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International Project to ID Antibiotics for Tuberculosis

Scientists are collaborating on a new international research project to identify antibiotics that can kill tuberculosis and fight resistant strains. "We want to accelerate the discovery of new compounds that can be turned into effective drugs," said Professor Tony Maxwell from the John Innes Centre, a key player in "More Medicines for Tuberculosis," a new European-centered research project. Two billion people are currently infected with TB and three million die every year. TB causes more deaths than any other infectious disease. Rates are increasing, especially in sub-Saharan Africa, where people with HIV are particularly vulnerable. It is also associated with intravenous drug use and increased rates may be linked to immigration. "The bacterium is difficult to get at," said Professor Maxwell. "It is slow growing, spends a lot of time hidden in cells before it makes itself known, and has very tough cell walls of its own." Treatment is relatively long term, requiring a drug regimen over four to six months. Non-compliance is a problem, exacerbating the challenge caused by resistant strains. "Drug discovery research for tuberculosis is dependent on academic labs and no single lab can do it," said Professor Maxwell. Scientists from 25 labs across Europe will collaborate on the new project as will some groups in the US and India. The John Innes Centre scientists will focus on compounds that target DNA gyrase, a target that they have already established as effective and safe. They will receive compounds from European collaborators including AstraZeneca. They will screen those that knock out DNA gyrase. Their research will continue on those compounds that are effective both against the target (DNA gyrase) and the bacterium.

Leaf Beetle Alters Defense Mechanism for Birch-Feeding Versus Willow-Feeding

Larvae of the leaf beetle Chrysomela lapponica attack two different tree species: willow and birch. To fend off predator attacks, the beetle larvae produce toxic butyric acid esters or salicylaldehyde, whose precursors they ingest with their leafy food. Scientists of the Max Planck Institute for Chemical Ecology in Jena, Germany, and colleagues have now found that a fundamental change in the genome has emerged in beetles that have specialized on birch: The activity of the salicylaldehyde-producing enzyme salicyl alcohol oxidase (SAO) is missing in these populations, whereas it is present in willow feeders. For birch beetles, the loss of this enzyme and thereby the loss of salicylaldehyde is advantagous: the enzyme is not needed anymore because its substrate salicyl alcohol is only present in willow leaves, but not in birch. Birch beetles can therefore save resources instead of producing the enzyme at a cost. First and foremost, however, the loss of salicylaldehyde also means that birch-feeding populations do not betray themselves to their own enemies anymore, that can trace them because of the odorous substance. These new findings were reported online on March 7, 2011, in PNAS. Beetle larvae are part of a food chain. They are attacked by predatory insects and parasites, such as hover flies and bugs, as well as infested by bacteria and fungi. To protect themselves, some leaf beetle larvae have developed interesting defense mechanisms, which function externally and metabolically: In case of danger, they emit substances from their defensive glands in form of vesicles (a short video is available at http://www.ice.mpg.de/ext/735.html). These defensive secretions contain toxins that the larvae sequester from chemical precursors they have ingested with their plant food.

Loss of Caspase-2 May Be Protective in Neurodegenerative Disorders

Cell biologists pondering the death of neurons have reported that by eliminating one ingredient from the cellular machinery, they prolonged the life of neurons stressed by a pesticide chemical. The finding identifies a potential therapeutic target to slow changes that lead to neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The researchers, from The University of Texas Health Science Center San Antonio, found that neurons lacking a substance called caspase-2 were better able to withstand pesticide-induced damage to mitochondria. The research is published in the March 11, 2011 issue of the Journal of Biological Chemistry. Caspase-2 appears to be a master switch that can trigger either cell death or survival depending on the amount of cellular damage, the team found. Neurons that lacked caspase-2 showed an increase in protective activities, including the efficient breakdown of obsolete or used proteins. This process, called autophagy, delays cell death. "This research shows, for the first time, that in the absence of caspase-2, neurons increase autophagy to survive," said study co-author Dr. Marisa Lopez-Cruzan, investigator in the cellular and structural biology department at the Health Science Center. Evidence suggests that mitochondrial dysfunction plays an important role in neuronal death in conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), and Huntington's disease. "Identifying initiators in the cell death process is important for determining therapeutic approaches to provide the maximum protection of neurons during neurodegenerative conditions," said senior author Dr. Brian Herman, vice president for research and professor of cellular and structural biology at the Health Science Center. The team studied neurons from young adult mice.

Creativity Appears an Upside to ADHD

A new study in the April 2011 issue of Journal of Personality and Individual Differences found that adults with attention deficit hyperactivity disorder (ADHD) enjoyed more creative achievement than those who didn't have the disorder. "For the same reason that ADHD might create problems, like distraction, it can also allow an openness to new ideas," said Dr. Holly White, assistant professor of cognitive psychology at Eckerd College in St. Petersburg, Florida, and co-author of the paper. "Not being completely focused on a task lets the mind make associations that might not have happened otherwise." Dr. White and Dr. Priti Shah at the University of Michigan gave 60 college students – half of them with ADHD – a series of tests measuring creativity across 10 domains. The ADHD group scored higher across the board. The ADHD group showed more of a preference for brainstorming and generating ideas than the non-ADHD group, which preferred refining and clarifying ideas. The study is a follow-up to one done in 2006, which focused on laboratory measures of creativity and found that ADHD individuals show better performance on tests of creative divergent thinking. "We didn't know if that would translate into real-life achievement," said Dr. Shah. "The current study suggests that it does." [Press release] [Journal of Personality and Individual Differences abstract]

Study Shows How Breast Cell Communities Organize into Breast Tissue

A study by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) of the different types of cells that make up the human breast shows that not only do cells possess an innate ability to self-organize into communities, but these communities of different types of cells can also organize themselves with respect to one another to form and maintain healthy tissue. Understanding this ability of different types of cell communities to self-organize into tissue may help explain how the processes of stem cell differentiation and tissue architecture maintenance are coordinated. It might also lead to a better understanding of what goes wrong in cancer. Dr. Mark LaBarge, a cell and molecular biologist in Berkeley Lab’s Life Sciences Division, and Dr. Mina Bissell, a Berkeley Lab Distinguished Scientist also with the Life Sciences Division, carried out a unique study of normal human mammary epithelial cells that had been enriched into pools of the two principal lineages that make up breast tissue – the milk-producing luminals and the myoepithelials that blanket them. In healthy breast tissue, these two lineages organize themselves into an ordered bi-layer. To observe and quantify changes in the distribution of these cell lines with respect to one another over time, Dr. LaBarge, Dr. Bissell and a team of collaborators used a unique “micropatterning” technique, in which the cells were confined to a three-dimensional cylindrical geometry. “We demonstrated that while bi-layered organization in mammary epithelium is driven mainly by the lineage-specific differential expression of the E-cadherin adhesion protein, the expression of the P-cadherin adhesion protein makes additional contributions that are specific to the organization of the myoepithelial layer,” Dr. LaBarge said.

Single Cell Sequencing Reveals Over 400 Receptors in Type of Nerve Cell

Scientists at The Scripps Research Institute and University of Pennsylvania have found a way to uncover potential drug targets that have so far remained hidden from researchers' view. By applying the new method to a type of nerve cell critical to regulating body temperature, the authors found more than 400 "receptors" (structures that bind other molecules, triggering some effect on the cell) responding to neurotransmitters, hormones, and other chemical signals. This represents 20 to 30 times more receptors than previous studies had identified. The technique, described in detail in a review article in the March 11, 2011 issue of the journal Pharmacology and Therapeutics, may be applied to finding "hidden" receptors in other types of nerve cells, expanding the repertoire of potential drug targets for diseases ranging from schizophrenia to Parkinson's disease. "This technique will enable people to uncover many more drug targets," said Dr. Tamas Bartfai, chair of the Department of Molecular and Integrative Neuroscience at Scripps Research. "That may be a game changer for some diseases." Receptors found on cells are among the most important targets for the development of drugs because of the key roles they play in the communication circuits regulating various body functions. So far scientists have identified only a few of the receptors present on different types of nerve cells. Dr. Bartfai's group has long been interested in a class of nerve cells in the brain called "warm sensitive neurons." These cells sense and respond to changes in body temperature, acting like a thermometer inside the brain. As body temperature increases, warm sensitive neurons become more active, telling the body to bring its temperature down. Without this regulation, body temperature could reach dangerous levels, even leading to death.

EGFR Blockers Should Be Considered for First-Line Therapy in Certain Lung Cancers

Louisiana State University oncologist Dr. Vince D. Cataldo is the lead author of a review article reporting two chemotherapy drugs now indicated for second and third-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) are remarkably effective in treating a certain subset of these patients. Dr. Cataldo, a Clinical Assistant Professor of Medicine at the LSU Health Sciences Center New Orleans School of Medicine, practicing at LSU's Earl K. Long Medical Center and Hematology-Oncology Clinic in Baton Rouge, and his colleagues say these drugs should be considered as a first-line treatment in people who are known to carry an epidermal growth factor receptor (EGFR) mutation. The paper is published in the March 10, 2011 issue of the New England Journal of Medicine. The drugs, erlotinib and gefitinib, which are in a class of highly-specific small molecule tyrosine kinase inhibitors, work by blocking the activation of EGFR which is involved in cell survival and growth, as well as the development of a nourishing blood supply and metastasis. "Targeting the genetic mutation contributing to the development of the cancer, this class of drugs produced a response rate that exceeded 70% in these patients," noted Dr. Cataldo. The drugs, taken by mouth, also had fewer side effects. Unlike traditional cytotoxic agents, erlotinib and gefitinib do not typically cause myelosuppression, neuropathy, alopecia, or severe nausea. Lung cancer, the leading cause of cancer-related death worldwide, accounted for an estimated 157,300 deaths in the United States in 2010. Approximately 85 to 90% of all cases of lung cancer are NSCLC, which is also associated with smoking.

FDA Approves First New Drug for Lupus in Over 50 Years

Human Genome Sciences, Inc., and GlaxoSmithKline PLC announced on March 9, 2011, that the U.S. Food and Drug Administration (FDA) has approved BENLYSTA® (belimumab) for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy. “We and GSK are honored to have the opportunity, with the approval of FDA, to bring BENLYSTA forward in the United States as the first new drug for systemic lupus in more than 50 years,” said H. Thomas Watkins, President and Chief Executive Officer, HGS. “We expect to have this novel therapy available to physicians and patients within about two weeks, and our entire organization looks forward to the positive impact we hope this new therapy will have for patients with systemic lupus.” Dr. Monsef Slaoui, Chairman, GSK Research and Development, said, “The approval of BENLYSTA is an important step for appropriate lupus patients. Patients have been waiting for new treatment options to help manage this chronic disease. We look forward to working together with HGS to bring this new medicine to patients in the U.S.” BENLYSTA (belimumab) is the first in a new class of drugs called BLyS-specific inhibitors. Belimumab blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. BLyS is a naturally occurring protein which was discovered by HGS in 1996.

Study Yields Explanation for Link Between Low Birth Weight and Later Obesity

Providing further understanding of the link between low birth weights and obesity later in life, researchers have found that nutritionally deprived newborns are "programmed" to eat more because they develop fewer neurons in the region of the brain that controls food intake, according to an article published on March 10, 2011, in the journal, Brain Research. The study, by a team of researchers at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed), suggests that overeating is programmed at the level of stem cells before birth when the mother has poor or inadequate nutrition. Using an animal model, the researchers found less division and differentiation of the neural stem cells of a newborn with low birth weight as compared to normal birth weight. Previous studies have found a small size at birth followed by accelerated "catch-up" growth is associated with an increased risk of adult obesity, cardiovascular disease, type 2 diabetes, hypertension and osteoporosis. "This study demonstrates the importance of maternal nutrition and health in reducing obesity," said Dr. Mina Desai, an LA BioMed principal investigator and corresponding author of the new study. "Obesity and its related diseases are the leading cause of death in our society, yet we have few effective strategies for prevention or treatment. These studies suggest maternal nutrition could play a critical role in preventing obesity and related disease." In addition to obesity, the findings of altered brain (neural stem cells) development suggest that fetal growth restriction may be associated with cognitive and/or behavioral alterations. Importantly, the study offers potential opportunities for prevention and treatment for obesity and other related disorders. In addition to Dr. Desai, LA BioMed investigators Dr.

Mutation Identified That Would Likely Increase Transmissibility of H1N1 Influenza

In the fall of 1917, a new strain of influenza swirled around the globe. At first, it resembled a typical flu epidemic: Most deaths occurred among the elderly, while younger people recovered quickly. However, in the summer of 1918, a deadlier version of the same virus began spreading, with disastrous consequence. In total, the pandemic killed at least 50 million people — about 3 percent of the world’s population at the time. That two-wave pattern is typical of pandemic flu viruses, which is why many scientists worry that the 2009 H1N1 (“swine”) flu virus might evolve into a deadlier form. H1N1, first reported in March 2009 in Mexico, contains a mix of human, swine, and avian flu genes, which prompted fears that it could prove deadlier than typical seasonal flu viruses. However, the death toll was much lower than initially feared, in large part because the virus turned out to be relatively inefficient at spreading from person to person. In a new study from MIT, researchers have identified a single mutation in the H1N1 genetic makeup that would likely allow it to be much more easily transmitted between people. The finding, reported on March 2, 2011 in the journal PLoS ONE, should give the World Health Organization, which tracks influenza evolution, something to watch out for, said Dr. Ram Sasisekharan, senior author of the paper.“There is a constant need to monitor the evolution of these viruses,” said Dr. Sasisekharan, the Edward Hood Taplin Professor and director of the Harvard-MIT Division of Health Sciences and Technology. Some new H1N1 strains have already emerged, and the key question, Dr. Sasisekharan added, is whether those strains will have greater ability to infect humans.

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