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Possible Explanation for Late Onset of Huntington Disease

Researchers have identified a molecular pathway that may play a role in delaying the onset of symptoms in Huntington disease (HD). The findings could possibly lead to the development of effective treatments for HD. The new data indicate that group I mGluR-mediated signaling pathways are altered in HD and that these cell signaling adaptations could be important for the survival of striatal neurons, neurons that are lost in the course of HD. The researchers used a genetically-modified mouse model of HD to look at the effects of the causative mutated huntingtin protein (mutant Htt) on the brain. "We found there was some kind of compensation going on early in the life of these mice that was helping to protect them from the development of the disease," said Dr. Stephen Ferguson, senior author of the paper and director of the Molecular Brain Research Group at the Robarts Research Institute at The University of Western Ontario in Canada, and also a professor in the Department of Physiology & Pharmacology at Western’s Schulich School of Medicine and Dentistry. "As they age, they lose this compensation and the associated protective effects, which could explain the late onset of the disease.” Dr. Ferguson added that the metabotropic glutamate receptors (mGluRs), which are responsible for communication between brain cells, play an important role in these protective effects. By interacting with the mutant Htt protein, mGluRs change the way the brain signals in the early stages of HD in an attempt to offset the disease, and save the brain from cell death. As a result, mGluRs could offer a drug target for HD treatment. HD is a dominant hereditary condition that leads to severe physical and mental deterioration, psychiatric problems, and eventually, death. Currently, there are no treatments to slow down or stop the disease.

It’s Not Magic—Merlin Works in Nucleus

According to previous models, the tumor suppressor protein Merlin, encoded by the neurofibromatosis type 2 (NF2) gene, inhibits mitotic signaling at or near the cell membrane. However, in the cover story of the February 19, 2010 issue of Cell, researchers present evidence supporting the proposal that Merlin actually suppresses tumorigenesis by translocating to the nucleus where it binds to the E3 ubiquitin ligase CRL4DCAF1 and inhibits its ability to ubiquitylate target proteins. The researchers stated that multiple converging lines of evidence now indicate that Merlin's inhibition of CRL4DCAF1 activity is required to induce growth arrest and suppress tumorigenesis. Notably, the scientists showed that the tumor-derived mutations in NF2 that they examined invariably disrupted Merlin’s ability to interact with or inhibit CRL4DCAF1. This represents a new mechanism for the production of certain tumors in the brain. These tumors occur in a range of cell types, including Schwann cells. Schwann cells produce the sheaths that surround and insulate neurons. The tumors most often occur spontaneously, but can also occur in significant numbers as part of the inherited disease NF2. In NF2, the sheer number of tumors can overwhelm a patient, often leading to severe disability and eventually death. Patients can suffer from 20 to 30 tumors at any one time, and the condition typically affects older children and young adults. No therapy, other than invasive (radio) surgery which is aimed at a single tumor and which may not eradicate the full extent of the tumors, exists. NF2 is estimated to affect one in every 2,500 people worldwide. It can affect any family, regardless of past history, through gene mutation, and currently there is no cure. Dr.

Calcineurin Critical to Healthy Heart Function

Researchers have reported the first-ever data to show that the enzyme calcineurin is critical to controlling normal development and function of heart cells, and that loss of the protein leads to heart problems and death in genetically modified mice. The near total absence of calcineurin in these experimental mice led to heart arrhythmia, failure, and death, according to the research team. This report was selected as the paper of the week for the February 26, 2010 issue of the Journal of Biological Chemistry and was published online on February 19. Calcineurin is a protein phosphatase that is uniquely regulated by sustained increases in intracellular calcium ions following signal transduction events. Calcineurin is known to control cellular proliferation, differentiation, apoptosis, and inducible gene expression following stress and neuroendocrine stimulation. In the adult heart, calcineurin has earlier been shown to regulate hypertrophic growth of cardiomyocytes in response to pathologic insults that are associated with altered Ca2+ handling. It was previously known that calcineurin is important to heart function, but the extent of its role had not been defined prior to the current study. Although the current research involved mice, it nevertheless offers important insights for future studies that could lead to new approaches in diagnosis and treatment of heart patients, said Dr. Marjorie Maillet, the study's lead author and a researcher in the laboratory of senior author Dr. Jeffery Molkentin, at the Cincinnati Children’s Hospital Medical Center. In their work, the researches determined that calcineurin signaling is directly linked to the proper control of cardiac contractility, rhythm, and the expression of Ca2+-handling genes in the heart.

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Parasitic Wasps May Aid Pest Control Efforts

Parasitoid wasps kill pest insects, but their existence is largely unknown to the public. Now, scientists have sequenced the genomes of three parasitoid wasp species, revealing many features that could be useful in pest control and medicine, and in the enhancement of our understanding of genetics and evolution. "Parasitic wasps attack and kill pest insects, but many of them are smaller than the head of a pin, so people don't even notice them or know of their important role in keeping pest numbers down," said Dr. John Werren, from the University of Rochester, a co-leader of the study along with Dr. Stephen Richards of the Baylor College of Medicine. "There are over 600,000 species of these amazing critters, and we owe them a lot. If it weren't for parasitoids and other natural enemies, we would be knee-deep in pest insects.” Parasitoid wasp females are like "smart bombs" that seek out and kill only specific kinds of insects, said Dr. Werren. "Therefore, if we can harness their full potential, they would be vastly preferable to chemical pesticides, which broadly kill or poison many organisms in the environment, including us." Parasitoid wasps are four times smaller than the common fruit fly. The females seek out specific insect, tick, or mite hosts, inject venom and lay their eggs, with the wasp young emerging to devour the host insect; traits that make the wasps valuable assets as agents for biological control. Although their size is insignificant, the importance of parasitoid wasps in the control of populations of agricultural pests is crucial. Thanks to these insects billions of dollars’ worth of crops is saved each year.

Carnivorous Plants May Yield Anti-Fungal Compounds

The sticky liquid-filled pitchers of carnivorous plants contain anti-fungal compounds that may prove useful for combating fungal diseases in humans, according to research being carried out at Tel Aviv University in Israel. "To avoid sharing precious food resources with other micro-organisms such as fungi, the carnivorous plant has developed a host of agents that act as natural anti-fungal agents," said Dr. Aviah Zilberstein, an author of the report. "In the natural habitat of the tropics, competition for food is fierce, and the hot, moist environment is perfect for fungi, which would also love to eat the plant's insect meal.” In a study conducted together with Dr. Haviva Eilenberg, Dr.Esther Segal, and Dr. Shmuel Carmeli; Dr. Zilberstein and her colleagues found that unusual secondary metabolites from the pitchers of the carnivorous Nepenthes khasiana plant (originally found in India) were effective against pathogens responsible for widespread fungal infections of people in hospitals. "The pitcher of the carnivorous plant produces these compounds in a gland," said Dr. Zilberstein. Until now, no one has published or discussed the anti-fungal metabolites found in the trap liquid of this plant, she said. Currently there is a need for additional, broadly effective anti-fungal drugs. Even mildly severe forms of athlete's foot or other skin fungal infections lack effective treatments. The problem becomes more severe at hospitals, where thousands of Americans die each year from secondary fungal infections they acquire during their stays as patients.

Gene Variations Associated with Endurance Running Ability

Scientists have shown that elite endurance runners are more likely to have particular variations (SNPs) of the NRF2 (nuclear respiratory factor 2) gene than are elite sprinters. Non-elite endurance runners were also more likely to have these NRF2 variations compared to sprinters, although the difference was not as pronounced. “These findings suggest that harboring this specific genotype might increase the probability of being an endurance athlete,” said lead author Dr. Nir Eynon of the Wingate Institute in Israel. The authors said that their data supports the notion that these specific gene variants might belong to a growing group of SNPs that are associated with endurance performance. The researchers investigated the NRF2 gene because previous studies had shown that it might play a role in endurance performance as it helps produce new mitochondria, a key cellular structure that produces energy. Earlier studies had also shown that the NRF2 gene can reduce the harmful effects of oxidation and inflammation, which increase during exercise. The researchers noted that their study shows an association between the gene variations and endurance, but does not establish a cause-effect relationship. Future studies are needed to unravel exactly what role the NRF2 gene plays in athletic performance. The current study is part of a larger body of research that is exploring the human genome and which aims to understand the genetic underpinnings of athletic performance. The results were published online in Physiological Genomics on December 22, 2009. The Sports Illustrated photo shows American marathon runner Bill Rodgers in 1979. [Press release] [Physiological Genomics abstract]

Panda Genome Sequenced—Reveals Clues to Bamboo Preference

Using next-generation sequencing technology, a Chinese-led international team has generated a draft genome sequence for the giant panda. The results provide clues to the panda’s predilection for a bamboo diet and demonstrate the feasibility of using next-generation sequencing technologies for accurate, cost-effective, and rapid de novo assembly of large eukaryotic genomes. The authors noted that insights gleaned from the giant panda genome sequence may aid conservation efforts for the endangered species. Although giant pandas are known for their largely bamboo diet, the researchers discovered that the animal actually lacks the genes necessary for compete digestion of this staple food source. Dr. Michael Bruford, an author of the report, noted that "the panda is a true bear and is a carnivore, so it possesses the genes necessary for being a meat-eater and yet its diet is almost exclusively herbivorous. This may suggest that it relies on microbes in its gut to digest bamboo rather than on anything in its genetic make-up. Taste is also important when it comes to the development of dietary habits and the sequencers discovered mutations in the panda's T1R1 gene which may affect its ability to taste meat, one possible explanation for why a potential carnivore would rely on a strict bamboo diet." The study found no signs of the low degree of variation that is usually linked to inbreeding and, in spite of the panda's low reproduction rate, the study identified nearly all the reproduction genes critical for mammalian gonad function and development. These results support the potential for successful survival despite the small population size of the species. Dr. Burford noted, "The panda is at high risk of extinction, with current estimates putting total population figures at less than 3,000.

Novel Method of Transcription Regulation Seen in Malaria Parasite

In trying to understand how the human malaria parasite (Plasmodium falciparum) multiplies in red blood cells, a research team has discovered that a kind of "histone crash" takes place--a massive breakdown of the chromatin architecture that explains how the parasite can extensively and rapidly replicate its DNA and coding genes. "If this mechanism can be stopped," said Dr. Karine Le Roch, an assistant professor of cell biology and neuroscience at the University of California-Riverside, and senior author of the report, "Plasmodium replication would cease or be severely inhibited, thus controlling the spread of malaria." "Dr. Le Roch's findings document a global mechanism mediating significant changes in gene expression as the parasites transition through developmental stages in the human hosts," said Dr. Anthony A. James, a distinguished professor of microbiology & molecular genetics and molecular biology & biochemistry at the University of California-Irvine, who was not involved in the research. "As well as being a major basic discovery, this provides a basis for probing the mechanisms for novel drug development." The current study was spurred, in part, by an earlier observation that, in Plasmodium falciparum, specific transcription factors are apparently under-represented relative to the size of the parasite’s genome, and by the fact that mechanisms underlying transcriptional regulation in Plasmodium have remained controversial. “Our results demonstrate that the processes driving gene expression in Plasmodium challenge the classical eukaryotic model of transcriptional regulation occurring mostly at the transcription initiation level. We found in our experiments that histones are massively evicted everywhere in the Plasmodium genome, resulting in most of the Plasmodium genes to be transcribed at once," said Dr. La Roch.

Many Copy Number Variations Universal Among Diverse Tumors

An international team of researchers has created a genome-scale map of 26 different cancers, revealing more than 100 genomic sites where DNA from tumors is either missing or abnormally duplicated compared to normal tissues. The study, the largest of its kind, finds that most of these genetic abnormalities are not unique to one form of cancer, but are shared across multiple cancers. "Our findings show that many genome alterations are universal across different cancers. Although this has been known for some types of changes, the degree to which so many alterations are shared was pretty surprising to us," said senior author Dr. Matthew Meyerson, a professor of pathology at the Dana-Farber Cancer Institute and senior associate member of the Broad Institute of Harvard and MIT. "It suggests that, in the future, a driving force behind cancer treatment will be common genomic alterations, rather than tumors' tissue of origin." In 2004, a scientific team led by researchers at the Dana-Farber Cancer Institute and the Broad Institute launched a project to systematically map genetic changes across different cancers. They focused on a particular type of DNA change in which segments of a tumor's genome are present in abnormal numbers of copies. Instead of the usual two copies, tumors often carry several copies of one piece of DNA (an "amplification") or may lack it altogether (a "deletion"). These genetic abnormalities are known as somatic copy-number alterations or SCNAs. As the foundation for their analysis, the scientists collected over 2,500 cancer specimens representing more than two dozen cancer types, including lung, prostate, breast, ovarian, colon, esophageal, liver, brain, and blood cancers.

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