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Archive - Jan 27, 2015

Pollinator Declines Place Millions at Risk of Malnutrition

Each year, millions of deaths result from diseases transmitted by insects. A new study shows that more than half the people in some developing countries could become newly at risk for malnutrition if crop-pollinating animals -- like bees -- continue to decline. Despite popular reports that pollinators are crucial for human nutritional health, no scientific studies have actually tested this claim -- until now. The new research by scientists at the University of Vermont (UVM) and Harvard University has, for the first time, connected what people actually eat in four developing countries to the pollination requirements of the crops that provide their food and nutrients. "The take-home is: pollinator declines can really matter to human health, with quite scary numbers for vitamin A deficiencies, for example," says UVM scientist Dr. Taylor Ricketts who co-led the new study, "which can lead to blindness and increase death rates for some diseases, including malaria." It's not just plummeting populations of bees. Scientists around the world have observed a worrisome decline of many pollinator species, threatening the world's food supply. Recent studies have shown that these pollinators are responsible for up to forty percent of the world's supply of nutrients. The new research takes the next step. It shows that in some populations -- like parts of Mozambique that the team studied, where many children and mothers are barely able to meet their needs for micronutrients, especially vitamin A -- the disappearance of pollinators could push as many as 56 percent of people over the edge into malnutrition. The study, "Do Pollinators Contribute to Nutritional Health?" was led by Drs. Alicia Ellis and Dr. Ricketts at UVM's Gund Institute for Ecological Economics and by Dr.Samuel Myers at the Harvard School of Public Health.

Newly Identified Plant Compounds Disrupt the Unique-to-Insects Juvenile Hormone Complex Receptor; Compounds Effectively and Safely Target Yellow-Fever Mosquitoes, Promise Similar Success Against Wide Range of Insect Pests & Disease Carriers

Each year, millions of deaths result from diseases transmitted by insects. Insects are also responsible for major economic losses, worth billions of dollars annually, by damaging crops and stored agricultural products. Many currently available insecticides present environmental and health risks. Further, insects develop resistance to existing insecticides, complicating pest-control strategies. The need to develop novel effective insecticides is therefore urgent. Enter "insect-specific growth regulators," which, as their name suggests, are compounds that regulate the growth of insects. They represent attractive pest-control agents because they pose no health risk to humans and are also environmentally safe. One hormone in insects, called juvenile hormone, is a particularly attractive target for insect growth regulators because this hormone exists only in insects. Juvenile hormone plays key roles in insect development, reproduction, and other physiological functions. An international team of scientists, including an entomologist at the University of California, Riverside (UCR), has investigated in detail how juvenile hormone acts and has devised a method to prevent its working. The researchers, led in the United States by Dr. Alexander Raikhel, a Distinguished Professor of Entomology at UCR, discovered potent compounds in plants that counteract the action of juvenile hormone. These compounds, called juvenile hormone antagonists (JHANs), make up plants' innate resistance mechanism against insect herbivores. In collaboration with Korean scientists, Dr. Raikhel's lab screened 1,651 plant species and chose active JHANs from these plants. They then identified five JHANs from two plants that are effective in causing mortality of yellow fever mosquito larvae, specifically by retarding the development of ovaries.

Nanoparticles That Effectively Deliver Charge-Neutral Oligonucleotide Analog Drugs into Cells

Therapeutic oligonucleotide analogs represent a new and promising family of drugs that act on nucleic acid targets such as RNA or DNA; however, their effectiveness has been limited due to difficulty crossing the cell membrane. A new delivery approach based on cell-penetrating peptide nanoparticles can efficiently transport charge-neutral oligonucleotide analogs into cells, as reported online on January 16, 2015 in an open-access article in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. In the article, entitled "Peptide Nanoparticle Delivery of Charge-Neutral Splice-Switching Morpholino Oligonucleotides," Dr. Peter Järver form the Medical Research Council (MRC) on the Cambridge Biomedical Campus (UK) and coauthors also from the Cambridge Biomedical Campus (U.K.), and also from Karolinska University Hospital (Huddinge, Sweden), Stockholm University (Sweden), Alexandria University (Egypt), and University of Oxford (UK), note that while delivery systems exist to facilitate cell entry of negatively charged oligonucleotide drugs, these approaches are not effective for charge-neutral oligonucleotide analogs. The authors describe lipid-functionalized peptides that form a complex with charge-neutral morpholino oligonucleotides, enabling them to cross into cells and retain their biological activity. "The exploitation of phosphorodiamidate morpholinos represents an exciting approach to treating a number of therapeutic targets," says Nucleic Acid Therapeutics Executive Editor Graham C. Parker, Ph.D., The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, Michigan, an who was not involved in the research.

Researchers Find Potential Breast Cancer Application for Widely Used, Anti-Sodium-Channel-Targeting Epilepsy Drug (Phenytoin)

Scientists at the University of York in the UK have discovered that a drug used widely to combat epilepsy has the potential to reduce the growth and spread of breast cancer. Researchers in the Department of Biology at York studied phenytoin, a drug that inhibits epilepsy by targeting sodium channels. These channels, known as VGSCs, exist in the membranes of excitable cells, such as neurons, where they are involved in transmission of electrical impulses. They are also present in breast cancer cells where they are thought to help the spread of tumors. In research published in Molecular Cancer, the York team found that “repurposing” anti-epileptic drugs, such as phenytoin, that effectively block the sodium channels, could provide a novel therapy for cancer. Despite extensive work to define the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there is little clinically relevant in vivo data exploring their value as potential therapeutic targets. The researchers found that treatment with phenytoin, at doses equivalent to those used to treat epilepsy significantly reduced tumor growth in a preclinical model. Phenytoin also reduced cancer cell proliferation in vivo and aslso reduced invasion into surrounding mammary tissue. Dr. Will Brackenbury, who led the research, said, “This is the first study to show that phenytoin reduces both the growth and spread of breast cancer tumor cells. This indicates that re-purposing antiepileptic and antiarrhythmic drugs is worthy of further study as a potentially novel anti-cancer therapy.” The research was funded by the Medical Research Council and the University of York. Some of the analysis was carried out by the proteomics team in the University’s Bioscience Technology Facility. The research team also included Michaela Nelson, Ming Yang, Adam A.

The Origin of Life: Water-Filled Pores in Hot Rocks on Sea Floor May Have Served As Crucibles for Formation of First RNA Molecules

Water-filled micropores in hot rock may have acted as the nurseries in which life on Earth began. A team at Ludwig-Maximilians-Universitaet (LMU) in Munich, Germany has now shown that temperature gradients in pore systems promote the cyclical replication and emergence of nucleic acids. How and in what habitats did the first life-forms arise on the young Earth? One crucial pre-condition for the origin of life is that comparatively simple biomolecules must have had opportunities to form more complex structures, which were capable of reproducing themselves and which could store genetic information in a chemically stable form. But this scenario requires some means of accumulating the precursor molecules in highly concentrated form in solution. In the early oceans, such compounds would have been present in vanishingly low concentrations. But LMU physicists, led by Professor Dieter Braun, now describe a setting that provides the necessary conditions. They show experimentally that pore systems on the seafloor that were heated by volcanic activity could have served as reaction chambers for the synthesis of RNA molecules, which serve as carriers of hereditary information in the biosphere today. “The key requirement is that the heat source be localized on one side of the elongated pore, so that the water on that side is significantly warmer than that on the other,” says Dr. Braun. Pre-formed biomolecules that are washed into the pore can then be trapped, and concentrated, by the action of the temperature gradient– thus fulfilling a major prerequisite for the formation and replication of more complex molecular structures. The molecular trapping effect is a consequence of thermophoresis: Charged molecules in a temperature gradient preferentially move from the warmer to the cooler region, allowing longer polymers in particular to be securely trapped.

Structure of Mitochondrial Complex I Determined

Mitochondria produce ATP, the energy currency of the body. The driver for this process is an electrochemical membrane potential, which is created by a series of proton pumps. These complex, macromolecular machines are collectively known as the respiratory chain. The structure of the largest protein complex in the respiratory chain, that of mitochondrial complex I, has now been elucidated by scientists from the Frankfurt "Macromolecular Complexes" cluster of excellence, working together with the scientists at University of Freiburg, by X-ray diffraction analysis. The results were published in the January 2, 2015 issue of Science. "Mitochondrial complex I plays a critical role in the production of cellular energy and has also been associated with the onset of diseases, such as Parkinson's disease," explains Dr. Volker Zickermann, an Assistant Professor at the Institute for Biochemistry II at the Goethe University in Frankfurt am Main, Germany. In order for the respiratory chain to function, there must be consistently sufficient amounts of oxygen available in all the cells in our bodies. The energy released during biological oxidation is used to transport protons from one side of the inner mitochondrial membrane to the other. The resulting proton gradient is the actual "battery" for ATP synthesis. What surprised the researchers was that previous studies had suggested that redox reactions and proton transport in complex I occurred spatially isolated from one another. The Frankfurt scientists in Dr. Zickermann's working group at Goethe University, and the working groups led by Professor Harald Schwalbe and Professor Ulrich Brandt, both also at Goethe University, have now been able to deduce how the two processes are connected to one another from the detailed analysis of the structure.

Chemogenetic Inhibition Shows That Different Areas of Brain Govern Unique Aspects of Vocalization in Singing Zebra Finches

New research published by the Neuronal Mechanism for Critical Period Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) in Okinawa, Japan, together with collarborators, has shown the effectiveness of chemogenetic inhibition used to suppress neuronal activity, as well as interesting results on how vocalization can be controlled through this technique’s application in zebra finches. The research conducted by Professor Yoko Yazaki-Sugiyama and Dr. Shin Yanagihara of the OIST was done in collaboration with scientists from the International Institute for Integrative Sleep Medicine at Tsukuba University and the Division of Sleep Medicine at Harvard University and shows that different areas of the brain govern unique aspects of vocalization. The results were pubished in the January 2015 issue of the European Journal of Neuroscience. The research showed that by silencing neurons in the arcopallium, a region in the brain known to be responsible for song generation, zebra finch songs would become erratic and incomplete. Previous studies that used micro lesions on this area of the brain showed a diminished ability to sing almost all components of a song. The chemogenetic inhibition method revealed, however, that the song was only diminished at specific parts, with only some syllables being affected or absent. The syllables affected differed from bird to bird, however the order of syllables did not change. This suggests that the portion of the brain studied, the arcopallium, is in control of the composition of acoustic structure of songs and not their order or timing. It also demonstrated how precise this neuronal suppression method can be in determining the function of very small groups of neurons.

Researchers Pinpoint Two Genes (ARID1A and PIK3CA ) That Triigger IL-6 and Cause Severest Form of Ovarian Cancer; Show How Known Drug (BKM120) Can Suppress Tumor Growth

In the battle against ovarian cancer, University of North Carolina (UNC) School of Medicine researchers have created the first mouse model of the worst form of the disease and found a potential route to better treatments and much-needed diagnostic screens. Led by Terry Magnuson, Ph.D., the Sarah Graham Kenan Professor and Chair of the Department of Genetics, a team of UNC genetics researchers discovered how two genes interact to trigger cancer and then spur on its development. "It's an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women," said Dr. Magnuson, who is also a member of the UNC Lineberger Comprehensive Cancer Center. Not all mouse models of human diseases provide accurate depictions of the human condition. Dr. Magnuson's mouse model, though, is based on genetic mutations found in human cancer samples. Mutations in two genes -ARID1A and PIK3CA - were previously unknown to cause cancer. "When ARID1A is less active than normal and PIK3CA is overactive," Dr. Magnuson said, "the result is ovarian clear cell carcinoma 100 percent of the time in our model." The research also showed that a drug called BKM120, which suppresses PI3 kinases, directly inhibited tumor growth and significantly prolonged the lives of mice. The drug is currently being tested in human clinical trials for other forms of cancer. The work, published online on January 27, 2015 in Nature Communications, was spearheaded by Ron Chandler, Ph.D., a postdoctoral fellow in Dr. Magnuson's lab. Dr. Chandler had been studying the ARID1A gene, which normally functions as a tumor suppressor in people, when results from cancer genome sequencing projects showed that the ARID1A gene was highly mutated in several types of tumors, including ovarian clear cell carcinoma. Dr.