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First Genetic Variants Associated with Biological Aging in Humans

Scientists announced that they have identified, for the first time, definitive genetic variants associated with biological aging, as indicated by mean telomere length, in humans. An international team, led by researchers at the University of Leicester and King’s College London, analyzed more than 500,000 genetic variations across the entire human genome to identify the aging-related variants which are located near a gene called TERC, a gene that is known to play a role in telomere length. Telomeres are capping-like structures located at the tips of chromosomes. “Individuals are born with telomeres of certain length and in many cells telomeres shorten as the cells divide and age,” said Dr. Nilesh Samani, a co-leader of the project. “Telomere length is therefore considered a marker of biological aging." Dr. Samani explained that there are two forms of aging--chronological aging, i.e., how old you are in years, and biological aging whereby the cells of some individuals are older (or younger) than suggested by their chronological age. “In this study,” Dr. Samani said, “what we found was that those individuals carrying a particular genetic variant had shorter telomeres, i.e., looked biologically older. Given the association of shorter telomeres with age-associated diseases, the finding raises the question whether individuals carrying the variant are at greater risk of developing such diseases." Dr. Tim Spector, also a co-leader of the project, noted, “What our study suggests is that some people are genetically programmed to age at a faster rate. The effect was quite considerable in those with the variant, equivalent to between 3-4 years of 'biological aging’ as measured by telomere length loss.

Serotonin Inhibitor Appears to Cure Osteoporosis in Rodents

An investigational drug that inhibits serotonin synthesis in the gut effectively cured osteoporosis in mice and rats when administered orally once a day, according to a report by an international team led by researchers from the Columbia University Medical Center. "New therapies that inhibit the production of serotonin in the gut have the potential to become a novel class of drugs to be added to the therapeutic arsenal against osteoporosis," said Dr. Gerard Karsenty, Chair of the Department of Genetics and Development at the Columbia University College of Physicians and Surgeons, and a senior author of the report. "With tens of millions of people worldwide affected by this devastating and debilitating bone loss, there is an urgent need for new treatments that not only stop bone loss, but also build new bone. Using these findings, we are working hard to develop this type of treatment for human patients." The current study followed up on an earlier report, in Cell (November 28, 2008), by Dr Karsenty’s group and colleagues, showing that serotonin released by the gut inhibits bone formation, and that regulating the production of serotonin within the gut affects the formation of bone. Prior to that discovery, serotonin was primarily known as a neurotransmitter acting in the brain. Yet, 95 percent of the body's serotonin is found in the gut, where its major function is to inhibit bone formation (the remaining 5 percent is in the brain, where it regulates mood, among other critical functions). By turning off the intestine's release of serotonin, the team was able, in the new study, to cure osteoporosis in rodents that had undergone menopause. The results demonstrated that osteoporosis was prevented from developing, or when already present, could be fully cured.

HPV Vaccines May Reduce Wide Range of Genital Diseases

High-coverage human papillomavirus (HPV) vaccinations among adolescent and young women may result in a rapid reduction of genital warts, cervical cell abnormalities, and diagnostic and therapeutic procedures, researchers report in a new study published online February 5 in the Journal of the National Cancer Institute. Some of these genital abnormalities are precursors of cervical, vulvar, and vaginal cancers. The study focused on 17,622 women enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine. All women underwent cervicovaginal sampling and Pap testing. In the group representing uninfected women, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and in reducing the risk of HPV6/11-related genital warts. In the group representing the general population, vaccination reduced the risk of any lesion, genital warts, Pap abnormalities, and definitive therapy, irrespective of HPV type. The reduction in risk was statistically significant. "Our results provide strong evidence to suggest that the ongoing HPV vaccination programs in adolescent girls and young women will result within a few years in a notable reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures related to precursor lesions in the cervix, vulva, and vagina," the authors wrote. "It is anticipated that these reductions will eventually translate into lower rates of cancer of the cervix, vulva, and vagina." [Press release] [JNCI abstract]

Artificial Pancreas System Shows Promise in Type 1 Diabetes

In a study in children and teenagers with type 1 diabetes, researchers have shown that using a first-generation artificial pancreas system overnight can lower the risk of low blood sugar emergencies while sleeping, and at the same time improve diabetes control. The closed-loop system combined commercially available blood glucose sensors and insulin pumps, controlled by a sophisticated computer program that determined insulin dosage based on blood glucose levels while participants slept. Maintaining recommended blood sugar levels overnight is a major issue for people with type 1 diabetes--and particularly for the families of children with diabetes--because of the possibility of blood glucose dropping dangerously low during sleep and going unnoticed, which can lead to seizures, coma, and in some cases be fatal. Notably, the study showed that the children and teenagers spent twice as much time during the night within targeted blood glucose levels when their diabetes was regulated with the artificial pancreas system than when they followed conventional "manual" therapy—and low blood sugars were minimized. "Without a doubt, the biggest worry for parents of kids with type 1 diabetes is that their child will have a low blood sugar emergency during the night, when they're hard to identify," said Dr. Aaron Kowalski, Assistant Vice President of Metabolic Control at the Juvenile Diabetes Research Foundation (JDRF) and Director of the JDRF Artificial Pancreas Project. "This study is proof of principle that diabetes in kids can be safely managed overnight with an artificial pancreas.

Potential New Class of AIDS Drugs Identified

Two compounds that act on novel binding sites for HIV protease--an enzyme critical to the life cycle of the virus that causes AIDS--have been identified by researchers at the Scripps Research Institute and collaborating institutions, including Pfizer and GlaxoSmithKline. The discovery lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus. Drugs that block the HIV protease already exist and currently make up an important part of the successful AIDS drug cocktail known as highly active anti-retroviral therapy (HAART). Compared with the nine U.S. Food and Drug Administration (FDA)-approved drugs that target HIV protease, however, the two new compounds, which are small chemical units or "fragments," bind with two novel parts of the molecule. This could make future drugs incorporating the fragments' novel structural elements a useful complement to existing treatments. "The study's results open the door to a whole new approach to drug design against HIV protease," said Scripps Research Associate Professor C. David Stout, senior author of the study. "The fragments bound at not one, but two, different crevices in protease outside the active site. This is an important proof-of-concept that the protease molecule has two non-active site binding pockets (allosteric sites) which can now be exploited as a powerful new strategy to combat drug-resistance in HIV." The article describing this work is currently available online and will be featured as the cover story of the March issue of Chemical Biology & Drug Design. [Press release]

Faster, Cheaper DNA Sequencing Using New Nanopore Technique

Researchers at Boston University, and colleagues, have developed a silicon nanopore-based method that promises to make future genome sequencing faster and cheaper by dramatically reducing the amount of DNA required, thus eliminating the expensive, time-consuming, and error-prone step of DNA amplification. The technique uses electrical fields to feed long strands of DNA through four-nanometer-wide pores, much like threading a needle. The method uses sensitive electrical current measurements to detect single DNA molecules as they pass through the nanopores. "The current study shows that we can detect a much smaller amount of DNA sample than previously reported," said senior author Dr. Amit Meller. "When people start to implement genome sequencing or genome profiling using nanopores, they could use our nanopore capture approach to greatly reduce the number of copies used in those measurements," said Dr. Meller. The group harnessed electric fields around the opening of the nanopore to attract long, negatively charged DNA strands and to slide them through the nanopore, where the DNA sequence can be detected. In doing this work, the researchers made the counterintuitive discovery that the longer the DNA strand, the more quickly it found the pore opening. "That's really surprising," Dr. Meller said. "You'd expect that if you have a longer 'spaghetti,' then finding the end would be much harder. At the same time, this discovery means that the nanopore system is optimized for the detection of long DNA strands--tens of thousands of basepairs, or even more. This could dramatically speed future genomic sequencing by allowing analysis of a long DNA strand in one swipe, rather than having to assemble results from many short snippets.” Dr. Meller added, "DNA amplification technologies limit DNA molecule length to under a thousand basepairs.

Peptide from Ancient Organism May Thwart Multi-Resistant Pathogens

A discovery made while investigating the ancient multicellular organism Hydra magnipapillata has revealed a new antimicrobial peptide that shows significant activity against a variety of bacteria, including multi-resistant human strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Once commonly thought of as a hospital-acquired infection, MRSA has now spread to the community (now known as community-acquired or CA-MRSA) and is infecting previously healthy young people who have not been recently hospitalized or undergone a medical procedure. Past research has proven that ancient organisms are well equipped at preventing infectious pathogens from entering the body and given the desperate need for new drug targets, further exploration of these organisms is warranted. MRSA has already developed resistance to CA-MRSA human antimicrobial peptides and prior studies have shown antibacterial immune responses in the simple metazoan Hydra magnipapillata to include bactericidal peptides with novel structural features and modes of action. In the current study, researchers identified the antimicrobial peptide arminin 1a from Hydra and found that it exhibited significant and wide-spread activity against bacteria including MRSA and enterococci, a common cause of hospital-acquired infections that is also drug-resistant. Further observations revealed that bacteria are killed when the bacterial cell wall is disrupted and that the antibacterial activity of arminin 1a is not affected by exposure to salt in human blood. Finally, researchers determined that arminin 1a does not share any ancestry with any known antimicrobial peptides.

Sexual Trickery by Orchids Promotes Efficient Pollination

New research has explained why orchids sometimes employ a seemingly limiting approach to attracting insect pollinators. While most flowering plants reward pollinators with tasty nectar, many orchid species turn to trickery. Some use what's called food deception. They produce flowers that look or smell as if they offer food, but actually offer no edible reward. Other orchids use sexual deception. They produce flowers that look or smell like female insects, usually bees or wasps. Males are drawn to the sexy flowers and attempt to mate with them. In doing so, they accidentally collect pollen on their bodies, which fertilizes the next orchid they visit. From an evolutionary perspective, the sexual strategy is a bit puzzling. Orchids that offer nectar or mimic food can attract a wide variety of food-seeking pollinators—bees, wasps, flies, ants, and so on. But sexual displays are only attractive to the males of a single species—a flower that looks like a female wasp is only going to attract male wasps, not other insects. So in appealing to sex, these orchids limit their potential pollinators, which would seem to be a reproductive disadvantage. The scientists, however, showed that populations of sexually deceptive orchids had higher "pollen transport efficiency" than the species with multiple pollinators. In other words, a higher percentage of the pollen that was taken from sexually deceptive orchids actually made it to another orchid of the same species. The orchids with multiple pollinators had more pollen taken from their flowers, but more of that pollen was lost—dropped to the ground or deposited in flowers of the wrong species. This research was published in the January 2010 issue of The American Naturalist.

Natural Human Proteins Prevent H1N1 and Other Virus Infections

Scientists have discovered a family of human proteins that prevent or slow H1N1 influenza particles, as well as certain other viruses, from infecting human cells at the earliest stage of the virus life cycle. The anti-viral action happens sometime after the virus attaches itself to the cell and before it delivers its pathogenic cargo into the cell. The researchers believe that their findings may lead to better ways to treat influenza and other viral infections. The protein family, called interferon-inducible transmembrane proteins (IFITM), was first discovered 25 years ago as products of one of the thousands of genes turned on by interferon. Since then, not much else has been discovered about the IFITM family. Versions of the IFITM genes are found in the genomes of many creatures, from fish to chickens to mice to people, suggesting that the antiviral mechanism has been working successfully for millions of years in protecting organisms from viral infections. In the current study, the surprisingly versatile antiviral proteins were found to protect cells against several devastating human viruses—not only the current influenza A strains including H1N1 and strains going back to the 1930s, but also the West Nile virus and dengue virus. While IFITM proteins did not protect against HIV or the hepatitis C virus, experiments suggested they may defend against other viruses, including the yellow fever virus. The report was published online on December 17 in Cell. [Press release 1] [Press release 2] [Cell article]

Next-Gen DNA Sequencing Illuminates Mutations in Lung Cancer

Aided by powerful next-generation DNA sequencing technology, researchers have identified nearly 23,000 mutations in a patient’s small cell lung cancer. The mutations were identified by comparing the entire genetic sequence of the cancer against that of normal DNA from the same patient. In the process, the researchers also identified a new gene (CHD7) associated with lung cancer. The number of mutations found in the study suggests that a person may develop one mutation for every 15 cigarettes smoked, said Dr. John Minna, director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern and one of the authors of the new study. The researchers said the findings illustrate the power of advanced technology to provide important new information about human cancer, including the effect of cancer-causing chemicals on the body and the identification of potential new therapeutic targets. "Cancer is driven by acquired mutations in genes, and we are at a point where it soon will be possible to actually know every mutation in the tumors of each of our patients," Dr. Minna said. "The key will be to use this information to find new ways to help prevent cancers, diagnose them earlier, and to select treatments that might be specific for each patient's tumor. While these findings are the first step, they have lighted our path to clearly point us in the right direction. In addition, they provide the first detailed analysis of a human cance–lung cancer–that is closely linked to smoking." Furthermore, Dr. Minna said, "The data demonstrate the power of whole-genome sequencing to untangle the complex mutational signatures found in cancers induced by cigarette smoke.

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