying hardest to predict the future," Zacks says. "It's harder across the event boundary, and they know that they are having trouble. When the film is stopped, the participants are heading into the time when prediction error is starting to surge. That is, they are noting that a possible error is starting to happen. And that shakes their confidence. They're thinking, 'Do I really know what's going to happen next?' " Zacks and his group were keenly interested in what the participants' brains were doing as they tried to predict into a new event. In the functional MRI experiment, Zacks and his colleagues saw significant activity in several midbrain regions, among them the substantia nigra — "ground zero for the dopamine signaling system" — and in a set of nuclei called the striatum. The substantia nigra, Zacks says, is the part of the brain hit hardest by Parkinson's disease, and is important for controlling movement and making adaptive decisions. Brain activity in this experiment was revealed by fMRI at two critical points: when subjects tried to make their choice, and immediately after feedback on the correctness or incorrectness of their answers. Mid-brain responses "really light up at hard times, like crossing the event boundary and when the subjects were told that they had made the wrong choice," Zacks says. Zacks says the experiments provide a "crisp test" of his laboratory's prediction theory. They also offer hope of targeting these prediction-based updating mechanisms to better diagnose early stage neurological diseases and provide tools to help patients.

MIT: Oxygen's watery past

Tue, 16 Aug 2011 18:27:05 PDT

Today, oxygen takes up a hefty portion of Earth's atmosphere: Life-sustaining O₂ molecules make up 21 percent of the air we breathe. However, very early in Earth's history, O₂ was a rare — if not completely absent — player in the turbulent mix of primordial gases. It wasn't until the "Great Oxidation Event" (GOE), nearly 2.3 billion years ago, when oxygen made any measurable dent in the atmosphere, stimulating the evolution of air-breathing organisms and, ultimately, complex life as we know it today.......> Full story

Dual-action protein developed at Stanford better restricts blood vessel formation

Thu, 11 Aug 2011 17:45:01 PDT

Cancer needs blood. In fact, some cancer medications work solely to slow or prevent cancer cells from creating new capillaries, choking off their much-needed blood and nutrient supply to halt the growth of tumors. In a paper published online Aug. 8 in the Proceedings of the National Academy of Sciences, researchers at Stanford University describe the creation of a new type of engineered protein that is significantly more effective at preventing the formation of blood vessels by targeting not one, but two of the chemical receptors that control the creation of new capillaries - a process known as angiogenesis. The study shows that the new protein blocks both receptors.......> Full story

Scared of the wrong things: Lack of major enzyme causes poor threat-assessment in mice

Wed, 10 Aug 2011 17:58:05 PDT

Do you run when you should stay? Are you afraid of all the wrong things? An enzyme deficiency might be to blame, reveals new research in mice by scientists at the University of Southern California. In a paper appearing in the October 2011 issue of the International Journal of Neuropharmacology, USC researchers show that mice lacking a certain enzyme due to genetic mutation are unable to properly assess threat. The mice exhibited defensive behaviors (such as biting or tail rattling) in the presence of neutral stimuli, such as plastic bottles. Conversely, in the presence of true danger cues such as predator urine or an anesthetized rat, the mice with the enzyme mutation were less cautious and defensive than their littermates, even climbing on the unconscious rat. Mice without the enzyme also took longer to leave an open chamber, indicating reduction in exploratory and escape tendencies. "Taken together, our findings suggest that monoamine oxidase A deficiency leads to a general inability to appropriately assess contextual risk, as indicated by the inappropriateness of their defensive behaviors," said senior author Jean C. Shih, University Professor and Boyd and Elsie Welin Professor of pharmacology and pharmaceutical sciences in the USC School of Pharmacy. Monoamine oxidase A is the main enzyme in the brain that breaks down serotonin, norepinephrine and dopamine, which have been shown to contribute to the "fight or flight" impulse by raising heart rates and increasing blood and oxygen flow. Previous research in Shih's lab and elsewhere has shown that deficiency in monoamine oxidase A causes aggression in mice and humans, but this study is among the first to clarify that what was perceived as aggressiveness may more accurately be described as an inability to properly adapt and respond to environmental cues. "Mice without monoamine oxidase A exhibited a distinct inability to attune their response to the situation," said Sean Godar, a post-doctoral research associate at the USC School of Pharmacy and co-lead author of the study. "The paradoxical responses to neutral and fear-inducing stimuli are markedly reminiscent of deficits in facial affect processing in schizophrenia and autism." The researchers found no significant differences in sensory ability between the mice with a monoamine oxidase A deficiency and their littermates — both groups found buried mini-chocolate cereal chips at about the same rate, on average, and were similarly able to traverse a ledge and recognize objects. "When compared to the broader, multi-faceted behavioral repertoire of other mice, the behavior observed in mice without monoamine oxidase A may reflect a limited range of emotional responses and flexibility," said Marco Bortolato, co-lead author of the study and research assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy. The researchers suggest that the strange defensive behavior exhibited by the enzyme-deficient mice may actually reflect a limited range of adaptive responses and lack of emotional flexibility — the mice may only have one gear for fear.

Molecular mechanisms offer hope for new pain treatments

Fri, 05 Aug 2011 19:25:21 PDT

By working with individuals suffering from a severe disorder that causes sensory neurons to degenerate, researchers at the University of Montreal Hospital and CHU Sainte-Justine Hospital have discovered how a specific genetic mutation causes their patients' condition, which in turn has revealed more information about the mechanisms in our bodies which enable us to sense pain. Genetic mutations are mistakes in our genetic code that can either be passed from parents to their children or created when DNA is replicated. Lead author Dr. Jean-Baptiste Rivière published the team's results in the American Journal of Human Genetics today. The currently untreatable disorder is called "hereditary sensory and autonomic neuropathy type II." It starts during early childhood and is characterized by a loss of perception of pain, touch and heat. Because affected individuals are unable to react to pain and protect themselves, they often develop ulcers that can become infected, leading to amputation of the affected body part. By working with their international colleagues under the direction of the University of Montreal's Dr. Guy Rouleau, the research team was able to pinpoint how the disorder is related to the patients' genetic code. "After showing that the WNK1/HSN2 protein interacts with the KIF1A gene, we were able to go back to the cohort of patients and identify mutations of the KIF1A gene," Rivière said. "The study results will be of immediate benefit to HSAN2 patients, as the identification of this new gene has made it possible to provide valuable genetic testing to assess the risk or the cause of the disease in individuals at risk or presenting the disease." While the genetic mutation affects very few people, the knowledge that the researchers have gained is applicable to everyone. Scientists know the different parts of our genetic code, but they don't know how every single specific gene contributes to the functioning of our bodies. When a gene does not function properly due to a mutation, the resulting disorder can provide insight into its normal role. These findings provide clues about the components underlying the transmission of pain signal from sites of injury to the central nervous system Researchers may be able to use their new knowledge about the KIF1A gene to develop new pain relief drugs. "Our results not only open the door to a better understanding of this disorder," Rouleau explained, "they also give us valuable information about the molecular mechanisms involved in pain perception, which is important for the development of new anti-pain drugs." A future drug might work by modulating interactions between different proteins associated with pain and KIF1A. "Further research could help us to identify other proteins that are transported by KIF1A or that interact with it, and that will help to better refine our understanding of pain mechanisms," noted Dr. Patrick Dion, who also contributed to the research.

Convergence in head and neck cancer

Fri, 29 Jul 2011 18:22:05 PDT

Powerful new technologies that zoom in on the connections between human genes and diseases have illuminated the landscape of cancer, singling out changes in tumor DNA that drive the development of certain types of malignancies such as melanoma or ovarian cancer. Now several major biomedical centers have collaborated to shine a light on head and neck squamous cell cancer. Their large-scale analysis has revealed a surprising new set of mutations involved in this understudied disease. In back-to-back papers published online July 28 in Science, researchers from the Broad Institute, Dana-Farber Cancer Institute, Johns Hopkins Kimmel Cancer Center, the University of Pittsburgh, and the University of Texas MD Anderson Cancer Center have confirmed genetic abnormalities previously suspected in head and neck cancer, including defects in the tumor suppressor gene known as p53. But the two teams also found mutations in the NOTCH family of genes, suggesting their role as regulators of an important stage in cell development may be impaired. "This adds a new dimension to head and neck cancer biology that was not on anyone's radar screen before," said Levi A. Garraway, a senior associate member of the Broad Institute, an assistant professor at Dana-Farber Cancer Institute and Harvard Medical School, and a senior author of one of the Science papers. "Head and neck cancer is complex and there are many mutations, but we can infer there is a convergence on a cellular process for which we previously did not have genetic evidence. It shows that if you do a genome sequencing project of this size you can gain major new biological insights." "The mutational analysis of NOTCH clearly indicated the power of genetic changes determining the function of these genes," said Kenneth W. Kinzler, professor of oncology and a molecular geneticist at Johns Hopkins, co-director of the Ludwig Center at Johns Hopkins, and an author of one of the Science papers. "It gives us an important clue to start studying their function." Head and neck cancer is the sixth most common non-skin cancer in the world, with more than half a million new cases each year. Smokers, drinkers, and people infected with the human papillomavirus (HPV) have the highest risk of developing head and neck cancer, which is the collective name for tumors found in the oral cavity, including the mouth, larynx, and pharynx. Patients often seek medical care only once they are in the later stages of the disease, when they may be offered surgery, radiation, chemotherapy, or a combination. Treatments can be disfiguring and debilitating, leaving patients unable to speak or swallow. The five-year survival rate of 50 percent has improved little over the past 40 years. Jennifer R. Grandis, a professor of otolaryngology and pharmacology and chemical biology at the University of Pittsburgh School of Medicine and a senior author of one of the Science papers, bemoaned the dearth of genetic information about head and neck cancer several years ago at a conference where Garraway had given a talk about the genomic landscape of melanoma. "There was a really big gap in knowledge that was an obstacle to doing the right kind of research" about head and neck cancer, she said. "If we didn't know the spectrum of the mutations that were in our patients' tumors, we couldn't begin to develop more appropriate therapies because we were sort of playing in the dark." Grandis and Garraway decided to study a University of Pittsburgh collection of 74 pairs of tumor and normal tissue samples using the Broad's capacity to perform whole-exome sequencing. The exome represents the tiny fraction of the genome that encodes proteins. Focusing on just these protein-producing genes allows scientists to zero in on mutations that alter key proteins involved in cancer growth. Another collaboration was unfolding among the cancer geneticists, sequencing experts, clinical researchers, and surgical oncologists at Johns Hopkins, MD Anderson, and Baylor College of Medicine to study 32 pairs of head and neck tumor and normal tissue samples by whole-exome sequencing and validate the findings in an additional 88 samples. Both teams found mutations in the p53 gene in a little more than half of the tumors they studied. The next most common mutation occurred in NOTCH1, which showed up in about 15 percent of tumors. Normally, NOTCH1 controls how cells differentiate into other kinds of cells, mature, stop dividing, and ultimately die. In head and neck cancer, the scientists saw mutations that turn NOTCH1 off, blocking differentiation and trapping cells in a proliferative, pro-cancer state. Their maturation is arrested, leaving them stuck in an earlier stage, where other damage from smoking or alcohol or even p53 mutations can destabilize the genome. NOTCH1's inactivation in head and neck cancer was surprising because in other cancers, such as leukemia, too much NOTCH signaling leads to cancer. "Our study suggests that a gene's role can depend on the tumor type. In some cases, a gene can act as a growth promoter in cancer, and in other cases, such as head and neck cancer, the same gene behaves as a growth suppressor," said Kinzler. Efforts to combat the mutated p53 tumor suppressor gene with targeted drugs, for example, have so far been unsuccessful. The next step based on these novel head and neck cancer discoveries, the scientists agree, is to tease out how the genes function in normal cells, whether they form the lining of the larynx, pharynx, or another anatomical site affected by head and neck cancer. "Both of our studies reveal few clues to the significance of NOTCH mutations. Further studies will be necessary to define its role in prognosis, diagnosis, and/or treatment," said Nishant Agrawal, a head and neck surgical oncologist at Johns Hopkins and a lead author of one of the Science papers. "The idea is to use these genetic alterations to predict a patient's prognosis and define personalized treatment strategies tailored to their cancer's genome." Both teams confirmed the role of HPV infection in head and neck cancer, particularly oropharyngeal cancer. Thought to be transmitted by oral sex, the infection has become more prominent. The studies reveal that HPV-positive tumors carried fewer mutations than HPV-negative tumors. Patients with HPV-positive head and neck cancers tend to fare better than patients whose cancers are not caused by the virus. Translating these discoveries into therapies for patients will take more studies and more time, the scientists all said, but the revelations set a course for the future. Jeffrey N. Myers, professor of head and neck surgery at M. D. Anderson, said both groups' work highlights the complexity of the disease and its multiple gene abnormalities. "It has told us new things that will give us both clinical and scientific opportunities to study in the near and long term," Myers said. "I think that we're also in a position to design very specific clinical studies to further understand the significance of these mutations, as well as to begin to think about potentially targeting some of the abnormalities." Those studies could include looking at patients with different mutations in addition to p53 and the NOTCH family to see how well they fare. "The race will be on to figure out the function and particularly the therapeutically relevant function of these mutations," Grandis said. Agrawal said the collaborative effort is necessary. "I think it's great we are advancing head and neck cancer research this way," he said. "Unfortunately, the cancer has been beating us. Now it's time for us to take a permanent lead."

Gene gives clues to self-injurious behavior in rare disorder

Wed, 27 Jul 2011 17:47:55 PDT

In humans, inherited mutations in a gene called HPRT1 lead to very specific self-destructive behavior. Boys with Lesch-Nyhan disease experience uncontrollable urges to bite their fingers, slam their arms into doorways and otherwise harm themselves. Puzzlingly, mice with mutations in the same gene don't behave differently than normal mice. Researchers at Emory University School of Medicine have identified a gene related to HPRT1, present in humans but not in mice that helps explain this discrepancy. The results were published this week by the journal PLoS One. Mice missing HPRT1 and engineered with a copy of the related human gene, called PRTFDC1, are more aggressive and, under the influence of amphetamines, display repetitive behavior resembling nail biting. "Other strains of mice don't do this, even under the influence of amphetamines," says first author Alaine Keebaugh, an Emory postdoctoral fellow. "It's not exactly the same as the finger-biting seen in Lesch-Nyhan patients, but they're close enough that we think it provides some insight into the biology. It suggests that PRTFDC1 could be a target for treating the disease." Keebaugh began researching HPRT1 and PRTFDC1 while a graduate student in the laboratory of James Thomas, PhD, former assistant professor of human genetics at Emory University School of Medicine. The co-first author is Emory postdoctoral fellow Heather Mitchell. HPRT1 was the first gene to be "knocked out" when scientists were first developing the technique in the 1980s, an accomplishment that earned Mario Capecchi and Oliver Smithies the Nobel Prize in Medicine. "HPRT1 has a special place in the history of genetics because of this," Keebaugh says. "It also shows that knockout mice don't always exactly parallel human disease." The HPRT1 gene is located on the X chromosome. Males are vulnerable to Lesch-Nyhan disease (and other X-linked disorders) because they have only one X chromosome. HPRT1 encodes an enzyme that recycles purines, which are building blocks of DNA. The PRTFDC1 gene looks like HPRT1, and apparently comes from a duplication of an ancestor gene millions of years ago. All mammals Keebaugh examined except mice have working copies of PRTFDC1. It's not clear whether the protein encoded by PRTFDC1 also recycles purines, she says. "In mice, the presence of PRTFDC1 seems to enhance the effects of not having HPRT1," she says. "This suggests the two proteins are not just doing the same things. One may be regulating the other, which is something we want to investigate further." In humans, the absence of HPRT1 leads to overabundant purines, which appears to perturb development of certain parts of the brain. In addition, the building blocks are broken down into uric acid, which accumulates in the body and can cause painful swelling of the joints. These gout-like symptoms can be treated with medication, but the striking behavior and other neurological problems don't go away. Lesch-Nyhan patients tend to have delayed development and stiff movements and are sometimes unable to walk. They have a deficiency of the chemical messenger dopamine in the basal ganglia, the same part of the brain affected by Parkinson's disease. Mice without HPRT1 do have reduced dopamine in the basal ganglia and are more sensitive to amphetamines, which work by enhancing dopamine's effects in the brain. This link with dopamine is what led Keebaugh to test the effects of amphetamines on the mice. Mice missing HPRT1 and with added PRTFDC1 displayed a unique behavior: they had a "distinctive hunched posture," bobbing their heads and appearing to bite their nails. However, they did not actually damage their paws. Keebaugh says she is continuing to study the function of PRTFDC1 with the aim of understanding how Lesch-Nyhan disease develops and identifying potential treatments.

NIH researchers identify gene variant in Proteus syndrome

Wed, 27 Jul 2011 17:45:59 PDT

A team of researchers has identified the genetic mutation that causes Proteus syndrome, a rare disorder in which tissue and bone grows massively out of proportion. The discovery, which has implications for potential drug therapies and even cancer, appears in the July 27, 2011, early online edition of the New England Journal of Medicine. The team was led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Proteus syndrome gained wide public attention in 1980, through the movie ``The Elephant Man,'' about a 19th century Londoner whom experts believe may have suffered from the disease. Researchers found that a point mutation — a single-letter misspelling in the DNA of the genetic code — in the AKT1 gene activates the sporadic tissue growth characteristic of Proteus syndrome. Physicians named the condition for the Greek god who could transform his shape. There are fewer than 500 people with the disease in the developed world, where it can be tracked. Unlike inherited disease-causing mutations, the gene variant that triggers Proteus occurs spontaneously in each affected individual during embryonic development. The severity of the disease depends on the timing during embryonic development that the genetic mistake occurs in a single cell and in which part of the developing organism. Only the cells that descend from the cell with the original AKT1 gene mutation display the hallmarks of the disease, leaving the individual with a mixture of normal and mutated cells. The affected newborn appears normal, but symptoms arise in the child's first two years. The mutation in AKT1 alters the ability of affected cells to regulate their own growth, leading some parts of the patient's body to grow to abnormal and even enormous sizes, while other parts of the body remain normal. The irregular overgrowth worsens with age and increases the susceptibility to tumors. "This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome," said NHGRI Director Eric D. Green, M.D., Ph.D. "This rare disorder has been the focus of curiosity and medical observation for decades but until now has never been biologically explained. With the analysis reported here, patients and families who face this condition have hope for future therapies." As follow up to the current study, NHGRI researchers plan to test DNA from the skeleton of Joseph Merrick to determine whether Proteus syndrome caused his dramatic disfigurement. Merrick gained celebrity — and for a time earned his livelihood in England and Europe — by being displayed in human novelty exhibitions as the Elephant Man. He died in 1890 at the age of 27 in London Hospital, now the Royal London Hospital, where he resided at the end of his life. The hospital preserved his skeleton in its pathology collection, providing modern researchers a chance to test his century-old DNA. Merrick's life has been portrayed on stage, and in a 1980 Hollywood movie titled ``The Elephant Man.'' Diagnosing Merrick will be no simple study. Because of the way the mutation occurs during embryonic development, the NHGRI-led team found that the gene variant of Proteus syndrome occurs in only a subset of the body's cells rather than in every cell, a condition called a genetic mosaicism. There are only a small number of known mosaic disorders in which an individual's cells have a different genetic composition from one another. Essentially, the person develops more than one genome. Since only a subset of the body's cells harbor the mutation, it is possible that during a medical biopsy, in which bits of tissue are cut out for analysis, the diagnosis may be missed because only normal cells are sampled. "Diagnosis in our patients has been really difficult," said senior author Leslie Biesecker, M.D., chief of NHGRI's Genetic Diseases Research Branch. "This molecular discovery gives us a basis for objective molecular diagnosis for patients with perplexing forms of overgrowth." Until now, clinical diagnosis has been based on observation of patient features. Besides overgrowth of limbs, the condition is characterized by a variety of skin lesions and thickening of the soles of the feet. Some patients have neurological complications, such as mental retardation, seizures and vision loss. To find the single-letter misspelling among the 3 billion letters that make up the human genome, the researchers performed whole-exome sequencing on the DNA of seven patients with Proteus syndrome. Whole-exome sequencing determines the sequence of letters that make up the 1 to 2 percent of the genome that contains protein-coding genes. The research team then analyzed more than 20 additional affected individuals, finding the same gene variant in DNA in more than 90 percent of these individuals. The team suspects that the three individuals so far negative for the mutation may actually have the mutation at low levels or in different tissues than those sampled in the initial biopsy. By contrast, the variant is never found in unaffected people, including a random study population of more than 400 individuals and in thousands of DNA sequences maintained in public genome research databases. The mutated gene, AKT1, is an oncogene, meaning that it can promote the kind of uncontrolled cell growth associated with cancer. The variant of AKT1 that causes Proteus syndrome is part of a cascade of mutations that also promotes metastasis, the process by which cancer cells spread to healthy parts of the body. AKT1 mutations have been detected in about two percent of cancer samples. In cancer, an AKT1 mutation develops as part of a chain of mutation events that occurs in a limited number of normal cells of a particular organ of the body. In Proteus syndrome, because the mutation occurs in embryonic development, many more tissues of the body are impacted by the gene variant, though not all have overgrowth. According to Dr. Biesecker, a person could not survive if the variant that causes Proteus syndrome occurred so early as to be in all cells of the body. Previous research demonstrated that the AKT1 mutation changes the cell growth-promoting activity of the AKT protein. NHGRI researchers found that cells from patients with Proteus syndrome had increased AKT activity at times when AKT would normally be inactive in unaffected individuals. The mutation acts like an accelerator of cell growth, but only in some tissues of the body. To study the mosaicism affect of Proteus syndrome, the researchers tested cells derived from affected tissue and unaffected tissue of individuals with the disease. They analyzed the level of activation of AKT, confirming that affected tissue had increased AKT protein activity. "We now have a better chance of making or finding a drug that can arrest this overgrowth and begin to use it early on in the disease progression," Dr. Biesecker said. "A factor in our favor is that it is much easier to find a drug that inhibits the activity of a protein, which is what we want to do with AKT in Proteus syndrome, than to activate a protein." In the cancer field, there are a number of potential therapeutics being developed to inhibit the pathway involving this gene, some of them by inhibiting AKT1 itself. "For Proteus syndrome, AKT1 will likely need to be targeted for optimal benefit to affected patients," Dr. Biesecker said. The researchers further demonstrated that tissue biopsies are required to genetically diagnose Proteus syndrome, since the variant that causes the AKT1 mutation is infrequently present in white blood cells typically sampled for genome analysis. "During the past 15 years, Proteus syndrome patients have come to the NIH Clinical Center, where we have operated to help stop bones from overgrowing," Dr. Biesecker said. "Our tissue bank has grown during this period because we have been able to obtained samples of affected tissue during surgeries that we would otherwise not have had for this study. If we just asked pediatricians to mail to us blood samples of children with Proteus syndrome we would not have found the mutation. The NIH Clinical Center was essential in providing support and expert colleagues to allow us to do this research."

Shuttle service in cells

Tue, 26 Jul 2011 17:49:28 PDT

Research scientists at the Ruhr University Bochum discovered a new enzyme, which gives decisive insights into protein import into specific cellular organelles (peroxisomes). In the Journal of Biological Chemistry, the team of Prof. Erdmann (Medical Faculty, Department of Systemic Biochemistry) reports that the enzyme Ubp15p collaborates with two other proteins to convert the protein transport machinery back into its initial condition after work has been completed. The enzyme detaches a specific signal sequence from a protein which is important for transportation and recycling of this protein. A new sequence of protein can then commence. "With Ubp15p we could unravel a further mystery concerning the transport of proteins into peroxisomes", explains Prof. Erdmann. "The comprehension of these organelles at a molecular level is a decisive prerequisite for the development of new diagnostic and therapeutic approaches for patients with peroxisomal disorders who only seldom survive the first year of their life." Shuttling to the peroxisome Peroxisomes are multifunctional "tools." They are involved, for example, in the catabolism of fatty acids, and detoxify poisonous hydrogen peroxide. A malfunction of these organelles, as is the case in Zellweger Syndrome disorders, can have disastrous influences on the functioning of the liver, kidneys and brain. To be able to function correctly, peroxisomes need specific proteins, but they cannot produce these themselves. Thus, a shuttle system consisting of several receptors has to import them from the cytosol. The receptors recognize the proteins specified for the peroxisomes within the cytosol and escort them to their destination. Here they bond with the membrane of the peroxisome and form part of the "gate" through which the proteins are transported into the interior. An export signal (ubiquitin) is attached to the receptors, which ensures that they are released from the peroxisome membrane and available for transport yet again. What subsequently happens to the ubiquitin signal remains to be clarified. New export components discovered In an earlier publication in Nature Cell Biology, Prof. Erdmann's team had already described two motor proteins that withdraw the ubiquitin-marked receptor Pex5p from the membrane and transport it back into the cytosol. In a further paper (Nature Reviews Molecular Cell Biology), they postulated that this export of the receptor is mechanistically linked to the import of the peroxisomal protein. To date, it has however not been possible to detect the ubiquitin together with Pex5p in the cytosol. "We thus assumed that the ubiquitin is removed from the receptor during or shortly after export", states Prof. Erdmann. His team, funded by the collaborative research center 642 of the German National Science Foundation (Sonderforschungsbereich 642 der Deutschen Forschungsgemeinschaft), has now established that the enzyme Ubp15p disconnects the export signal and collaborates with the two motor proteins to remove the receptor from the membrane of the peroxisome. Enzyme could be important for recycling The scientists managed to locate Ubp15p in living yeast cells and to prove that the enzyme comes into direct contact with one of the motor proteins to reach the peroxisomes. When Prof. Erdmann's team deactivated the Ubp15p in the cells, the amount of ubiquitinated Pex5p increased. This result confirms the role of Ubp15p in cleaving the ubiquitin signal. The enzyme seems to have an important function in the import of proteins into the peroxisomes, particularly under stress conditions. "Ubp15p appears to play a vital role in the recycling of the receptor", points out Prof. Erdmann.

Elusive gene discovered that makes platelets grey

Mon, 25 Jul 2011 17:44:02 PDT

Researchers have identified an elusive gene responsible for Grey Platelet Syndrome, an extremely rare blood disorder in which only about 50 known cases have been reported. As a result, it is hoped that future cases will be easier to diagnose with a DNA test.......> Full story

UCI-led butterfly study sheds light on convergent evolution

Thu, 21 Jul 2011 18:34:23 PDT

For 150 years scientists have been trying to explain convergent evolution. One of the best-known examples of this is how poisonous butterflies from different species evolve to mimic each other's color patterns – in effect joining forces to warn predators, "Don't eat us," while spreading the cost of this lesson. Now an international team of researchers led by Robert Reed, UC Irvine assistant professor of ecology & evolutionary biology, has solved part of the mystery by identifying a single gene called optix responsible for red wing color patterns in a wide variety of passion vine butterfly species. The result of 10 years of work, the finding is detailed in a paper that appears online today in the journal Science. "This is our first peek into how mimicry and convergent evolution happen at a genetic level," Reed said. "We discovered that the same gene controls the evolution of red color patterns across remotely related butterflies. "This is in line with emerging evidence from various animal species that evolution generally is governed by a relatively small number of genes. Out of the tens of thousands in a typical genome, it seems that only a handful tend to drive major evolutionary change over and over again." The scientists spent several years crossbreeding and raising the delicate butterflies in large netted enclosures in the tropics so they could map the genes controlling color pattern. UCI postdoctoral researcher Riccardo Papa (now an assistant professor at the University of Puerto Rico, Rio Piedras) then perfected a way to analyze the genome map by looking at gene expression in microdissected butterfly wings. Finding a strong correlation between red color patterns and gene expression in one small region of the genome was the breakthrough that led to discovery of the gene. Population genetics studies in hybrid zones, where different color types of the same species naturally interbreed, confirmed it. "Biologists have been asking themselves, 'Are there really so few genes that govern evolution?'" Reed said. "This is a beautiful example of how a single gene can control the evolution of complex patterns in nature. Now we want to understand why: What is it about this one gene in particular that makes it so good at driving rapid evolution?"

New anti-cancer agents show promise for treating aggressive breast cancers

Mon, 18 Jul 2011 17:40:16 PDT

Some of the most aggressive forms of breast cancer are more vulnerable to chemotherapy when it is combined with a new class of anti-cancer agent, researchers from the Walter and Eliza Hall Institute have shown. ABT-737 is one of a new class of anti-cancer agents called BH3 mimetics that target and neutralise the so-called Bcl-2 proteins in cancer cells. Bcl-2 proteins act to 'protect' the cells after they have been damaged by chemotherapy drugs, and prevent the cancer cells from dying. Professors Geoff Lindeman and Jane Visvader, who led the research with colleagues Dr Samantha Oakes and Dr François Vaillant from the institute's Stem Cells and Cancer division, said that the BH3 mimetics showed promise for treating breast cancers, including 'triple negative' cancers. Their research is published today in the Proceedings of the National Academy of Sciences USA. Triple negative breast cancers are so-called because they test negative for oestrogen, progesterone and HER2 receptors, and cannot be treated with hormone therapy or trastuzumab. They account for up to 20 per cent of all breast cancers and are typically aggressive with a poor prognosis. Dr Lindeman said that early results suggest navitoclax (an orally-available BH3 mimetic) could provide new hope for treating some breast cancers that are not candidates for other currently available treatments. "ABT-737 targets proteins from the Bcl-2 family, which are found at high levels in up to 70 per cent of breast cancers," Dr Lindeman said. "We have shown that breast tumours that have high levels of Bcl-2 respond well to treatment with ABT-737 when used in combination with a conventional chemotherapy drug." ABT-737 and navitoclax were discovered by Abbott scientists and are based on the discovery made at the Walter and Eliza Hall Institute in the 1980s that Bcl-2 is a 'pro-survival' protein responsible for preventing cell death in healthy and diseased cells. ABT-737 and navitoclax are not yet available for patient treatment, but navitoclax is currently in phase II clinical trials to establish its efficacy in treating some types of leukaemia and lymphoma. Navitoclax is being jointly developed by Abbott and Genentech, Inc. Dr Visvader said combined treatment with ABT-737 and docetaxel (a commonly used chemotherapy drug for treating breast cancer) in mice transplanted with human breast cancer cells improved tumour response and survival rates, when compared to docetaxel as a single agent. ABT-737 alone was not effective in treating cancers with high levels of Bcl-2, nor was it effective in treating cancers that did not express Bcl-2. "The research suggests that these agents make the cancer cells more vulnerable to chemotherapy," Dr Visvader said. "We are particularly excited that the research shows a good response in Bcl-2-expressing breast cancer, including basal-like breast cancer, which is often the most aggressive and hardest to treat." Dr Lindeman said the research could lead to the development of new treatment regimens that make resistant and difficult-to-treat breast cancers more vulnerable to conventional chemotherapy treatments. "We have had a good result in pre-clinical models of disease, but we are still a way off this being used in humans," Dr Lindeman, who is also an oncologist at The Royal Melbourne Hospital, said. "We hope that these results could see a clinical trial of navitoclax for treating breast cancer with high Bcl-2 levels within the next few years."

Stem cell study reveals complexity of glue molecule's role in cancer

Thu, 14 Jul 2011 19:12:52 PDT

A protein molecule that 'glues' cells together and so has a key role in cancer is also responsible for many other important functions of cells, a new study has found. University of Manchester scientists say their unexpected findings are important because they could lead to a better understanding of why some cancer cells are difficult to eradicate in patients and lead to new cancer treatments. The research – published in PLoS One today – looked at the role of the cell-adhesion molecule E-cadherin in embryonic stem (ES) cells. As well as the expected findings associated with changes in adhesion, the team found that the protein may also regulate up to 25% of the genes within cells. "E-cadherin is a 'glue' that keeps cells together in the body – without it we would not develop beyond a bundle of cells a few days after conception," said Dr Chris Ward, who led the study in the University's School of Dentistry. "E-cadherin is also important during cancer progression from benign to malignant states, with loss of this molecule leading to increased movement of the cells which can lead to secondary tumours within the body. "Whilst E-cadherin has been studied intensively there has been no research that has identified all of the genes that E-cadherin regulates. Our lab has carried out profiling of ES cells lacking E-cadherin and found this protein is responsible for regulating up to 25% of the genes within cells. "As well as the expected findings associated with changes in cell adhesion, we found that E-cadherin exerts an effect on a diverse range of biological functions within the cell. This unexpected result demonstrates that E-cadherin, often viewed as no more than a cell 'glue', is an important part of regulating the biology of ES cells." The group found that E-cadherin regulates genes associated with, amongst other things, cell proliferation, cell death, metabolism of fats and sugars and the deciphering of messages received by cells from outside. Since loss of E-cadherin is implicated in higher death rates in cancer patients and a more aggressive tumour type, the group has suggested that this molecule may have a much more important role to play in preventing tumour development. Dr Ward added: "Essentially, abnormal regulation of E-cadherin can lead to a significant change in a cell and this may be one of the reasons why such cells are difficult to eradicate in cancer patients. Further investigation of specific changes in these cells may lead to the development of novel treatments for cancer."