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Archive - 2016

December 12th

Mayo Scientists Identify UCHL3 Enzyme That Regulates BRCA2 Pathway

Researchers at the Mayo Clinic have identified an enzyme called UCHL3 that regulates the BRCA2 pathway, which is important for DNA repair. Results of this research were published online on December 9, 2016 in Genes & Development. The article is titled “A Phosphorylation–Deubiquitination Cascade Regulates The BRCA2–RAD51 Axis in Homologous Recombination.” "DNA encodes the blueprints for our body, and DNA repair is a fundamental mechanism to prevent the accumulation of mutations in DNA and human disease," says senior author Zhenkun Lou, Ph.D., a molecular pharmacologist at the Mayo Clinic. "The BRCA2 pathway is important for DNA repair, and mutation of the BRCA2 gene is linked to increased cancer risk, especially breast cancer and ovarian cancer." Dr. Lou says UCHL3 is highly expressed in some cancers, and mutated or deleted in other cancers. Cancer cells with high UCHL3 expression are resistant to chemotherapy; whereas, cancer cells with low UCHL3 are more sensitive to chemotherapy. Therefore, the expression of UCHL3 could be a guide to develop more precise cancer therapy. "UCHL3 could be a potential therapeutic target to overcome resistance to chemotherapy in cancer cells that have a high level of UCHL3," Dr. Lou says. He says UCHL3 gene also could be developed into a biomarker in the clinic to guide precision medicine. "While more research is needed, our studies may provide a novel therapeutic venue to treat women's cancer and thereby contribute to the health and welfare of women," says Dr. Lou.

[Press release] [Genes & Development abstract]

Famine Alters Metabolism for Successive Generations

The increased risk of hyperglycemia associated with prenatal exposure to famine is also passed down to the next generation, according to a new study of hundreds of families affected by widespread starvation in mid-20th Century China. Hyperglycemia is a high blood glucose level and a common sign of diabetes. The new study, published online on December 7, 2016 in American Journal of Clinical Nutrition, reports that hundreds of people who were gestated during a horrific famine that afflicted China between 1959 and 1961 had significantly elevated odds of both hyperglycemia and type 2 diabetes. Even more striking, however, was that their children also had significantly higher odds of hyperglycemia, even though the famine had long since passed when they were born. Public health researchers at Brown University and Harbin Medical University in China were able to make the findings by studying more than 3,000 local residents and their children. Some of the subjects were gestated during famine and some were gestated just afterward. Some of the studied offspring were born to two, one or no parents who had been famine-exposed. The article is titled “Prenatal Exposure to Famine and the Development of Hyperglycemia and Type 2 Diabetes in Adulthood Across Consecutive Generations: A Population-Based Cohort Study of Families In Suihua, China.” This study population allowed the scientists, who interviewed and took blood samples from the participants in 2012, to make well-controlled, multigenerational comparisons of the effects of in utero famine exposure that would never be ethical to intentionally create.

December 11th

New Evidence Links Inflammation and Increased Prostate Cancer Risk

UCLA researchers, and collaborators, have discovered a previously unrecognized type of progenitor cell that, though rare in most regions of the human prostate, is found in uncommonly high numbers in inflamed areas of the gland. These progenitor cells have the ability to initiate prostate cancer in response to genetic changes. The study results suggest inflammation increases overall risk for the disease by increasing the available pool of progenitor cells that can develop into prostate cancer. Scientists have known that one of the risk factors for high-grade prostate cancer is chronic inflammation of the prostate (a process in which cells from the immune system have taken up residence in the gland), but they have been unsure how this process led to cancer. UCLA-led research previously showed that two different types of cells, known as basal and luminal cells, represented potential progenitor cells and, with varying degrees of aggressiveness, could initiate prostate cancer. Further research by colleagues at Johns Hopkins Medical Center observed that prostate cells in the proximity of inflammation appeared different under the microscope and expressed different genes, leading to the hypothesis that they were more likely to proliferate than prostate cells from areas without inflammation. The UCLA-led team was able to test this hypothesis in human cells and found that cells from areas with inflammation are progenitor cells that can initiate aggressive tumors, validating their previous hypothesis and laying the foundation for the new study. Led by Dr. Andrew Goldstein, an Assistant Professor of Molecular Biology, the UCLA researchers investigated the CD38 gene, which is expressed by most (but not all) luminal cells in the human prostate.

Rockefeller Scientists Develop 3D Map of Cystic Fibrosis Protein

Rockefeller University scientists have created the first three-dimensional map of the protein responsible for cystic fibrosis, an inherited disease for which there is no cure. This achievement, described in the December 1, 2016 issue of Cell, offers the kinds of insights essential to better understanding and treating this incurable disease, which clogs the lungs with sticky mucus, leading to breathing problems or respiratory infections. The Cell article is titled “Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator.” “With the three-dimensional structure, which we have resolved down to the level of atoms, we can say more about how the cystic fibrosis protein works normally and visualize how it becomes altered in patients,” says senior author Jue Chen, Ph.D., William E. Ford Professor and Head of the Laboratory of Membrane Biology and Biophysics at Rockefeller. Dr. Chen and first author Dr. Zhe Zhang, a postdoc in her lab, plotted out the locations of disease-causing mutations within the structure and revealed a vulnerable spot in the protein that appears responsible for many cases of the disease. “By examining what goes wrong here and at other sites, we hope it may become possible to devise treatments that correct these errors,” Dr. Zhang says. The protein in question, the cystic fibrosis transmembrane conductance regulator (CFTR), forms a channel on the surfaces of cells that allows particles of chloride, a component of salt, to pass through the cell membrane. Because the distribution of salt affects the movement of water, a disruption to the channel dehydrates the mucus lining certain organs—including the lungs, where the accumulation of thick mucus can allow bacteria to flourish and potentially lead to life-threatening complications.

Genetic Factors Control Regenerative Properties of Blood-Forming Stem Cells, UCLA Studies Show

Researchers from the UCLA Department of Medicine, Division of Hematology Oncology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have published two studies that define how key genetic factors affect blood-forming stem cells by either accelerating or hindering the cells’ regenerative properties. The findings could one day lead to improved treatments for people undergoing common therapies for cancer such as chemotherapy and radiation. Blood-forming stem cells, or hematopoietic stem cells, are found in the bone marrow. These cells have two unique properties: They can self-renew and, through a process called differentiation, they can form any type of blood cell. A healthy immune system depends on the regenerative abilities of hematopoietic stem cells. Common cancer therapies such as chemotherapy and radiation can eliminate cancer by killing cancer cells. But these treatments also damage hematopoietic stem cells, which can impede the cells’ ability to regenerate blood, slowing the immune system and resulting in a longer, more complicated recovery for people with cancer. Previous research indicated that certain genes may alter hematopoietic stem cells’ regenerative capacity by either accelerating or hindering the cells’ ability to restore the immune system, but more research was needed to pinpoint the specific genetic activity and effects. One of the new studies focused on a gene called Grb10 that is expressed by hematopoietic stem cells. Grb10’s function was previously not known, so to better understand its role, the scientists deleted Grb10 from hematopoietic stem cells in lab dishes and in mice that had received radiation. They found that deleting Grb10 strongly promotes hematopoietic stem cell self-renewal and differentiation.

Brains of Those with Autism Spectrum Disorder Share Similar Molecular Abnormalities

Autism spectrum disorder is caused by a variety of factors, both genetic and environmental. But a new study led by UCLA scientists provides further evidence that the brains of people with the disorder tend to have the same “signature” of abnormalities at the molecular level. The scientists analyzed 251 brain tissue samples from nearly 100 deceased people — 48 who had autism and 49 who didn’t. Most of the samples from people with autism showed a distinctive pattern of unusual gene activity. The findings, published online on December 5, 2016 in Nature, confirm and extend the results of earlier, smaller studies, and provide a clearer picture of what goes awry, at the molecular level, in the brains of people with autism. The Nature article is titled “Genome-Wide Changes in lncRNA, Splicing, and Regional Gene Expression Patterns in Autism.” “This pattern of unusual gene activity suggests some possible targets for future autism drugs,” said Dr. Daniel Geschwind, the paper’s senior author and UCLA’s Gordon and Virginia MacDonald Distinguished Professor of Human Genetics. “In principle, we can use the abnormal patterns we’ve found to screen for drugs that reverse them — and thereby hopefully treat this disorder.” According to the Centers for Disease Control and Prevention, about 1.5 percent of children in the U.S. have autism; the disorder is characterized by impaired social interactions and other cognitive and behavioral problems. In rare cases, the disorder has been tied to specific DNA mutations, maternal infections during pregnancy, or exposures to certain chemicals in the womb. But in most cases, the causes are unknown. In a much-cited study in Nature in 2011, Dr.

Neurons That Control Judgment of Time Discovered in Mouse Brain

Time flows, time flies, time stands still. All these expressions show just how highly variable, depending on multiple factors, our perception of the passage of time can be. How is this subjective experience embodied in the human brain? Scientists in Portugal have begun to unravel this fundamental question. A team of neuroscientists at the Champalimaud Centre for the Unknown, in Lisbon, Portugal, has discovered that the activity of certain neurons in a deep region of the mouse brain can be manipulated to induce the animal to under- or over-estimate the duration of a fixed time interval. In other words, they have, for the first time, identified neural circuitry that modulates judgments of elapsed time -- at least in the mouse brain. These results, which were published in the December 9, 2016 issue of Science by Joe Paton, Ph.D., Principal Investigator of the Learning Lab, Ph.D. student Sofia Soares, and post-doc Dr. Bassam Atallah, offer a neurobiological answer to the long-standing question of how the brain produces such variable estimates of time. And not only that: the results may also help to explain why time seems to fly when we are having fun, or to endlessly stretch when we are bored. The Science article is titled “Midbrain Dopamine Neurons Control Judgment of Time.” The group has been studying the neuroscience of how duration is judged for a number of years now, as part of a larger interest in understanding how the brain learns to link causes with effects even over extended over time periods. However, never has the work felt so personally relevant. Recently, two of Dr. Paton's friends were in a serious accident. "The few hours between when we knew about the accident, and when we knew that they would be ok... felt like weeks.

December 10th

Bird Song Studies Reveal Wealth of Information Conveyed by Silence

Like humans learning to speak, juvenile birds learn to sing by mimicking vocalizations of adults of the same species during development. Juvenile birds preferentially learn the song of their own species, even in noisy environments with a variety of different birdsongs. But how they can recognize their species' song has, until now, remained a mystery. In a collaborative study, neuroscientists and a physicist at the Okinawa Institute of Science and Technology Graduate University (OIST) in Japan have uncovered an innate mechanism for species identification based on the silent gaps between birdsong syllables. "We co-designed an experiment that works within the constraints of neuroscience while satisfying the requirements of physics," says Professor Mahesh Bandi, head of the Collective Interactions Unit at OIST. Dr. Makoto Araki and Professor Yoko Yazaki-Sugiyama of OIST's Neuronal Mechanism for Critical Period Unit and Professor Bandi performed a cross-fostering experiment in which juvenile zebra finches were raised by Bengalese finch foster parents to examine how their birdsong develops under the tutoring of a different species. Birdsong is comprised of stereotypical repeats of a few syllables, called “song motifs,” in which syllables are separated by silent gaps. The findings, published in the December 9, 2016 issue of Science, revealed that the fostered zebra finches learned morphologies of Bengalese finch syllables, including syllable duration, but transposed onto zebra finch silent gap patterns. This suggests that temporal gaps between syllables are innate, while syllable morphology can be learned. The Science article is titled “Mind the Gap: Neural Coding of Species Identity in Birdsong Prosody.” "The fostered zebra finches sang the Bengalese finch song with a zebra finch accent," says Professor Yoko Yazaki-Sugiyama.

UCLA Advance Will Enable Deeper Insights into Astrocyte Function & Possibly Increased Understanding of ALS & Other Neurological Disorders

An achievement by UCLA neuroscientists could lead to a better understanding of astrocytes, a type of cell in the brain that is thought to play a role in Lou Gehrig’s disease (also called amyotrophic lateral sclerosis, or ALS); Alzheimer’s disease; Huntington’s disease; and other neurological disorders. The researchers are the first to have bred mice in which an artificial gene called Cre/ERT2, a basic tool for studying the functions of cells, can be activated exclusively in astrocytes. A paper describing their work was published online on December 8, 2016 in the journal Neuron. The article is titled “New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo.” Neuroscientists have been trying for years to engineer mice in which Cre/ERT2 or other artificial genes can be activated just in astrocytes without significant “leakage” into other cell types. “We’ll now be able to delete or mutate astrocyte genes that are suspected of contributing to diseases such as ALS to see whether they really do contribute,” said Baljit Khakh, Ph.D., Professor of Physiology and Neurobiology at the David Geffen School of Medicine at UCLA. “That, in turn, could open up many new strategies for treating those diseases.” To give the mice the Cre/ERT2 gene, Dr. Khakh and colleagues inserted it into another gene, Aldh1-l1. Aldh1-I1 had been found in a previous study to only be active in adult astrocytes. Cre/ERT2 normally can be activated in mice by giving them a drug called tamoxifen, which is best known as a breast cancer treatment. The UCLA researchers, however, built the combination gene so that tamoxifen could only “turn on” the Cre/ERT2’s when it was in astrocytes.

Cow Study Explains High Failure Rate of Mammalian Clones

It has been 20 years since Dolly the sheep was successfully cloned in Scotland, but cloning mammals remains a challenge. A new study by researchers from the U.S. and France of gene expression in developing clones now shows why most cloned embryos likely fail. Dolly was cloned using the technique of "somatic cell nuclear transfer," when a nucleus from an adult cell is transferred into unfertilized egg that has had its nucleus removed, and is then shocked with electricity to start cell growth. Embryos are then transferred to recipient mothers who carry the clones to birth. Cloning cattle is an agriculturally important technology and can be used to study mammalian development, but the success rate remains low, with typically fewer than 10 percent of the cloned animals surviving to birth. The majority of losses are due to embryonic death, a failure during the implantation process, or the development of a defective placenta. In a study published online on December 8, 2016 in PNAS, Harris Lewin, Ph.D., Professor in the UC Davis Department of Evolution and Ecology, and colleagues in France and the U.S. used RNA sequencing to look at gene expression in cloned cows during implantation in order to get a better understanding of the molecular mechanisms that lead to a high rate of pregnancy failure for clones. The study is the culmination of 12 years of collaboration and combines the French team's expertise in cloning and reproductive biology with the U.S. team's expertise in functional genomics. The PNAS article is titled “Massive Dysregulation of Genes Involved in Cell Signaling and Placental Development in Cloned Cattle Conceptus and Maternal Endometrium.” "Our work tackled fundamental questions relating to the cloning process," said Dr. Lewin.