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Archive - Jan 31, 2017

Tuberculosis-Resistant Cows Developed for First Time Using CRISPR Technology

CRISPR/Cas9 gene-editing technology has been used for the first time to successfully produce live cows with increased resistance to bovine tuberculosis, according to new research published in the open-access journal Genome Biology. The article is titled “Single Cas9 Nickase Induced Generation of NRAMP1 Knockin Cattle with Reduced Off-Target Effects.” The researchers, from the College of Veterinary Medicine, Northwest A&F University in Shaanxi, China, used a modified version of the CRISPR gene-editing technology to insert a new gene into the cow genome with no detected off target effects on the animals genetics (a common problem when creating transgenic animals using CRISPR). Dr. Yong Zhang, lead author of the research, said: "We used a novel version of the CRISPR system called CRISPR/Cas9n to successfully insert a tuberculosis resistance gene, called NRAMP1, into the cow genome. We were then able to successfully develop live cows carrying increased resistance to tuberculosis. Importantly, our method produced no off-target effects on the cow genetics meaning that the CRISPR technology we employed may be better suited to producing transgenic livestock with purposefully manipulated genetics." CRISPR technology has become widely used in the laboratory in recent years as it is an accurate and relatively easy way to modify the genetic code. However, sometimes unintentional changes to the genetic code occur as an off-target effect, so finding ways to reduce these is a priority for genomics research. Dr. Zhang explained: "When you want to insert a new gene into a mammalian genome, the difficulty can be finding the best place in the genome to insert the gene. You have to hunt through the genome, looking for a region that you think will have the least impact on other genes that are in close proximity.

Select Antiviral Cells Can Access HIV's Hideouts

When someone is HIV-positive and takes antiretroviral drugs, the virus persists in a reservoir of infected cells. Those cells hide out in germinal centers, specialized areas of lymph nodes, which most "killer" antiviral T cells don't have access to. Scientists at Yerkes National Primate Research Center, Emory University, in Georgia, have identified a group of antiviral T cells that do have the entry code into germinal centers, i.e., a molecule called CXCR5. Knowing how to induce antiviral T cells displaying CXCR5 will be important for designing better therapeutic vaccines, as well as efforts to suppress HIV long-term, says Rama Rao Amara, Ph.D., Professor of Microbiology and Immunology at Yerkes National Primate Research Center and Emory Vaccine Center. The findings are scheduled for publication in PNAS the week of Jan. 30, 2017. "We think these cells are good at putting pressure on the virus," Dr. Amara says. "They have access to the right locations - germinal centers - and they're functionally superior." Dr. Amara and his colleagues looked for these antiviral cells in experiments with rhesus macaques, which were vaccinated against HIV's relative SIV and then repeatedly exposed to SIV. The vaccine regimens were described in a previous publication. The vaccines provided good, but imperfect protection against pathogenic SIV, which means that a group of 20 animals ended up infected, with a range of viral levels. In some animals, a large fraction (up to 40 percent) of anti-viral CD8 T cells in lymph nodes displayed CXCR5. Having more CXCR5-positive antiviral T cells was strongly associated with better viral control, the researchers found. T cells can be divided into "helper" cells and "killer" cells, based on their function and the molecules they have on their surfaces.

Hyper-Connected Neurons Seen in Developing Brains in Mouse Model of Autism Spectrum Disorder; Early Development of Neural Circuitry May Be Possible New Paradigm for Autism Research

Autism is not a single condition, but a spectrum of disorders that affect the brain's ability to perceive and process information. Recent research suggests that too many connections in the brain could be at least partially responsible for the symptoms of autism, from communication deficits to unusual talents. New research from the University of Maryland (UMD) suggests that this overload of connections begins early in mammalian development, when key neurons in the brain region known as the cerebral cortex begin to form their first circuits. By pinpointing where and when autism-related neural defects first emerge in mice, the study results could lead to a stronger understanding of autism in humans--including possible early intervention strategies. The researchers outline their findings in a research paper published online on January 31, 2017 in the journal Cell Reports. The article is titled “Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder.” "Our work suggests that the neural pathology of autism manifests in the earliest cortical circuits, formed by a cell type called subplate neurons," said UMD Biology Professor and senior study author Patrick Kanold, Ph.D. "Nobody has looked at developing circuits this early, in this level of detail, in the context of autism before. This is truly a new discovery and potentially represents a new paradigm for autism research." Subplate neurons form the first connections in the developing cerebral cortex--the outer part of the mammalian brain that controls perception, memory, and, in humans, higher functions such as language and abstract reasoning. As the brain develops, the interconnected subplate neurons build a network of scaffolding believed to support other neurons that grow later in development.

Changes in EMSY Gene Contribute Independently to Breast and Ovarian Cancer

Defects in a key gene (EMSY) - long thought to drive cancer by turning off the protection afforded by the well-known BRCA genes - spur cancer growth on their own, according to a study led by researchers from NYU Langone Medical Center. The studied gene, known as EMSY, has some of the same functions as BRCA1 and BRCA2, which are known to protect against breast and ovarian cancer when normal. When defective, BRCA genes block the body's self-defense against cancer-causing genetic mistakes. The new study, published online January 13, 2017 in Oncotarget, helps to explain why some women with healthy BRCA1 and BRCA2 genes develop cancer. The findings may also expand treatment options for the roughly 11 percent of women with breast and ovarian cancer and normal BRCA genes, say the study authors. "Now that we know exactly how changes in EMSY spur cancer cell growth, we can start to design therapies to specifically target that activity and hopefully stop it," says senior author Douglas Levine (photo), M.D., Director of the Division of Gynecologic Oncology at NYU Langone and its Perlmutter Cancer Center. The Oncotarget article is titled “The EMSY Threonine 207 Phospho-Site Is Required for EMSY Driven Suppression of DNA Damage Repair.” "This work also suggests that treatments that work for patients with BRCA1 or BRCA2 mutations might also be effective against EMSY-driven cancers because the disease mechanism is similar," says first study author Petar Jelinic, Ph.D., a research assistant professor at NYU Langone. "The best way to go rapidly from bench to bedside is to find new ways to use existing treatments." When normal, EMSY, BRCA1, and BRCA2 give the body's cells instructions to create proteins that help to repair DNA damage that can cause cancer. When those genes are altered, the repair process fails and cancer grows.

Epigenetic Variation Defines a Disease Spectrum in Ewing Sarcoma

Tumors of the elderly, such as breast cancer and colon cancer, accumulate thousands of DNA mutations. These genetic defects contribute to cancer-specific properties including uncontrolled growth, invasion in neighboring tissues, and evasion from the immune system. Similar properties are also found in childhood cancers, although those tumors carry many fewer genetic defects, making it difficult to explain their clinical heterogeneity. This is particularly true for Ewing sarcoma, an aggressive bone cancer in children and adolescents. A single genetic defect - the EWS-ETS fusion - is present in all tumors, initiating cancer development and defining Ewing sarcoma as a disease. But the tumors carry very few DNA mutations that could explain the observed differences in the disease course of Ewing sarcoma patients. Tackling this question, a team of scientists from Austria, France, Germany, and Spain led by Dr. Eleni Tomazou from the St. Anna Children's Cancer Research Institute in Vienna, Austria profiled many Ewing tumors. They found that the disease's clinical diversity is reflected by widespread epigenetic heterogeneity. Using novel bioinformatic methods developed by Dr. Nathan Sheffield at CeMM, the team studied the tumors' DNA methylation patterns - one of the most important facets of the human epigenome. Ewing sarcoma showed unique characteristics that differ markedly from others cancers, and the DNA methylation patterns also varied between patients. Moreover, the researchers found that Ewing sarcoma tumors appear to retain part of the characteristic DNA methylation patterns of their cell-of-origin.

Novel Risk Genes Identified for Bipolar Disorder

A research collaboration in Japan, led by Dr. Nakao Iwata, professor at the Fujita Health University, conducted a genome-wide association study of bipolar disorder (BD), and identified novel risk genes. One of these genes (FADS) is related to lipid metabolism (e.g., omega3/6 polyunsaturated fatty acids); therefore, the scientists concluded that lipid abnormality may be involved in BD pathophysiology. Elucidating an independent association between these two phenotypes provides a foundation for new therapeutic strategies. Bipolar disorder (BD), characterized by mood swings between positive manic/hypomanic and negative/depressive states, is a common psychiatric disorder with a lifetime prevalence of ~1%. Although epidemiological studies indicate that genetic components contribute to BD development, several genome-wide association studies (GWASs) have identified a limited number of susceptibility (risk) genes for BD, most of which are yet unidentified. Collaborative research in Japan, under the guidance of the principle investigators from Fujita Health University and RIKEN, led to the identification of a novel risk gene (FADS1 and FADS2) for bipolar disorder via GWAS performed using samples collected in Japan (2,964 cases and 61,887 comparison subjects). The function of this gene is well established: metabolism of lipids, including blood lipids (e.g., cholesterol and triglyceride) and omega3/6 polyunsaturated fatty acids (PUFA). Previous epidemiological surveys have shown that prevalence of hyperglycemia or metabolic syndrome in patients with BD was higher than that of the general population; hence, the researchers concluded that lipid abnormality may be involved in BD pathophysiology.