New Target for Cancer Therapy

The plasma membrane transporter SLC5A8 can inhibit the spread of tumours by decreasing the amount of the anti-apoptotic protein surviving in tumour cells.

Tumour cells need far more nutrients that normal cells and these nutrients cannot get into the malignant cells without transporters.

These are compounds that are responsible for the absorption of peptides, amino acids, sugars, vitamins and other nutrients. They exist in all cell types, particularly in those tissues responsible for the absorption of nutrients, such as the intestine and kidneys.

What if you could turn off a transporter that was important to tumour cells, but not to normal cells?

Dr Vadivel Ganapathy, of the Medical College of Georgia, suggests we can do that. He and his team report in a paper published in the Biochemical Journal on January 24 that the plasma membrane transporter SLC5A8 can inhibit the spread of tumours by decreasing the amount of the anti-apoptotic protein surviving in tumour cells. This induces apoptosis (cell death) and renders the tumour cells more sensitive to anti-cancer drugs. All this without affecting the activity of SLC5A8 in normal cells.

Tests in breast cancer cells in mice have proved promising. "Our studies unravel a novel, hitherto unrecognized, mechanism for the tumour-suppressive role of a plasma membrane transporter independent of its transport function," he says.

Journal Reference:

1. Veena Coothankandaswamy, Selvakumar Elangovan, Nagendra Singh, Puttur D. Prasad, Muthusamy Thangaraju, Vadivel Ganapathy. The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function. Biochemical Journal, 2013; 450 (1): 169 DOI: 10.1042/BJ20121248

Courtesy: ScienceDaily

Drinking Water Unexpectedly Rich in Microbial Life

Flow cytometry (FCM) can now be officially used for the quantification of microbial cells in drinking water. The new analytical method -- developed at Eawag and extensively tested both in Switzerland and abroad -- has been incorporated into the Swiss Food Compendium (SLMB) by the Federal Office of Public Health (FOPH). FCM provides much more realistic results than the conventional method, in which bacterial colonies are grown on agar plates. The results demonstrate that even good-quality drinking water harbours 100 to 10,000 times more living cells than the conventional plate count method would suggest.

For over 100 years, the method used to assess the microbiological safety of drinking water has remained essentially unchanged: bacteria present in water are allowed to grow on solid nutrient media (incubated at a warm temperature), and the colonies formed are then counted. The intestinal bacteria Escherichia coli and enterococci serve as indicators of fecal contamination. At the same time, the heterotrophic plate count (HPC) is determined as a measure of general microbiological quality. This method quantifies all the microorganisms present which can reproduce at temperatures of around 20-45°C (mesophilic). According to the global standard, the number of colonies formed should not exceed 300 per millilitre.

Cell counts significantly underestimated

The cultivation-based method has two major drawbacks: it is time-consuming -- results are only available after 3-10 days in the case of the HPC -- and only a fraction of the living cells actually present in samples are counted. This is because the method only detects those bacteria which can grow and form colonies under the specified conditions -- generally 0.01-1% of the total. Thus, the limit of 300 colony-forming units per millilitre (CFU/mL) also specified in the Swiss Ordinance on Food Hygiene (HyV) is based on a significant underestimate of the actual number of microorganisms present. The cultivation of E. coli and enterococci does, however, normally yield reliable results. 

Total cell count and fingerprint

In December 2012, the FOPH incorporated method no. 333 "Determining the total cell count and ratios of high and low nucleic acid content cells in freshwater using flow cytometry" into the Swiss Food Compendium as a recommended test method. Instead of the HPC, which is no longer considered relevant for food hygiene purposes, FCM (see Box) can now be used to determine the total cell count in a water sample within a matter of minutes. Unlike the AMC, this count provides a realistic indication of the microbial content of water and -- at least indirectly -- allows conclusions to be drawn about contamination. In addition, with the same method, the ratio of larger to smaller cells can also be determined (i.e. cells with a high or low nucleic acid content). This is seen by experts as the "fingerprint" of drinking water: sudden changes in this value may indicate, for example, damage or misconnections in the water network, or faults at water treatment facilities.  

New standard method

Switzerland is the first country worldwide to have adopted this advanced method for the quantification of microbial cells in water. Eawag drinking water specialist Stefan Koetzsch believes that other countries, such as the Netherlands, will follow soon. Given the much higher total cell counts, should the federal authorities now specify new limits? "No," says Koetzsch, "that would not be appropriate; nor would it really be possible since the microbiological composition of water will depend on its particular origin, and high cell counts do not in themselves provide conclusive evidence of possible pathogens".  However, Koetzsch and his colleagues are convinced that FCM will become established as a new standard in the monitoring of drinking water. The method is ideally suited for monitoring an entire supply system (from drinking water abstraction through treatment and distribution to consumers), optimizing processes and identifying problems. Efforts are already underway to develop an automated version of the method, which would permit "online" monitoring of bacterial cell counts.

Box: How does flow cytometry work?

Flow cytometry was developed for applications in the field of medicine, where it has been used since the 1980s, e.g. for counting (relatively large) blood cells. When this method is employed for drinking water analysis, the (generally small) cells contained in a sample are first stained with fluorescent dyes, which bind to DNA. The cells are then passed in single file through a glass capillary, where they are exposed to a beam of light from a laser. The resultant scatter and fluorescence signals are picked up by detectors, and analytical software is used to classify each individual particle (cell).

Before the flow cytometry method could be applied for water analysis in day-to-day practice, it had to undergo rigorous testing. Financial support for this standardization and validation was provided by the Commission for Technology and Innovation (CTI) and the Swiss Gas and Water Industry Association (SVGW). A total of 24 partners from academia, administration and public/private laboratories participated in this process.

Story Source:

The above story is reprinted from materials provided by EAWAG: Swiss Federal Institute of Aquatic Science and Technology. 

Courtesy: ScienceDaily

Can Men Prevent Diabetes With Testosterone Boost?

Australian researchers have begun a world-first study that aims to help men lose weight and prevent diabetes -- by giving them more testosterone.

The $4.8 million study will look at the potential benefits of treating men with testosterone supplements in conjunction with a dedicated weight-loss program through Weight Watchers.

Up to 1500 Australian men most at risk of developing type 2 diabetes, aged 50-74, are now being recruited to join the study in the States of South Australia, Victoria, New South Wales and Western Australia.

"We know that as men get older and gain weight -- especially when they become large around the belly -- they often suffer from reduced testosterone levels," says the leader of the study, Professor Gary Wittert from the University of Adelaide's School of Medicine.

"Lower testosterone has many implications for men's health, such as reduced motivation to exercise and lack of sexual function. It is also closely associated with type 2 diabetes, which is an enormous health burden for Australia.

"By giving testosterone supplements to men in that critical pre-diabetes stage, and by putting them on a dedicated weight-loss program, we expect to see sustained reductions in weight and a reduced chance to develop type 2 diabetes."

Men who sign up for the study will have complimentary access to Weight Watchers and can follow the program either by attending meetings or online, which is ideal for men who prefer not to attend a weight loss group.

Professor Wittert says the study, which will be conducted over at least two years of the participants' lives, could potentially have a range of other health benefits for those who take part in it.

He says: "Our hope is that this study will be a life-changing event for many men in Australia. Older men who have developed a large belly and are at risk of diabetes now have an opportunity to do something about their weight, improve their lives, and provide us with all-important research results that could benefit many others in the future."

The study is known as T4DM (Testosterone 4 the prevention of Diabetes Mellitus) and is funded by the National Health and Medical Research Council (NHMRC).

Story Source:

The above story is reprinted from materials provided by University of Adelaide. 

Courtesy: ScienceDaily

Stem Cells Found to Heal Damaged Artery in Lab Study in Baboons

Scientists at the Texas Biomedical Research Institute in San Antonio have for the first time demonstrated that baboon embryonic stem cells can be programmed to completely restore a severely damaged artery. These early results show promise for eventually developing stem cell therapies to restore human tissues or organs damaged by age or disease.

"We first cultured the stem cells in petri dishes under special conditions to make them differentiate into cells that are the precursors of blood vessels, and we saw that we could get them to form tubular and branching structures, similar to blood vessels," said John L. VandeBerg, Ph.D., Texas Biomed's chief scientific officer.

This finding gave VandeBerg and his team the confidence to do complex experiments to find out if these cells could actually heal a damaged artery. Human embryonic stem cells were first isolated and grown in 1998.

The results are presented in a manuscript, co-authored by Texas Biomed's Qiang Shi, Ph.D., and Gerald Shatten, Ph.D., of the University of Pittsburgh, published in the January 10, 2013 issue of the Journal of Cellular and Molecular Medicine.

The scientists found that cells derived from embryonic stem cells could actually repair experimentally damaged baboon arteries and "are promising therapeutic agents for repairing damaged vasculature of people," according to the authors.

Researchers completely removed the cells that line the inside surface from a segment of artery, and then put cells that had been derived from embryonic stem cells inside the artery. They then connected both ends of the arterial segment to plastic tubing inside a device called a bioreactor which is designed to grow cells and tissues. The scientists then pumped fluid through the artery under pressure as if blood were flowing through it.

The outside of the artery was bathed in another fluid to sustain the cells located there. Three days later, the complex structure of the inner surface was beginning to regenerate, and by 14 days, the inside of the artery had been perfectly restored to its complex natural state. It went from a non-functional tube to a complex fully functional artery.

"Just think of what this kind of treatment would mean to a patient who had just suffered a heart attack as a consequence of a damaged coronary artery. And this is the real potential of stem cell regenerative medicine -- that is, a treatment with stem cells that regenerates a damaged or destroyed tissue or organ," VandeBerg said.

To show that the artery couldn't heal itself in the absence of stem cells, the researchers took a control arterial segment that also was stripped of the cells on its interior surface, but did not seed it with stem cells. No healing occurred.

Stains for proteins that indicate functional characteristics showed that the healed artery had completely normal function and could do everything that a normal artery does in a healthy individual.

"This is evidence that we can harness stem cells to treat the gravest of arterial injuries," said VandeBerg.

Eventually, scientists hope to be able to take a skin cell or a white blood cell or a cell from any other tissue in the body, and induce it to become just like an embryonic stem cell in its capacity to differentiate into any tissue or organ.

"The vision of the future is, for example, for a patient with a pancreas damaged because of diabetes, doctors could take skin cells, induce them to become stem cells, and then grow a new pancreas that is just like the one before disease developed," VandeBerg said.

This work was supported by NIH grants P01 HL028972 and P51 OD011133, the Voelcker Foundation and Texas Biomed's Founder's Council. The baboons used for this study were housed in facilities constructed with support from NIH Research Facilities Improvement Grant C06 RR015456.

Journal Reference:

1. Qiang Shi, Gerald Schatten, Vida Hodara, Calvin Simerly, John L. VandeBerg. Endothelial reconstitution by CD34 progenitors derived from baboon embryonic stem cells. Journal of Cellular and Molecular Medicine, 2013; DOI: 10.1111/jcmm.12002

Courtesy: ScienceDaily

New Discovery in Autism-Related Disorder Reveals Key Mechanism in Brain Development and Disease

A new finding in neuroscience for the first time points to a developmental mechanism linking the disease-causing mutation in an autism-related disorder, Timothy syndrome, and observed defects in brain wiring, according to a study led by scientist Ricardo Dolmetsch and published online January 14 in Nature Neuroscience. These findings may be at the heart of the mechanisms underlying intellectual disability and many other brain disorders.

The present study reveals that a mutation of the disease-causing gene throws a key process of neurodevelopment into reverse. That is, the mutation underlying Timothy syndrome causes shrinkage, rather than growth, of the wiring needed for the development of neural circuits that underlie cognition.

"In addition to the implications for autism, what's really exciting is that we now have a way to get at the core mechanisms tying genes and environmental influences to development and disease processes in the brain," said Dolmetsch, Senior Director of Molecular Networks at the Allen Institute for Brain Science.

"Imagine what we can learn if we do this hundreds and hundreds of times for many different human genetic variations in a large-scale, systematic way. That's what we are doing now at the Allen Institute," Dolmetsch continued.

In normal brain development, brain activity causes branches emanating from neural cells to stretch or expand. In cells with the mutation, these branched extensions, called dendrites, instead retract in response to neural activity, according to this study. This results in abnormal brain circuitry favoring connections with nearby neurons rather than farther-reaching connections. Further, the study identified a previously unknown mode of signaling to uncover the chemical pathway that causes the dendritic retraction.

This finding may have wide-reaching implications in neuroscience, as impaired dendrite formation is a common feature of many neurodevelopmental disorders. Further, the same gene has been implicated in other disorders including bipolar disorder and schizophrenia.

Under Dolmetsch's leadership, the Molecular Networks program at the Allen Institute, one of three major new initiatives announced by the Institute last March, is using similar methods on a grand scale. The Institute is probing a large number of human genetic variations and many pathways in the brain to untangle the cellular mechanisms of neurodevelopment and disease. In addition to identifying the molecular and environmental rules that shape how the brain is built, the program will create new research tools and data sets that it will share publicly with the global research community.

Timothy syndrome is a neurodevelopmental disorder associated with autism spectrum disorders and caused by a mutation in a single gene. In addition to autism, it is also characterized by cardiac arrhythmias, webbed fingers and toes, and hypoglycemia, and often leads to death in early childhood.

The study was led by Ricardo Dolmetsch with colleagues at Stanford University.

Journal Reference:

1. Jocelyn F Krey, Sergiu P Paşca, Aleksandr Shcheglovitov, Masayuki Yazawa, Rachel Schwemberger, Randall Rasmusson, Ricardo E Dolmetsch. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nature Neuroscience, 2013; DOI: 10.1038/nn.3307

Courtesy: ScienceDaily

Risk Genes for Alzheimer's and Mental Illness Linked to Brain Changes at Birth

Some brain changes that are found in adults with common gene variants linked to disorders such as Alzheimer's disease, schizophrenia, and autism can also be seen in the brain scans of newborns.

"These results suggest that prenatal brain development may be a very important influence on psychiatric risk later in life," said Rebecca C. Knickmeyer, PhD, lead author of the study and assistant professor of psychiatry in the University of North Carolina School of Medicine. The study was published by the journal Cerebral Cortex on Jan. 3, 2013.

The study included 272 infants who received MRI scans at UNC Hospitals shortly after birth. The DNA of each was tested for 10 common variations in 7 genes that have been linked to brain structure in adults. These genes have also been implicated in conditions such as schizophrenia, bipolar disorder, autism, Alzheimer's disease, anxiety disorders and depression.

For some polymorphisms -- such as a variation in the APOE gene which is associated with Alzheimer's disease -- the brain changes in infants looked very similar to brain changes found in adults with the same variants, Knickmeyer said. "This could stimulate an exciting new line of research focused on preventing onset of illness through very early intervention in at-risk individuals."

But this was not true for every polymorphism included in the study, said John H. Gilmore, MD, senior author of the study and Thad & Alice Eure Distinguished Professor and Vice Chair for Research and Scientific Affairs in the UNC Department of Psychiatry.

For example, the study included two variants in the DISC1 gene. For one of these variants, known as rs821616, the infant brains looked very similar to the brains of adults with this variant. But there was no such similarity between infant brains and adult brains for the other variant, rs6675281.

"This suggests that the brain changes associated with this gene variant aren't present at birth but develop later in life, perhaps during puberty," Gilmore said.

"It's fascinating that different variants in the same gene have such unique effects in terms of when they affect brain development," said Knickmeyer.

In addition to Knickmeyer and Gilmore, authors of the study were Jiaping Wang, PhD; Hongtu Zhu, PhD; Xiujuan Geng, PhD; Sandra Woolson, MPh; Robert M. Hamer, PhD; Thomas Konneker, BA; Weili Lin, PhD; and Martin Styner, PhD. All are at UNC except Konneker, who was at UNC but is now a PhD student at the University of California, Santa Cruz.

The study was funded by grants from the National Institutes of Health.

Journal Reference:

1. Rebecca C. Knickmeyer, Jiaping Wang, Hongtu Zhu, Xiujuan Geng, Sandra Woolson, Robert M. Hamer, Thomas Konneker, Weili Lin, Martin Styner, and John H. Gilmore. Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth. Cereb. Cortex, January 2, 2013 DOI: 10.1093/cercor/bhs401

Courtesy: ScienceDaily

Alzheimer's Breakthrough? Drug Intended for Diabetes Appears to Restore Memory in Alzheimer’s Brain Cells

Medical researchers at the University of Alberta have discovered a drug intended for diabetes appears to restore memory in Alzheimer's brain cells.

Jack Jhamandas, a researcher with the Faculty of Medicine & Dentistry at the U of A, is the principal investigator with the team whose research results were recently published in the peer-reviewed publication The Journal of Neuroscience. He works in the Division of Neurology.

The team took brain tissue from animal models with Alzheimer's disease and tested the tissue in the lab, looking specifically at the cells' memory capacity. When brain cells are shocked by a barrage of electrical impulses, the cells "remember" the experience and this is a typical way to test or measure memory in the lab setting.

Amyloid protein, which is found in abnormally large amounts in the memory and cognition parts of the brains of Alzheimer's patients, diminishes memory. A sister protein, known as amylin, which comes from the pancreas of diabetic patients, has the same impact on memory cells.

Jhamandas and his team demonstrated last year that a diabetes drug that never made it to market, known as AC253, could block the toxic effects of amyloid protein that lead to brain cell death.

In the lab, Jhamandas and his teammates, which included Ryoichi Kimura, a visiting scientist from Japan, tested the memory of normal brain cells and those with Alzheimer's -- both from animal models. When the drug AC253 was given to brain cells with Alzheimer's and the shock memory tests were redone, memory was restored to levels similar to those in normal cells.

"This is very important because it tells us that drugs like this might be able to restore memory, even after Alzheimer's disease may have set in," says Jhamandas.

His team is continuing their research in this area and wants to see if the drug, when given before symptoms appear, can "stop the impairment of behaviour and cognition altogether in animals destined to develop Alzheimer's," says Jhamandas. Their continued research tests will take a least a year to complete.

He noted it is difficult for AC253 to cross the brain barrier, so research teams in pharmaceutical companies would need to design a similar drug that is easier to penetrate brain cells. Jhamandas says if the tests are successful, he thinks clinical trials could start within about five years, but he stressed that further testing needs to be done before such trials can occur.

"I think what we discovered may be part of the solution, but I can't say it will be the solution. There is a long list of drugs and approaches that haven't panned out as expected in the fight against Alzheimer's. I don't think one drug or approach will solve Alzheimer's disease because it's a complicated disease, but I am cautiously optimistic about our discovery and its implications."

The Canadian Institutes of Health Research funded the work of Jhamandas and his team.

Journal Reference:

1. Ryoichi Kimura, David Mactavish, Jing Yang, David Westaway and Jack H. Jhamandas. Beta Amyloid-Induced Depression of Hippocampal Long-Term Potentiation Is Mediated through the Amylin Receptor. Journal of Neuroscience, 2012 DOI: 10.1523/%u200BJNEUROSCI.3028-12.2012

Courtesy: ScienceDaily

Gene Therapy Reprograms Scar Tissue in Damaged Hearts Into Healthy Heart Muscle

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect, said researchers from Weill Cornell Medical College, Baylor College of Medicine and Stony Brook University Medical Center in a report that appears online in the Journal of the American Heart Association.

"The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting," said Dr. Todd K. Rosengart, chair of the Michael E. DeBakey Department of Surgery at BCM and the report's corresponding author. "The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle. However, in these animal studies, we found that even the effect is enhanced when combined with the VEGF gene."

"This experiment is a proof of principle," said Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College and a pioneer in gene therapy, who played an important role in the research. "Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts."

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure.

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, Rosengart and his colleagues transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material. (A transcription factor binds to specific DNA sequences and starts the process that translates the genetic information into a protein.)

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. (Ejection fraction refers to the percentage of blood that is pumped out of a filled ventricle or pumping chamber of the heart.)

The hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

Rosengart emphasizes that more work needs to be completed to show that the effect of the VEGF is real, but it has real promise as part of a new treatment for heart attack that would minimize heart damage.

"We have shown both that GMT can effect change that enhances the activity of the heart and that the VEGF gene is effective in improving heart function even more," said Dr. Crystal.

The idea started with the notion of induced pluripotent stem cells -- reprograming mature specialized cells into stem cells that are immature and can differentiate into different specific cells needed in the body. Dr. Shinya Yamanaka and Sir John B. Gurdon received the Nobel Prize in Medicine and Physiology for their work toward this goal this year.

However, use of induced pluripotent stem cells has the potential to cause tumors. To get around that, researchers in Dallas and San Francisco used the GMT cocktail to reprogram the scar cells into cardiomyocytes (cells that become heart muscle) in the living animals.

Now Rosengart and his colleagues have gone a step farther -- encouraging the production of new blood vessels to provide circulation to the new cells.

Journal Reference:

1. Megumi Mathison, Robert P. Gersch, Ahmed Nasser, Sarit Lilo, Mallory Korman, Mitchell Fourman, Neil Hackett, Kenneth Shroyer, Jianchang Yang, Yupo Ma, Ronald G. Crystal, and Todd K. Rosengart. In Vivo Cardiac Cellular Reprogramming Efficacy Is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium With Vascular Endothelial Growth Factor. J Am Heart Assoc., December 19, 2012 DOI: 10.1161/JAHA.112.005652

Courtesy: ScienceDaily

Gene Variant Linked to Active Personality Traits Also Linked to Human Longevity

A variant of a gene associated with active personality traits in humans seems to also be involved with living a longer life, UC Irvine and other researchers have found.

This derivative of a dopamine-receptor gene -- called the DRD4 7R allele -- appears in significantly higher rates in people more than 90 years old and is linked to lifespan increases in mouse studies.

Robert Moyzis, professor of biological chemistry at UC Irvine, and Dr. Nora Volkow, a psychiatrist who conducts research at the Brookhaven National Laboratory and also directs the National Institute on Drug Abuse, led a research effort that included data from the UC Irvine-led 90+ Study in Laguna Woods, Calif. Results appear online in The Journal of Neuroscience.

The variant gene is part of the dopamine system, which facilitates the transmission of signals among neurons and plays a major role in the brain network responsible for attention and reward-driven learning. The DRD4 7R allele blunts dopamine signaling, which enhances individuals' reactivity to their environment.

People who carry this variant gene, Moyzis said, seem to be more motivated to pursue social, intellectual and physical activities. The variant is also linked to attention-deficit/hyperactivity disorder and addictive and risky behaviors.

"While the genetic variant may not directly influence longevity," Moyzis said, "it is associated with personality traits that have been shown to be important for living a longer, healthier life. It's been well documented that the more you're involved with social and physical activities, the more likely you'll live longer. It could be as simple as that."

Numerous studies -- including a number from the 90+ Study -- have confirmed that being active is important for successful aging, and it may deter the advancement of neurodegenerative diseases, such as Alzheimer's.

Prior molecular evolutionary research led by Moyzis and Chuansheng Chen, UC Irvine professor of psychology & social behavior, indicated that this "longevity allele" was selected for during the nomadic out-of-Africa human exodus more than 30,000 years ago.

In the new study, the UC Irvine team analyzed genetic samples from 310 participants in the 90+ Study. This "oldest-old" population had a 66 percent increase in individuals carrying the variant relative to a control group of 2,902 people between the ages of 7 and 45. The presence of the variant also was strongly correlated with higher levels of physical activity.

Next, Volkow, neuroscientist Panayotis Thanos and their colleagues at the Brookhaven National Laboratory found that mice without the variant had a 7 percent to 9.7 percent decrease in lifespan compared with those possessing the gene, even when raised in an enriched environment.

While it's evident that the variant can contribute to longevity, Moyzis said further studies must take place to identify any immediate clinical benefits from the research. "However, it is clear that individuals with this gene variant are already more likely to be responding to the well-known medical adage to get more physical activity," he added.

First author Deborah Grady, Maria Corrada, Valentina Ciobanu, Alexandra Moyzis, Chuansheng Chen and Dr. Claudia Kawas of UC Irvine; Diana Shustarovich and Gene-Jack Wang of Brookhaven; David Grandy of Oregon Health & Science University; Marcelo Rubinstein of Argentina's National Scientific & Technical Research Council; and Qi Dong of Beijing Normal University also contributed to the study, which was supported by the U.S. Department of Energy, the National Institute on Aging, and the National Institute on Alcohol Abuse & Alcoholism intramural program.

Journal Reference:

1. D. L. Grady, P. K. Thanos, M. M. Corrada, J. C. Barnett, V. Ciobanu, D. Shustarovich, A. Napoli, A. G. Moyzis, D. Grandy, M. Rubinstein, G.-J. Wang, C. H. Kawas, C. Chen, Q. Dong, E. Wang, N. D. Volkow, R. K. Moyzis. DRD4 Genotype Predicts Longevity in Mouse and Human. Journal of Neuroscience, 2013; 33 (1): 286 DOI: 10.1523/JNEUROSCI.3515-12.2013

Courtesy: ScienceDaily

Staphylococcus Aureus: Why It Just Gets Up Your Nose

A collaboration between researchers at the School of Biochemistry and Immunology and the Department of Microbiology at Trinity College Dublin has identified a mechanism by which the bacterium Staphylococcus aureus (S. aureus) colonizes our nasal passages. The study, published December 28 in the open access journal PLOS Pathogens, shows for the first time that a protein located on the bacterial surface called clumping factor B (ClfB) has high affinity for the skin protein loricrin.

S. aureus is a major human pathogen, with the potential to cause severe invasive diseases. It is a major cause for concern in hospitals and healthcare facilities, where many infections are caused by strains resistant to commonly used antibiotics [MRSA]. Interestingly, S. aureus persistently colonizes about 20% of the human population by binding to skin-like cells within the nasal cavity. Being colonized predisposes an individual towards becoming infected so it is vital that we understand the mechanisms involved.

ClfB was previously shown to promote S. aureus colonization in a human nasal colonization volunteer study. This paper now identifies the mechanism by which ClfB facilitates S. aureus nasal colonization. Purified ClfB bound loricrin with high affinity and this interaction was shown to be crucial for successful colonization of the nose in a mouse model. A knockout mouse lacking loricrin in its skin cells allowed fewer bacterial cells to colonize its nasal passages than a normal mouse. When S. aureus strains that lacked ClfB were used nasal colonization could not be achieved at all. Finally it was shown that soluble loricrin could reduce binding of S. aureus to human nasal skin cells and that nasal administration of loricrin reduced S. aureus colonization of mice.

Rachel McLoughlin, the study's corresponding author and Lecturer at the School of Biochemistry and Immunology at Trinity College Dublin concludes, "Loricrin is a major determinant of S. aureus nasal colonization." This discovery therefore opens new avenues for developing therapeutic strategies to reduce the burden of nasal carriage and consequently infections with this bacterium. This is particularly important given the difficulties associated with treating MRSA infections.

Journal Reference:

1. Mulcahy ME, Geoghegan JA, Monk IR, O'Keeffe KM, Walsh EJ, et al. Nasal Colonisation by Staphylococcus aureus Depends upon Clumping Factor B Binding to the Squamous Epithelial Cell Envelope Protein Loricrin. PLOS Pathog, 2012 DOI: 10.1371/journal.ppat.1003092

Courtesy: ScienceDaily

Fluctuating Environment May Have Driven Human Evolution

A series of rapid environmental changes in East Africa roughly 2 million years ago may be responsible for driving human evolution, according to researchers at Penn State and Rutgers University.

"The landscape early humans were inhabiting transitioned rapidly back and forth between a closed woodland and an open grassland about five to six times during a period of 200,000 years," said Clayton Magill, graduate student in geosciences at Penn State. "These changes happened very abruptly, with each transition occurring over hundreds to just a few thousand years."

According to Katherine Freeman, professor of geosciences, Penn State, the current leading hypothesis suggests that evolutionary changes among humans during the period the team investigated were related to a long, steady environmental change or even one big change in climate.

"There is a view this time in Africa was the 'Great Drying,' when the environment slowly dried out over 3 million years," she said. "But our data show that it was not a grand progression towards dry; the environment was highly variable."

According to Magill, many anthropologists believe that variability of experience can trigger cognitive development.

"Early humans went from having trees available to having only grasses available in just 10 to 100 generations, and their diets would have had to change in response," he said. "Changes in food availability, food type, or the way you get food can trigger evolutionary mechanisms to deal with those changes. The result can be increased brain size and cognition, changes in locomotion and even social changes -- how you interact with others in a group. Our data are consistent with these hypotheses. We show that the environment changed dramatically over a short time, and this variability coincides with an important period in our human evolution when the genus Homo was first established and when there was first evidence of tool use."

The researchers -- including Gail Ashley, professor of earth and planetary sciences, Rutgers University -- examined lake sediments from Olduvai Gorge in northern Tanzania. They removed the organic matter that had either washed or was blown into the lake from the surrounding vegetation, microbes and other organisms 2 million years ago from the sediments. In particular, they looked at biomarkers -- fossil molecules from ancient organisms -- from the waxy coating on plant leaves.

"We looked at leaf waxes because they're tough, they survive well in the sediment," said Freeman.

The team used gas chromatography and mass spectrometry to determine the relative abundances of different leaf waxes and the abundance of carbon isotopes for different leaf waxes. The data enabled them to reconstruct the types of vegetation present in the Olduvai Gorge area at very specific time intervals.

The results showed that the environment transitioned rapidly back and forth between a closed woodland and an open grassland.

To find out what caused this rapid transitioning, the researchers used statistical and mathematical models to correlate the changes they saw in the environment with other things that may have been happening at the time, including changes in the Earth's movement and changes in sea-surface temperatures.

"The orbit of the Earth around the sun slowly changes with time," said Freeman. "These changes were tied to the local climate at Olduvai Gorge through changes in the monsoon system in Africa. Slight changes in the amount of sunshine changed the intensity of atmospheric circulation and the supply of water. The rain patterns that drive the plant patterns follow this monsoon circulation. We found a correlation between changes in the environment and planetary movement."

The team also found a correlation between changes in the environment and sea-surface temperature in the tropics.

"We find complementary forcing mechanisms: one is the way Earth orbits, and the other is variation in ocean temperatures surrounding Africa," Freeman said. The researchers recently published their results in the Proceedings of the National Academy of Sciences along with another paper in the same issue that builds on these findings. The second paper shows that rainfall was greater when there were trees around and less when there was a grassland.

"The research points to the importance of water in an arid landscape like Africa," said Magill. "The plants are so intimately tied to the water that if you have water shortages, they usually lead to food insecurity.

"Together, these two papers shine light on human evolution because we now have an adaptive perspective. We understand, at least to a first approximation, what kinds of conditions were prevalent in that area and we show that changes in food and water were linked to major evolutionary changes."

The National Science Foundation funded this research.

Journal Reference:

1. C. R. Magill, G. M. Ashley, K. H. Freeman. Feature Article: Water, plants, and early human habitats in eastern Africa. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1209405109

Courtesy: ScienceDaily

New Insight Into Cell Development and Cancer

Long-standing research efforts have been focused on understanding how stem cells, cells capable of transforming into any type of cell in the body, are capable of being programmed down a defined path to contribute to the development of a specific organ like a heart, lung, or kidney. Research from the University of North Carolina at Chapel Hill School of Medicine has shed new light on how epigenetic signals may function together to determine the ultimate fate of a stem cell.

The study, published December 27, 2012 by the journal Molecular Cell, implicates a unique class of proteins called polycomb-like proteins, or PCL's, as bridging molecules between the "on" and "off" state of a gene. While all of these specialized types of cells share the same genetic information encoded in our DNA, it is becoming increasingly clear that information outside the genome, referred to as epigenetics, plays a central role in orchestrating the reprogramming of a stem cell down a defined path.

Although it is understood that epigenetics is responsible for turning genes "on" and "off" at defined times during cellular development, the precise mechanisms controlling this delicate process are less well understood.

"This finding has important implications for both stem cell biology and cancer development, as the same regulatory circuits controlled by PCL's in stem cells are often misregulated in tumors," said Dr. Greg Wang, senior author of the study and Assistant Professor of Biochemistry and Biophysics in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.

The study, led by postdoctoral research fellows Drs. Ling Cai and Rui Lu in the Wang lab, and Dr. Scott Rothbart, a Lineberger postdoctoral fellow in the lab of Dr. Brian Strahl, Associate Professor of Biochemistry and Biophysics in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center, identified that PCL's interact with an epigenetic signal associated with genes that are turned on to recruit a group of proteins called the PRC2 complex which then turn genes off.

"In stem cells, the PRC2 complex turns genes off that would otherwise promote reprogramming into specialized cells of organs like the heart or lungs," said Wang.

In addition to its fundamental role in cellular development, elevated levels of PRC2 have been found in cancers of the prostate, breast, lung, and blood, and pharmaceutical companies are already developing drugs to target PRC2. Wang and colleagues determined that the same mechanisms controlling PRC2 function in stem cells also applies in human cancers.

"The identification of a specific PCL in controlling PRC2 in cancer cells suggests we may be able to develop drugs targeting this PCL to regulate PRC2 function in a more controlled manner that may maintain PRC2 function in stem cells while inhibiting it in the tumor," said Wang.

This research was funded by the National Institutes of Health grants (GM085394 and GM068088), the Department of Defense, the V Foundation for Cancer Research, and the University Cancer Research Fund, and was performed in collaboration with scientists at the University of California at Riverside, Rockefeller University, Memorial Sloan-Kettering Cancer Center, and the Albert Einstein College of Medicine. Study co-authors from UNC also included Bowen Xu, a student in the Wang Lab, and Ashutosh Tripathy, a Research Professor in the Department of Biochemistry and Biophysics.

Story Source:

The above story is reprinted from materials provided by University of North Carolina Health Care. 

Courtesy: ScienceDaily