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Gene drive

Yawara Kawano, Oksana Zavidij, Jihye Park, Michele Moschetta, Katsutoshi Kokubun, Tarek H Mouhieddine, Salomon Manier, Yuji Mishima, Naoka Murakami, Mark Bustoros, Romanos Sklavenitis Pistofidis, Mairead Reidy, Yu J Shen, Mahshid Rahmat, Pavlo Lukyanchykov, Esilida Sula Karreci, Shokichi Tsukamoto, Jiantao Shi, Satoshi Takagi, Daisy Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P Leif Bergsagel, Aldo M Roccaro, Jamil Azzi, Irene M Ghobrial
Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression, is the expansion of regulatory T-cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type-1 interferon (IFN). Blocking IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosuppressive function and myeloma progression...
March 20, 2018: Journal of Clinical Investigation
Amna Zehra, Jamie Burns, Christopher Kure Liu, Peter Manza, Corinde E Wiers, Nora D Volkow, Gene-Jack Wang
Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. Here we evaluate cannabis use through the neurobiological model of addiction proposed by Koob and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated into three distinct stages, each of which perpetuates the cycle of addiction...
March 19, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Laura A Hug, Rebecca Co
An enduring theme in microbial ecology is the interdependence of microbial community members. Interactions between community members include provision of cofactors, establishment of redox gradients, and turnover of key nutrients to drive biogeochemical cycles. Pathways canonically conducted by isolated organisms in laboratory cultures are instead collective products of diverse and interchangeable microbes in the environment. Current sequence-based methods provide unprecedented access to uncultivated microorganisms, allowing prediction of previously cryptic roles in biogeochemical cycles and interactions within communities...
March 2018: MSystems
Goro Katsuumi, Ippei Shimizu, Yohko Yoshida, Tohru Minamino
In mammals, aging is associated with accumulation of senescent cells. Stresses such as telomere shortening and reactive oxygen species induce "cellular senescence", which is characterized by growth arrest and alteration of the gene expression profile. Chronological aging is associated with development of age-related diseases, including heart failure, diabetes, and atherosclerotic disease, and studies have shown that accumulation of senescent cells has a causative role in the pathology of these age-related disorders...
2018: Frontiers in Cardiovascular Medicine
Judith A Smith
Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defense against pathogens, but when aberrantly produced, may also drive pathologic inflammation...
2018: Frontiers in Immunology
Anniina Vihervaara, Fabiana M Duarte, John T Lis
Proteotoxic stress, that is, stress caused by protein misfolding and aggregation, triggers the rapid and global reprogramming of transcription at genes and enhancers. Genome-wide assays that track transcriptionally engaged RNA polymerase II (Pol II) at nucleotide resolution have provided key insights into the underlying molecular mechanisms that regulate transcriptional responses to stress. In addition, recent kinetic analyses of transcriptional control under heat stress have shown how cells 'prewire' and rapidly execute genome-wide changes in transcription while concurrently becoming poised for recovery...
March 19, 2018: Nature Reviews. Genetics
C Vega-Retter, N Rojas-Hernandez, I Vila, R Espejo, D E Loyola, S Copaja, M Briones, A W Nolte, D Véliz
How organisms adapt to unfavorable environmental conditions by means of plasticity or selection of favorable genetic variants is a central issue in evolutionary biology. In the Maipo River basin, the fish Basilichthys microlepidotus inhabits polluted and non-polluted areas. Previous studies have suggested that directional selection drives genomic divergence between these areas in 4% of Amplified Fragment Length Polymorphism (AFLP) loci, but the underlying genes and functions remain unknown. We hypothesized that B...
March 19, 2018: Scientific Reports
Daichi Inoue, Takeshi Fujino, Paul Sheridan, Yao-Zhong Zhang, Reina Nagase, Sayuri Horikawa, Zaomin Li, Hirotaka Matsui, Akinori Kanai, Makoto Saika, Rui Yamaguchi, Hiroko Kozuka-Hata, Kimihito Cojin Kawabata, Akihiko Yokoyama, Susumu Goyama, Toshiya Inaba, Seiya Imoto, Satoru Miyano, Mingjiang Xu, Feng-Chun Yang, Masaaki Oyama, Toshio Kitamura
ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kiyomichi Imamura, Hikari Yoshitane, Kazuki Hattori, Mitsuo Yamaguchi, Kento Yoshida, Takenori Okubo, Isao Naguro, Hidenori Ichijo, Yoshitaka Fukada
Daily rhythms of behaviors and physiologies are generated by the circadian clock, which is composed of clock genes and the encoded proteins forming transcriptional/translational feedback loops (TTFLs). The circadian clock is a self-sustained oscillator and flexibly responds to various time cues to synchronize with environmental 24-h cycles. However, the key molecule that transmits cellular stress to the circadian clockwork is unknown. Here we identified apoptosis signal-regulating kinase (ASK), a member of the MAPKKK family, as an essential mediator determining the circadian period and phase of cultured cells in response to osmotic changes of the medium...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Joke Terryn, Tine Tricot, Madhavsai Gajjar, Catherine Verfaillie
Pluripotent stem cells have the property of long-term self-renewal and the potential to give rise to descendants of the three germ layers and hence all mature cells in the human body. Therefore, they hold the promise of offering insight not only into human development but also for human disease modeling and regenerative medicine. However, the generation of mature differentiated cells that closely resemble their in vivo counterparts remains challenging. Recent advances in single-cell transcriptomics and computational modeling of gene regulatory networks are revealing a better understanding of lineage commitment and are driving modern genome editing approaches...
2018: F1000Research
Daniel Pensold, Geraldine Zimmer
The correct establishment of inhibitory circuits is crucial for cortical functionality and defects during the development of γ-aminobutyric acid-expressing cortical interneurons contribute to the pathophysiology of psychiatric disorders. A critical developmental step is the migration of cortical interneurons from their site of origin within the subpallium to the cerebral cortex, orchestrated by intrinsic and extrinsic signals. In addition to genetic networks, epigenetic mechanisms such as DNA methylation by DNA methyltransferases (DNMTs) are suggested to drive stage-specific gene expression underlying developmental processes...
2018: Journal of Experimental Neuroscience
Michela Lupia, Francesca Angiolini, Giovanni Bertalot, Stefano Freddi, Kris F Sachsenmeier, Elisa Chisci, Barbara Kutryb-Zajac, Stefano Confalonieri, Ryszard T Smolenski, Roberto Giovannoni, Nicoletta Colombo, Fabrizio Bianchi, Ugo Cavallaro
Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs...
March 10, 2018: Stem Cell Reports
Anna Rubio-Cosials, Eike C Schulz, Lotte Lambertsen, Georgy Smyshlyaev, Carlos Rojas-Cordova, Kristoffer Forslund, Ezgi Karaca, Aleksandra Bebel, Peer Bork, Orsolya Barabas
Conjugative transposition drives the emergence of multidrug resistance in diverse bacterial pathogens, yet the mechanisms are poorly characterized. The Tn1549 conjugative transposon propagates resistance to the antibiotic vancomycin used for severe drug-resistant infections. Here, we present four high-resolution structures of the conserved Y-transposase of Tn1549 complexed with circular transposon DNA intermediates. The structures reveal individual transposition steps and explain how specific DNA distortion and cleavage mechanisms enable DNA strand exchange with an absolute minimum homology requirement...
March 2, 2018: Cell
Grant C O'Connell, Madison B Treadway, Connie S Tennant, Noelle Lucke-Wold, Paul D Chantler, Taura L Barr
Our group recently identified a panel of ten genes whose RNA expression levels in whole blood have utility for detection of stroke. The purpose of this study was to determine the mechanisms by which these genes become differentially expressed during stroke pathology. First, we assessed the transcriptional distribution of the ten genes across the peripheral immune system by measuring their expression levels on isolated neutrophils, monocytes, B-lymphocytes, CD-4+ T-lymphocytes, CD-8+ T-lymphocytes, and NK-cells generated from the blood of healthy donors (n = 3)...
March 17, 2018: Translational Stroke Research
Kozue Uchio-Yamada, Mayuri Tanaka, Noboru Manabe
C1s deficiency is strongly associated with the development of human systemic lupus erythematosus (SLE); however, the mechanisms by which C1s deficiency contributes to the development of SLE have not yet been elucidated in detail. Using ICR-derived-glomerulonephritis (ICGN) mouse strain that develops SLE and very weakly expresses C1s in the liver, we investigated the protective roles of C1s against SLE. A genetic sequence analysis revealed complete deletion of the C1s1 gene, a mouse homolog of the human C1s gene, with partial deletion of the C1ra and C1rb genes in the ICGN strain...
March 18, 2018: Genes and Immunity
Vaideesh Parasaram, Nasim Nosoudi, Aniqa Chowdhury, Naren Vyavahare
mphysema is characterized by degradation of lung alveoli that leads to poor airflow in lungs. Irreversible elastic fiber degradation by matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) activity leads to loss of elasticity and drives the progression of this disease. We investigated if a polyphenol, pentagalloyl glucose (PGG) can increase elastin production in pulmonary fibroblasts. We also studied the effect of PGG treatment in reducing MMP activity and ROS levels in cells. We exposed rat pulmonary fibroblasts to two different types of inflammatory environments i...
March 14, 2018: Biochemical and Biophysical Research Communications
Anny Waloski Robert, Addeli Bez Batti Angulski, Lucia Spangenberg, Patrícia Shigunov, Isabela Tiemy Pereira, Paulo Sergio Loiacono Bettes, Hugo Naya, Alejandro Correa, Bruno Dallagiovanna, Marco Augusto Stimamiglio
Mesenchymal stem cells (MSCs) have been widely studied with regard to their potential use in cell therapy protocols and regenerative medicine. However, a better comprehension about the factors and molecular mechanisms driving cell differentiation is now mandatory to improve our chance to manipulate MSC behavior and to benefit future applications. In this work, we aimed to study gene regulatory networks at an early step of osteogenic differentiation. Therefore, we analyzed both the total mRNA and the mRNA fraction associated with polysomes on human adipose tissue-derived stem cells (hASCs) at 24 h of osteogenesis induction...
March 16, 2018: Scientific Reports
Zachary S Lorsch, Yong-Hwee Eddie Loh, Immanuel Purushothaman, Deena M Walker, Eric M Parise, Marine Salery, Michael E Cahill, Georgia E Hodes, Madeline L Pfau, Hope Kronman, Peter J Hamilton, Orna Issler, Benoit Labonté, Ann E Symonds, Matthew Zucker, Tie Yuan Zhang, Michael J Meaney, Scott J Russo, Li Shen, Rosemary C Bagot, Eric J Nestler
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression...
March 16, 2018: Nature Communications
Yu Chen, Zhen Li, Zhu Xu, Huanyin Tang, Wenxuan Guo, Xiaoxiang Sun, Wenjun Zhang, Jian Zhang, Xiaoping Wan, Ying Jiang, Zhiyong Mao
The homologous recombination (HR) pathway is a promising target for cancer therapy as it is frequently upregulated in tumors. One such strategy is to target tumors with cancer-specific, hyperactive promoters of HR genes including RAD51 and RAD51C. However, the promoter size and the delivery method have limited its potential clinical applications. Here we identified the ~2.1 kb promoter of XRCC2, similar to ~6.5 kb RAD51 promoter, as also hyperactivated in cancer cells. We found that XRCC2 expression is upregulated in nearly all types of cancers, to a degree comparable to RAD51 while much higher than RAD51C...
March 16, 2018: Cell Death & Disease
Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
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