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Archive - 2010

Date

February 24th

Clue to Schizophrenia Late Manifestation from Early Developmental Changes

Scientists from Johns Hopkins and collaborating institutions have discovered a clue as to how schizophrenia might develop after puberty as the result of genetic influences that occur in early development. In a new study, the researchers have manipulated (knocked down) a known schizophrenia susceptibility gene (DISC-1) in the brains of fetal mice in an attempt to unravel the complex link between prenatal brain development and the maturation of information processing and cognition in adult animals. The scientists showed that a transient reduction of DISC-1 (disrupted in schizophrenia-1) gene expression in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia--including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities. These findings are significant because they provide a concrete link between a nonlethal genetic disruption during prenatal brain development and specific abnormalities in adult brain maturation. "Prior to our study, the kinds of neurodevelopmental defects that cause the defined anatomical changes observed in schizophrenia patients--clinical onset 15+ years after birth, psychosis, impaired cognition and information processing, and aberrant dopaminergic neurotransmission--were not clear," offered Dr. Toshitaka Nabeshima, the senior author of the report. "However, the model in our study represents a majority of these characteristics.” The authors were careful to caution that while their findings shed some light on how early disease-associated events impact adult brain function, manipulation of one gene cannot fully define the complex neuropathology associated with schizophrenia.

February 23rd

Known Oncogene Discovered in Pancreatic Cancer

Researchers at the Mayo Clinic have found that protein kinase C-iota (PKCi), an oncogene known to be important in colon and lung cancers, is over-produced in pancreatic cancer and is linked to poor patient survival. They also found that genetically inhibiting PKCi in laboratory animals led to a significant decrease in pancreatic tumor growth and spread. The scientists said that their results strongly indicate that PKCi will be an effective target for pancreatic cancer therapy. The discovery is especially encouraging, they said, because an experimental agent that targets PKCi is already being tested in patients at the Mayo Clinic for other indications. "This is the first study to establish a role for PKCi in growth of pancreatic cancer, so it is exciting to know that an agent already exists that targets PKCi which we can now try in preclinical studies," said the study's senior investigator, Dr. Nicole Murray, of the Mayo Clinic’s Department of Cancer Biology. The drug, aurothiomalate, which was once used to treat rheumatoid arthritis, is now being tested in a Phase 1 clinical trial in patients with lung cancer at the Mayo Clinic's sites in Minnesota and Arizona. Based on findings to date, a Phase 2 clinical trial is being planned to combine aurothiomalate with agents targeted at other molecules involved in cancer growth. Dr. Murray stressed that her group’s new study has not yet tested aurothiomalate against pancreatic cancer, but that any treatment that targets this major cancer pathway offers a new avenue for therapy. "This is such a deadly disease. No standard treatment has shown much promise," she said. "New ideas and fresh, targeted therapies such as this are sorely needed." Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of less than 5 percent.

Tiny RNA Molecule Has Big Implications for Origin of Life

The smallest RNA enzyme ever known to perform a cellular chemical reaction has been described in a paper published online on February 22 in PNAS. Scientists at the University of Colorado at Boulder (UCB) have synthesized an extremely small RNA molecule that can catalyze a key reaction needed to synthesize proteins, the building blocks of life. The findings could be a substantial step toward understanding "the very origin of earthly life," contended graduate student and first author Rebecca Turk. The research team, led by Dr. Michael Yarus, focused on a ribozyme—a form of RNA that can catalyze chemical reactions—that was made up of only five nucleotides. Because proteins are complex, one vexing question has been where the first proteins came from, said Dr. Tom Blumenthal, chairman of the Molecular, Cellular, and Developmental Biology (MCDB) department at UCB, who was not involved in the research. "It now appears that the first catalytic macromolecules could have been RNA molecules, since they are somewhat simpler, were likely to exist early in the formation of the first life forms, and are capable of catalyzing chemical reactions without proteins being present," he said. "In this paper, the Yarus group has made the amazing discovery that even an extremely tiny RNA can by itself catalyze a key reaction that would be needed to synthesize proteins," said Dr. Blumenthal. “Nobody expected an RNA molecule this small and simple to be able to do such a complicated thing as that." The finding adds weight to the "RNA World" hypothesis, which proposes that life on Earth evolved from early forms of RNA. "Mike Yarus has been one of the strongest proponents of this idea, and his lab has provided some of the strongest evidence for it over the past two decades," Dr. Blumenthal said. Dr.

Pesky Aphid Thrives Despite Weak Immune System

Pea aphids, expert survivors of the insect world, appear to lack major biological defenses, according to the first genetic analysis of their immune system. "It's surprising," said Emory University biologist Dr. Nicole Gerardo, who led the study."Aphids have some components of an immune system, but they are missing the genes that we thought were critical to insect immunity." One hypothesis is that aphids may compensate for their lack of immune defenses by focusing on reproduction. From birth, a parthenogenic female aphid contains embryos that also contain embryos. This is called "telescoping of generations." "She is born carrying her granddaughters," Dr. Gerardo said. "In a lab, a female aphid can produce up to 20 copies of herself per day. About 10 days later, those babies will start producing their own offspring." Over 50 million years, aphids have evolved complex relationships with beneficial bacteria that supply them with nutrients or protect them from predators and pathogens. It's possible that the weak immune response in aphids developed as a way to keep from killing off these beneficial microbes, Dr. Gerardo noted. "A key question is whether these microbes could have changed the aphid genome, or changed how the aphid uses its genes." Further study of how the aphid immune system interacts with microbes could yield better methods for controlling them in agriculture. Pea aphids are major agricultural pests and also important biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and genetic plasticity. These resilient insects thrive despite a host of enemies, including parasitic wasps, lady bugs, fungal pathogens, and frustrated farmers and gardeners the world over.

Gene Identified for Atrial Fibrillation

By analyzing data from multiple genome-wide association studies (GWAS), scientists have identified common variants in the KCNN3 gene that are associated with a form of irregular heartbeat known as “lone atrial fibrillation” (lone AF). This is a type of AF seen in younger individuals with no other signs of heart disease. The finding may open the way to the development of innovative treatments not only for lone AF in specific, but for AF in general. The KCNN3 gene, located on chromosome 1, codes for a potassium channel protein that carries signals across cell membranes in organs including the brain and the heart. While the exact cardiac role of the protein is unknown, it may play a part in resetting the electrical activity of the atria, a process that goes awry in AF. Animal studies have suggested that a related protein, KCNN2, may help control signals originating in the atria and in the pulmonary veins, areas known to be involved in lone AF. The researchers replicated the association of KCNN3 variants with lone AF in data from two additional GWAS involving another 1,000 lone AF patients and 3,500 controls. "The genetic location we have identified could be a new drug target for the treatment of AF," said cardiologist Dr. Patrick Ellinor of the Massachusetts General Hospital Cardiovascular Research Center and Cardiac Arrhythmia Service and an assistant professor of medicine at Harvard Medical School, the first author of the report. "We also will be investigating whether these variants can help us predict patients' clinical outcomes or their response to the various treatments for AF."

Cancer Stem Cells Created from Normal Prostate Stem Cells

Researchers reported that they have been able to break apart normal human prostate tissue, extract the stem cells in that tissue, and alter those cells genetically so that they spur cancer. This effort should provide a model for studying so-called “cancer stem cells,” i.e., cancer cells that develop from stem cells in the body and that are believed to be the origin of many cancers. This model may prove useful in understanding how cancers grow--and provide a new opportunity to test and identify novel cancer drugs. Many tissues contain pools of normal stem cells that replenish the tissue when it's damaged or when changes take place. For instance, stem cells in the skin produce new cells to replace those irreparably damaged by the sun, and stem cells in the breast create milk-producing cells when a woman is pregnant. The hallmark of these stem cells is that they self-renew. This means that in addition to making cells with a specific function, they also make many new stem cells. Mounting evidence suggests that these self-renewing cells are also tied to cancer. They tend to collect mutations, said Dr. Owen Witte, a Howard Hughes Medical Institute (HHMI) Investigator at UCLA, who was scheduled to present his group’s data on February 20, 2010, at the annual meeting of the American Association for the Advancement of Science (AAAS) in San Diego; and not much separates tumor cells, with their capacity for unchecked growth, from healthy, tissue-forming stem cells. "These cells have a huge capacity for self-renewal, and when the pathways that control self-renewal are augmented or changed, they can form tumors," Dr. Witte said.

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.

February 22nd

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.

February 21st

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