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Transcriptomic Immaturity, Inducible by Neural Hyperexcitation, Is Shared by Multiple Neuropsychiatric Disorders, Including Schizophrenia, Alzheimer Disorders, and ALS; Gene Expression Patterns for Synaptic Function & Chromosomal Modification ID’d

Two gene expression patterns—decreases in maturity markers and increases in immaturity markers—have been found by a group that noted the need for biomarkers to improve diagnosis of neuropsychiatric disorders, which are often associated with excitatory/inhibitory imbalances in neural transmission and abnormal maturation. The researchers, from Fujita Health University and Astellis Pharma in Japan, and Astellis Research Institute of America in San Diego, characterized different disease conditions by mapping changes in the expression patterns of maturation-related genes whose expression had been altered by experimental neural hyperexcitation in published studies. The scientists found that genes for maturity markers were characterized over-representation of genes related to synaptic function, while the genes for immaturity markers were characterized by over-representation of genes related to chromosomal modification. The research team used these two groups of biomarker genes (maturity & immaturity markers) in a transdiagnostic analysis of 87 disease datasets for eight neuropsychiatric disorders and 12 datasets from corresponding animal models. The scientists found that transcriptomic pseudoimmaturity, inducible by neural hyperexcitation, is shared by multiple neuropsychiatric disorders, such as schizophrenia, Alzheimer disorders, and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). The research said that “our results indicate that this endophenotype serves as a basis for the transdiagnostic characterization of these disorders.” The new work was reported in article published online on January 22, 2019 in Communications Biology. The open-access article is titled “Transcriptomic Immaturity Inducible by Neural Hyperexcitation Is Shared by Multiple Neuropsychiatric Disorders.”

Genetic Alliance & LunaPBC Partner to Support Personal Health & Accelerate Medical Breakthroughs

On January 22, 2019, LunaPBC, founder of LunaDNA, the first community-owned genomic and health data platform, announced its partnership with Genetic Alliance, a non-profit dedicated to providing ordinary people with powerful tools to transform research. Over the course of 2019, the organizations will merge Genetic Alliance's Platform for Engaging Everyone Responsibly engagement platform with LunaDNA to provide individuals and communities with more resources to support health management while maximizing research opportunities. The partnership enables LunaPBC and Genetic Alliance to unite their shared mission and technologies to create seamless solutions to support individuals, disease foundations, and patient advocacy organizations, while also powering disease research at scale. Shared values across both organizations will ensure the ongoing focus of honoring a person’s preferences and rights for data transparency, privacy, and control, while accelerating science and creating shared value. In December 2018, LunaDNA received precedent-setting approval from the U.S. Securities and Exchange Commission (SEC) to recognize an individual’s health data as currency with which to acquire shares of ownership in the company. Researchers from non-profits, for-profits, disease organizations, and research communities can request access to the LunaDNA platform to conduct research studies. LunaDNA members’ de-identified, aggregated, and encrypted health data helps power research at the scope and scale needed for medical breakthroughs.

Craig Venter Praises Mike Hunkapiller for Huge Contribution to Sequencing of Human Genome While Leading Applied Biosystems (ABI); Statement Comes in Fireside Chat at PMWC 2019

Perhaps the highlight of a spectacular second day of the Precision Medicine World Conference (PMWC 2019), being held in Santa Clara, California January 20-23, was the late afternoon “Fireside Chat” among Ralph Snyderman, MD, Chancellor Emeritus, Duke University, & Director of the Duke Center for Personalized Health Care; J. Craig Venter, PhD, Founder & CEO, J. Craig Venter Institute; and Brook Byers, Senior Partner at Kleiner Perkins Caufield & Byer, and an early investor in Applied Biosystems and Genentech. In response to a BioQuick News question from a large audience (~400 top-level scientists) from the over 1,800 conference attendees from 35 countries, Dr. Venter said that he believed that the human genome would not have been sequenced, or certainly not sequenced as fast as it was, without the major technological contributions of Michael W. Hunkapiller, PhD (then President of Applied Biosystems (ABI), and now CEO & President, Pacific Biosciences), who had played a major role in the invention of the first automated DNA Sequencer in the laboratory of Leroy Hood, MD, PhD, at Cal Tech in the 1980’s. Dr. Venter also praised Dr. Hunkapiller for his more recent efforts leading the development of technology for long-read DNA sequencing (as many as 30,000 bases at one time) at Pacific Biosciences. Please stay tuned to BioQuick News for a more detailed article on this historic Fireside Chat in the coming days. Live hourly tweets from PMWC 2019 can be accessed at @JohnRONeill1 or #PMWC19. IMAGE: Photo shows Dr. Craig Venter with famed microbiologist Dr. Rita Colwell, Distinguished University Professor, University of Maryland College Park and Johns Hopkins Bloomberg School of Public Health; First female Director of the National Science Foundation (NSF); & President, CosmosID, Inc., after the PMWC fireside chat had wrapped up late Tuesday afternoon. The 84-year-old Dr.

World’s Premier Precision Medicine Conference (PMWC 2019) Opens 10th Annual Meeting in California’s Silicon Valley; Awards Given to Four Major Contributors to Advance of Precision Medicine

The Precision Medicine World Conference (PMWC 2019) opened its tenth annual meeting ("Celebrating 10 Years of Precision Medicine Innovation) Sunday evening, January 20, in Santa Clara, Caifornia, with an awards ceremony honoring four distinguished contributors to the advance of precision medicine. ( Live tweets from the conference can be accessed on Twitter using @JohRONeill1 or #pmwc19 ). The award recipients were Carl June, MD, PhD, (Director, Center for Cellular Immunotherapies, University of Pennsylvania) for developing CAR-T therapy (the world’s first gene-based cancer therapy); Feng Zhang, PhD, (Professor, Neuroscience, MIT/Broad) for spearheading the development of optogenetics and CRISPR; George Yancopoulos, MD, PhD, (President & CSO & Director, Regeneron Pharmaceuticals) for developing foundational technologies designed to invent groundbreaking therapies; and Sharon Terry (President, Genetic Alliance) for initiating the movement to build systems for individuals to access and share health data. The master of ceremonies for the awards event was Dawn Berry (Co-Founder & President, Luna DNA) and she opened the evening by welcoming everyone and then introduced event organize Tal Behar (Co-Founder & President, PMWC, LLC) to make some opening remarks. Behar first expressed her thanks the Program Co-Chairs Nancy Davidson, MD (Director Clinical Research Division, Fred Hutchinson Cancer Research Center), and India Hook-Barnard, PhD (Director Research Strategy, UCSF), and then introduced Program Chairman William Dalton, MD, PhD (former President, CEO & Center Director of the Moffitt Cancer Center) to kick off the awards ceremony. Dr.

Mutations in Gene Associated with Hereditary Parkinson’s Disease Lead to Toxic Accumulation of Manganese

Researchers have found that mutations in a gene linked to hereditary forms of Parkinson’s disease — SLC30A10 — cause accumulation of toxic levels of manganese inside cells, which disturbs protein transport and alters nerve cell function, leading to parkinsonian symptoms. The study, titled “SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus” was published in the the January 16, 2019 issue of ACS Chemical Neuroscience. Manganese is an essential metal that helps enzymes carry out their functions in the body. However, too much manganese is toxic, especially for the central nervous system (brain and spinal cord), where its accumulation can lead to parkinsonian-like syndromes. The SLC30A10 gene encodes an important manganese transport protein, which sits at the membrane of cells and pumps out manganese, to protect cells against this metal’s toxicity. However, mutations in the SLC30A10 gene block the protein’s pumping activity, resulting in manganese accumulation. Mutations in this gene have been identified as the cause of new forms of hereditary Parkinson’s disease. “Understanding the means by which mutations in SLC30A10 alter cellular Mn [manganese] homeostasis [manganese equilibrium] is expected to enhance understanding of the principles underlying Mn toxicity itself,” researchers wrote, which may render important information to fight certain forms of familial Parkinson’s disease. A team of French researchers,together with colleagues from Germany and the United States, used advanced imaging techniques to find where manganese accumulates inside cells (cell lines available for laboratory research) carrying disease-causing SLC30A10 mutations versus cells carrying a normal, functional SLC30A10 gene (control cells).

Genetic Variants Affecting N-Methyl-D-Aspartate Receptor (NMDAR) Implicated in Development of Schizophrenia

Genetic variants that prevent a neurotransmitter receptor from working properly have been implicated in the development of schizophrenia, according to research by scientists at the University College London (UCL) Genetics Institute. The N-methyl-D-aspartate receptor (NMDAR) is a protein that normally carries signals between brain cells in response to a neurotransmitter called glutamate. Previous research has shown that symptoms of schizophrenia can be caused by drugs that block NMDAR or by antibodies that attack it. Genetic studies have also suggested that molecules associated with NMDAR might be involved in the development of schizophrenia. "These results, and others which are emerging, really focus attention on abnormalities in NMDAR functioning as a risk factor for schizophrenia. Given all the pre-existing evidence, it seems tempting to conclude that genetic variants which by one means or another reduce NMDAR activity could increase the risk of schizophrenia," said Professor David Curtis (UCL Genetics, Evolution & Environment), the psychiatrist who is the senior author of the article reporting the recent findings. For the study, the results of which were published online on January 16, 2019 in Psychiatric Genetics, the DNA sequences of over 4,000 people with schizophrenia and 5,000 controls were used to study variants in the three genes that code for NMDAR (GRIN1, GRIN2A and GRIN2B) and a fourth (FYN), that codes for a protein called Fyn, which controls NMDAR functioning.

Review Examines the Impact of Genome Doubling on Biology of the Cell; Considers Polyploidy, Nucleotype, and Novelty

In an open-access review article titled "Polyploidy, the Nucleotype, and Novelty: The Impact of Genome Doubling on the Biology of the Cell," that was published in the January 2019 print issue of the International Journal of Plant Sciences(180: 1-52), Dr. Jeff J. Doyle and Dr. Jeremy E. Coate examine the effects of genome doubling on cell biology and the generation of novelty in plants. Polyploid organisms are those containing more than two paired (homologous) sets of chromosomes, and polyploidy is common across many plant species. This "genome doubling" generates evolutionary novelty and is a prime facilitator of new species. How polyploidy alters cells to generate novelty, however, is complex, and, as Dr. Doyle (School of Integrative Plant Science, Plant Breeding and Genetics Section, Cornell University) and Dr. Coate (Biology Department, Reed College) illustrate, not well understood, even on a fundamental level. Rapidly developing technology, however, will enable researchers to shed light, not only on this integral part of plant evolution and biology, but also on the function of cells in general. Many of the documented effects of genome doubling on cells, such as increases in cell size, nuclear volume, and cell cycle duration, are hypothesized to be "nucleotypic" – i.e., effects induced by changes in bulk DNA amount, irrespective of genotype. Dr. Doyle and Dr. Coate update our understanding of the nucleotype and other mechanisms by which genome doubling can alter cell biology, highlighting insights gained from studies of synthetic autopolyploids and relating these to the current state of knowledge in the field of cell biology. Cell size, in particular, was of great interest to the authors, because it is strongly associated with genome doubling.

HUGE DISCOVERY REPORTED IN CELL: Activated PMN Exosomes Are Pathogenic Entities That Cause Destruction in COPD Lung; COPD Is Fourth-Leading Cause of Death in World

University of Alabama at Birmingham (UAB) researchers have found a novel, previously unreported pathogenic entity that is a fundamental link between chronic inflammation and tissue destruction in the lungs of patients with chronic obstructive pulmonary disease (COPD). COPD is the fourth-leading cause of death in the world. This pathogenic entity -- exosomes from activated polymorphonuclear leukocytes (PMNs) -- caused COPD damage when the small, subcellular particles, collected from purified PMNs, were instilled into the lungs of healthy mice. Remarkably, the UAB researchers also collected exosomes from the lung fluids of human patients with COPD and the lung fluids of neonatal ICU babies with the lung disease bronchopulmonary dysplasia; when those human-derived exosomes were instilled into the lungs of healthy mice, they also caused COPD lung damage. Damage was primarily from PMN-derived exosomes from the human lungs. "This report seems to provide the first evidence of the capability of a defined non-infectious subcellular entity to recapitulate disease phenotype when transferred from human to mouse," said J. Edwin Blalock, PhD, Professor of Pulmonary, allergy and Critical Care Medicine in the UAB Department of Medicine. "I think this could be a very profound discovery. A lot of what we have found here will apply in other tissues, depending on the disease." Other diseases marked by immune cell inflammation and tissue destruction include heart attacks, metastatic cancer and chronic kidney disease. The activated PMN exosomes may also contribute to lung damage in othelung diseases that have excessive PMN-driven inflammation, such as cystic fibrosis. The study is reported in the prestigious journal Cell.

PMWC 2019 Will Include Two Sessions on Real-World Evidence (RWE); World’s Premier Conference on Precision Medicine Will Take Place in California’s Silicon Valley Jan 20-23; Registration Still Open

The Precision Medicine World Conference 2019 (PMWC 2019) will be held January 20-23 at the Santa Clara Convention Center in California’s Silicon Valley and will include two sessions focused specifically on real-world data (RWD) and real-world evidence RWE). These sessions will bring together top experts, including representatives from Qiagen and N-of-One (400 Speaker Program). Please see additional details on these PMWC sessions on RWD and RWE at the end of this note. Registration for this outstanding PMWC conference is still open and can be accomplished at this link (https://www.pmwcintl.com/registration/?page_scroll=2019sv). In a January 15, 2019 PMWC release, Tal Behar, Co-Founder & President, PMWC Silicon Valley, noted that the FDA has created a framework for evaluating the use of RWE to support additional indications for approved drugs, as well as to satisfy drug post-marketing study requirements. This framework lays out the Agency’s approach to developing guidelines for using RWD in drug regulation. Qiagen announced last week that it has entered into an agreement to acquire N-of-One (both Qiagen & N-of-One will be presenting at PMWC 2019), a molecular decision support company and pioneer in clinical interpretation services for complex genomic data. N-of-One has built a proprietary somatic cancer database of more than 125,000 patient samples. Its technology helps pathologists create reports for clinicians that include genetic variant interpretation, DNA change, effect, and causative condition. RWE collected from a variety of sources offers new insights and opportunities to make better clinical decisions, understand clinical outcomes, and to enable better-informed regulatory decisions.

Exosomes from Nischarin-Expressing Cells Reduce Breast Cancer Cell Motility & Tumor Growth; Researchers Conclude That "Nischarin-Expressing Exosomes in Combination with Drugs Will Likely Have Very Good Therapeutic Effect on Breast Cancer Patients"

Dr. Suresh K Alahari discovered the novel protein, Nischarin, which is involved in a number of biological processes, including the regulation of breast cancer cell migration and movement. Although his lab has shown that Nischarin functions as a tumor suppressor, research continues to uncover new information that may lead to better treatments. In the current study, the research team investigated Nischarin's function in exosome release. Exosomes are nano-sized vesicles (fluid-filled sacs) containing proteins, and genetic and other material involved in both physiological and pathological processes. Tumor-derived exosomes contain various signaling messengers for intercellular communication involved in tumor progression and metastasis of cancer. Tumor exosomes influence the interactions of various types of cells within the tumor microenvironment, regulating tumor development, progression, and metastasis. Primary tumors release exosomes that can enhance seeding and growth of metastatic cancer cells. Among the researchers' findings: Nischarin regulates cell attachment and alters the properties of exosomes. Exosomes from Nischarin-positive cells reduce breast cancer cell motility and adhesion, as well as tumor volume. Nischarin-positive cells release fewer exosomes, and cell survival is decreased. Co-culturing breast cancer cells with Nischarin-positive exosomes decreases tumor growth and lung metastasis. "This novel role for the tumor suppressor Nischarin not only increases our understanding of the exosome biology, but can be translated to identifying new targets for modulating cancer metastasis," notes Dr. Alahari.

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