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Archive - Nov 2011

Date
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November 10th

Protein Interactions and Queen Determination in Honey Bees

A honey bee becomes a royal queen or a common worker as a result of the food she receives as a larva. While it has been well established that royal jelly is the diet that makes bees queens, the molecular path from food to queen is still in dispute. However, scientists at Arizona State University, led by Adam Dolezal and Dr. Gro Amdam, together with colleagues at other institutions, have helped reconcile some of the conflicts about bee development and the role of insulin pathways and partner proteins. Their article "IRS and TOR nutrient-signaling pathways act via juvenile hormone to influence honey bee cast fate" has been published in the December 2011 issue of the Journal of Experimental Biology. Central to the dispute within the scientific community about "who would be queen" has been a ground-breaking study published in the journal Nature in 2011 by Japanese scientist Dr. Masaki Kamakura of the Biotechnology Research Center, Toyama Prefectural University. He found that a single protein in royal jelly, called royalactin, activated queen development in larval bees through interaction with an epidermal growth factor receptor (EGFR). Dr. Kamakura's work suggested that insulin signals do not play a role in queen development, despite previous studies suggesting otherwise, including work pioneered with the insulin receptor protein by Dr. Amdam's group. Undeterred by Dr. Kamakura's findings, Dolezal, a doctoral student, and Dr. Amdam, a Pew Biomedical Scholar and professor in ASU's School of Life Sciences, looked for ways to resolve the disparity between the research studies. Amdam's team's first step involved taking control of the insulin receptor's partner protein, IRS, which the insulin receptor relies upon for signaling.

November 9th

Scientists Investigate “Panhandle” Structure of Salmon Virus RNA

A research team at the National Institute of Standards and Technology (NIST) has provided the first look at a genetic structure that may play a critical role in the reproduction of the infectious salmon anemia virus (ISAV), more commonly known as the "fish flu." A scourge in fish farms with a mortality rate as high as 90 percent, ISAV was recently found in wild salmon in the Pacific Northwest for the first time, threatening an already dwindling population and the vast food web it supports. The new research was published online on October 12, 2011 in the Journal of Virology. While there is a vaccine for the virus, it must be administered by injection—a task that is both cumbersome and economically impractical for the aquaculture industry. A drug or vaccine that prevents the spread of the disease by interfering with the virus' ability to replicate its genetic code (contained in eight segments of RNA) would be far more practical for fish farmers and marine biologists to deliver. Dr. Robert Brinson, a NIST scientist working at the Hollings Marine Laboratory (HML) in Charleston, South Carolina, and NIST colleagues Drs. Andrea Szakal and John Marino working at the Institute for Bioscience and Biotechnology Research (IBBR) in Rockville, Maryland, knew from the scientific literature that the family of viruses that includes both the many types of influenza—the causes of yearly human flu outbreaks—and infectious salmon anemia, form "panhandle" structures in their genomic RNA. In human influenza, these panhandles are known to interact with proteins that begin the process of copying and replicating the virus.

Proof-of-Principle for RNAi Treatment of Genetic Bone Disease

Scientists at Penn’s Perelman School of Medicine Center for Research in FOP and Related Disorders have developed a new genetic approach to specifically block the damaged copy of the gene for a rare bone disease, while leaving the normal copy untouched. Lead author Dr. Josef Kaplan, postdoctoral fellow; and senior authors Dr. Eileen M. Shore and Dr. Frederick S. Kaplan, both from the Department of Orthopaedic Surgery, published this new proof-of-principle approach for treating the disease, called FOP, online on October 20, 2011 in Gene Therapy. FOP (fibrodysplasia ossificans progressive) is a rare genetic disorder of progressive extra bone formation for which there is presently no cure. It is caused by a mutation in the gene for ACVR1/ALK2, a bone morphogenetic protein (BMP) receptor that occurs in all classically affected individuals. Individuals who have FOP harbor one normal copy and one damaged copy of the ACVR1/ALK2 gene in each cell. The mutation increases the amount of BMP in cells to greater than normal levels, which initiates the transformation of muscles and cartilage into a disabling second skeleton of bone. Using a special type of RNA molecule engineered to specifically silence the damaged copy of the gene rather than the normal copy -- a process known as RNA interference, or RNAi -- the scientists restored the cellular function caused by the FOP mutation by ridding cells of the mutant ACVR1/ALK2 mRNA. Cells were essentially left with only normal copies of ACVR1/ALK2 mRNA, thus adjusting the protein’s activity to normal, similar to that of cells without the FOP mutation. The human cells used in the experiments were adult stem cells obtained directly from discarded baby teeth donated by FOP patients.

Lipid Blocks Influenza Infection

A natural lipid in the fluid lining the lungs inhibits influenza infections in both cell cultures and mouse models, according to researchers at National Jewish Health. These findings, combined with previous studies demonstrating effectiveness against respiratory syncytial virus, suggest that the lipid molecule, known as POPG, may have broad antiviral activity. “Supplemental POPG could be an important, inexpensive, and novel approach for the prevention and treatment of influenza and other respiratory virus infections,” said Dr. Dennis Voelker, Professor of Medicine, and senior author of the report, published online on November 3, 2011 in the American Journal of Respiratory Cell and Molecular Biology. Influenza infects millions of people across the globe, killing 500,000 each year. Vaccines are highly effective, but must be reformulated each year to counter new viral strains. Two classes of drug are currently available to treat established influenza infections, although widespread resistance has developed against one class and is developing against the other. Several proteins that inhibit viral activity have been identified in the fluid lining the lungs. Until recently, however, the antiviral role of POPG (palmitoyl-oleoyl-phosphatidylglycerol) has been unknown. Previous research by Dr. Voelker, Dr. Mari Numata, and their colleagues demonstrated that POPG reduces inflammation in the lung and prevents infection by respiratory syncytial virus. In the most recent study, the researchers looked at the ability of POPG to inhibit infection by two strains of influenza, H1N1-PR8 and H3N2. They found that POPG suppressed inflammatory responses, viral propagation, and cell death normally associated with influenza infection.

Advance in Understanding the Genetics of High Blood Pressure

A researcher from the UK’s University of Leicester's Department of Cardiovascular Sciences has been involved in a ground-breaking study into the causes of high blood pressure. The study, published online on October 31, 2011 in the academic journal Hypertension, analyzed genetic material in human kidneys in a search for genes that might contribute to high blood pressure. The findings open up new avenues for future investigation into the causes of high blood pressure in humans. The study identified key genes, messenger RNAs, and micro RNAs present in the kidneys that may contribute to human hypertension. It also uncovered two microRNAs that contribute to the regulation of renin – a hormone long thought to play to part in controlling blood pressure. Although scientists have long known that the kidneys play a role in regulating blood pressure, this is the first time that key genes involved in the process have been identified through a large, comprehensive gene expression analysis of the human kidneys. It is also the first time that researchers have identified miRNAs that control the expression of the hormone renin. The scientists studied tissue samples from the kidneys of 15 male hypertensive patients and 7 male patients with normal blood pressure, and compared their messenger RNA (mRNA) and microRNA (miRNA). Messenger RNA (mRNA) is a single-stranded molecule that helps in the production of protein from DNA. Genetic information is copied from DNA to mRNA strands, which provide a template from which the cell can make new proteins. MicroRNA (miRNA) is a very small molecule that helps regulate the process of converting mRNA into proteins. The study was co-authored by the University of Leicester's Dr.

Polio Still a Threat to Public Health

Health professionals and researchers across the globe believe they are on the verge of eradicating polio, a devastating virus which can lead to paralysis and death. Despite successful eradication in most countries, there are still four countries where the virus is considered endemic -- and many more in which the virus still lurks. Dr. Lester Shulman of Tel Aviv University's Sackler Faculty of Medicine and the Israeli Ministry of Health has spent years tracking isolated cases of live poliovirus infections, often discovered in countries that are supposedly polio-free. When the live-virus version of the vaccine, called Oral Polio Vaccine (OPV) evolves, he says, it can act like wild poliovirus and continue the threat of contagion. Medical professionals widely believe that after the wild virus is eradicated, resources dedicated to polio immunization can be redirected. But this isn't so, Dr. Shulman says. He recommends that public health agencies take a three-pronged approach: vaccination policies to maintain "herd immunity" (a 95 percent immunization rate for polio) should be maintained to prevent the spread of wild and evolved vaccine strains of the virus; environmental surveillance of sewage systems should continue; and a switch to Inactivated Polio Vaccine (IPV) instead of OPV should be implemented. Dr. Shulman's research was recently published in PLoS ONE. He has also been invited as an informal expert to the World Health Organization's annual meeting on polio this fall. While the eradication of polio is seemingly within reach, this is not the time to relax, Dr. Shulman warns. Most countries only investigate the possibility of poliovirus outbreaks when paralytic cases appear in the human population. But this doesn't take into account a potential problem posed by the live virus vaccine.

November 8th

HPV Vaccine Shows Potential to Substantially Reduce Incidence of Cervical Cancer

The bivalent human papillomavirus (HPV) vaccine (Cervarix, GlaxoSmithKline) offers excellent protection against the more serious immediate precursor to invasive cervical cancer (ICC), particularly when given to young adolescent girls before they become sexually active. The findings of two studies published Online First on November 8, 2011 in The Lancet Oncology, also show that the vaccine partially protects against four other cancer-causing HPV types not targeted by the formulation, that together with HPV16/18, cause about 85% of cervical cancer worldwide. "Provided that organized vaccination programmes achieve high coverage in early adolescents before sexual debut, HPV vaccination has the potential to substantially reduce the incidence of cervical cancer, probably allowing modification of screening programs… when conducted alongside vaccination strategies," explains one of the lead authors, Dr. Matti Lehtinen from the University of Tampere in Finland. The bivalent vaccine targets HPV types 16 and 18 that are responsible for about 70% of cervical cancers. Most studies of vaccine efficacy have focused on prevention of cervical intraepithelial neoplasia 2 (CIN2) or higher. However, CIN3 is generally believed to be a more reproducible and predictive endpoint than CIN2, and often progresses to ICC. In 2009, the PApilloma TRIal against Cancer In young Adults (PATRICIA), the largest study of HPV16/18 vaccine efficacy to date, reported that the bivalent vaccine had high efficacy against the precancerous cervical lesions CIN2+. The study included almost 20 000 healthy women aged 15-25 years from 14 countries in Asia-Pacific, Europe, Latin America, and North America. Women were randomly assigned to receive the bivalent HPV vaccine or a control (hepatitis A) vaccine, given in three doses at enrollment, 1 month, and 6 months.

Possible Treatment Target Found for Severe Liver Disease in Children

Unexpected discovery of a new molecular signature for a destructive and often lethal pediatric liver disease may lead to a new therapeutic target for the hard-to-treat condition. In a study that included human livers and a mouse model of biliary atresia, researchers report in the November 2011 issue of the Journal of Clinical Investigation that not all children with biliary atresia share the same disease process. Some patients have a second molecular conductor of disease called the Th2 (T helper cell 2) immune system. Biliary atresia is disease that destroys the bile ducts in and near the liver in the first few months of life. Driven by an overly aggressive immune system response after birth, the condition is the most common cause of severe pediatric liver disease. The ducts, which normally carry bile from the liver and gall bladder to the intestines, become blocked over time. Even with treatment, which can include surgery, children often need a liver transplant within two years of birth. Despite the need for better therapies, progress has been hampered by a limited knowledge of biological processes driving the disease, according to Dr. Jorge Bezerra, principal study investigator and a researcher/physician in the division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's Hospital Medical Center. "Our findings add a new dimension to the understanding of biliary atresia," Dr. Bezerra said. "They provide a potential target for new therapies and have implications for clinical trials. Now, depending on the molecular signature of a child's disease, we can develop new strategies to also target the Th2 immune system with anti-inflammatory agents." Dr. Bezerra said physicians have learned in clinical trials that not all children with biliary atresia respond in similar fashion to the same treatment protocols.

Noise Used to Tune Logic Circuit Made from Virus Genes

In the world of engineering, "noise" – random fluctuations from environmental sources such as heat – is generally a bad thing. In electronic circuits, it is unavoidable, and as circuits get smaller and smaller, noise has a greater and more detrimental effect on a circuit's performance. Now some scientists are saying: if you can't beat it, use it. Engineers from Arizona State University in Tempe and the Space and Naval Warfare Systems Center (SPAWAR) in San Diego, California, are exploiting noise to control the basic element of a computer – a logic gate that can be switched back and forth between two different logic functions, such as AND\OR – using a genetically engineered system derived from virus DNA. In a paper accepted to the American Institute of Physics (AIP) journal Chaos, the team has demonstrated, theoretically, that by exploiting sources of external noise, they can make the network switch between different logic functions in a stable and reliable way. The scientists focused on a single-gene network in a bacteriophage λ (lamda). The gene they use regulates the production of a particular protein in the virus. Normally, there are biological reactions that regulate the creation and destruction of this protein; upsetting that balance results in a protein concentration that is either too high or too low. The scientists assigned a "1" to one concentration and a "0" to the other. By manipulating the protein concentration, the team could encode the logic gate input values and obtain the desired output values. Researchers modeled the system as two potential energy "wells" separated by a hump, corresponding to an energy barrier. In the presence of too much noise, the system never relaxes into one of the two wells, making the output unpredictable.

Scientists ID Diabetes Link to Cognitive Impairment in Older Adults

Many complications of diabetes, including kidney disease, foot problems, and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked. For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Dr. Vera Novak, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression, and other types of cognitive impairment are a serious consequence of this widespread disease. Now, Dr. Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory, and complex tasks – is the area most affected by these events. "In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Dr. Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent." Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Dr.