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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.

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.

Scientists Investigate “Second Hit” Model in Burkitt’s Lymphoma

Although Burkitt’s lymphoma is thankfully fairly rare in the general population, it is the most common form of malignancy in children in Equatorial Africa and is very frequent in immunocompromised persons, such as those suffering from AIDS. It is invariably accompanied by an increase in the expression of a particular gene, the so-called c-myc gene. An increased level of c-myc is not usually enough to cause cancer and most patients also have alterations to another gene. The groups of Dr. Veronika Sexl at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna), and Dr. Dagmar Stoiber at the Ludwig Boltzmann Institute for Cancer Research, Vienna, have recently provided important new information on how the nature of the additional alterations shapes the course and onset of disease. The results are published in the October 27, 2011 issue of the journal Blood and are of immediate relevance to lymphoma treatment. The human c-myc gene encodes a transcription factor (MYC) involved in the regulation of a vast number of other genes – it has been estimated that the transcription of about one in six genes is somehow under the control of MYC. Perhaps because of MYC’s wide range of targets, mutations of the c-myc gene are frequently associated with a variety of tumors, not only with Burkitt’s lymphoma. Mutations that lead to excessive amounts of the MYC protein are particularly threatening. It has long been known that Burkitt’s lymphoma only develops when MYC is mutated or overexpressed, although experiments in mice have shown that some animals live quite happily and healthily with higher levels of the MYC protein. This observation is consistent with the “second hit” model for the origin of cancer: as well as a change to c-myc, a second gene must also be disturbed before disease is initiated.

Findings Suggest Personalized Brain Tumor Therapy with Src Inhibitors

The embryonic enzyme pyruvate kinase M2 (PKM2) has a well-established role in metabolism and is highly expressed in human cancers. Now, a team led by researchers at the University of Texas MD Anderson Cancer Center reports online on November 6, 2011 in the journal Nature that PKM2 has important non-metabolic functions in cancer formation. "Our research shows that although PKM2 plays an important role in cancer metabolism, this enzyme also has an unexpected pivotal function – it regulates cell proliferation directly," said senior author Dr. Zhimin Lu, associate professor in the Department of Neuro-Oncology at MD Anderson. "Basically, PKM2 contributes directly to gene transcription for cell growth – a finding that was very surprising." The researchers demonstrated that PKM2 is essential for epidermal growth factor receptor (EGFR)–promoted beta-catenin activation, which leads to gene expression, cell growth, and tumor formation. They also discovered that levels of beta-catenin phosphorylation and PKM2 in the cell nucleus are correlated with brain tumor malignancy and prognosis and might serve as biomarkers for customized treatment with Src inhibitors. In response to epidermal growth factor (EGF), the team found, PKM2 moves into the cell nucleus and binds to beta-catenin that has had a phosphate atom and three oxygen atoms attached at a specific spot called Y333 by the protein c-Src. This binding is essential for beta-catenin activation and expression of downstream gene cyclin D1. This newly discovered way to regulate beta-catenin is independent of the Wnt signaling pathway previously known to activate beta-catenin. In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumor cells.

How Brain Cells Degrade Dangerous Protein Aggregates

Researchers at the RIKEN Brain Science Institute (BSI) in Japan have discovered a key mechanism responsible for selectively degrading aggregates of ubiquitinated proteins from the cell. Their findings indicate that the capture and removal of such aggregates is mediated by the phosphorylation of a protein called p62, opening the door to new avenues for treating neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. One of the most important activities of a cell is the production of proteins, which play essential functions in everything from oxygen transport, to immune defense, to food digestion. Equally important to the cell's survival is how it deals with these proteins when they pass their expiration date: damaged or misfolded proteins have been associated with a range of debilitating conditions, including neurodegenerative diseases such as Alzheimer's disease. In eukaryotic cells, the recycling of damaged or misformed proteins is governed by a small regulatory protein called ubiquitin in a process called "ubiquitination." By attaching itself to a protein, a ubiquitin molecule can tag the protein for destruction by proteasomes, large protein complexes that degrade and recycle unneeded proteins in the cell. This recycling of proteins by proteasomes is crucial to the maintenance of cellular homeostasis. With their research, the BSI research group sought to shed light on one area where proteasome-based recycling falls short: protein complexes or aggregates, which proteasomes have trouble degrading. The group shows that this weakness is made up for by the phosphorylation of a protein called p62 at the serine 403 (S403) loci of its ubiquitin-associated (UBA) domain, which triggers a catabolic process called selective autophagy that degrades protein aggregates.

Pigeonpea Genome Sequenced; Should Speed Development of High-Yield Varieties

Once referred to as an "orphan crop" grown mainly by poor farmers, pigeonpea is now joining the world's league of major food crops with the completion of its genome sequence. The completed genome sequence of pigeonpea is featured as an advance online publication on November 6, 2011 on the website of the journal Nature Biotechnology. The paper provides an overview of the structure and function of the genes that define the pigeonpea plant. It also reveals clues on how the genomic sequence can be useful to crop improvement for sustainable food production particularly in the marginal environments of Asia and sub-Saharan Africa. Years of genome analysis by a global research partnership led by the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) based in Hyderabad, India have resulted in the identification of 48,680 pigeonpea genes. A couple of hundreds of these genes were found unique to the crop in terms of drought tolerance, an important trait that can be transferred to other similar crops like soybean, cowpea, or common bean that belong to the same family. In the fight against poverty and hunger amid the threat of climate change, highly nutritious, drought-tolerant crops are the best bets for smallholder farmers in marginal environments to survive and improve their livelihoods. Pigeonpea, grown on about 5 million hectares in Asia, sub-Saharan Africa, and South-Central America, is a very important food legume for millions of the poor in the semi-arid regions of the world. Known as the "poor people's meat" because of its high protein content, it provides a well-balanced diet when accompanied with cereals. "The mapping of the pigeonpea genome is a breakthrough that could not have come at a better time.

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