المؤلفون: Ple, Coline, Fan, Ying, Yahia, Saliha Ait, Vorng, Han, Everaere, Laetitia, Chenivesse, Cécile, Balsamelli, Joanne, Azzaoui, Imane, Nadai, Patricia De, Wallaert, Benoit, Lazennec, Gwendal, Tsicopoulos, Anne

المساهمون: Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

المصدر: ISSN: 1932-6203.

مصطلحات موضوعية: MESH: Adult, MESH: Asthma, MESH: Benzo(a)pyrene, MESH: Receptors, Aryl Hydrocarbon, MESH: Cells, Cultured, MESH: Th17 Cells, MESH: Up-Regulation, MESH: Vehicle Emissions, MESH: CD4-Positive T-Lymphocytes, MESH: Cytochrome P-450 CYP1A1, MESH: Interleukins, MESH: Down-Regulation, MESH: Leukocytes, Mononuclear, MESH: Female, MESH: Humans, MESH: Interleukin-17, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Male, MESH: Polycyclic Aromatic Hydrocarbons, MESH: Middle Aged, MESH: Nuclear Receptor Subfamily 1, Group F, Member 1, Member 3, MESH: Phosphatidylinositol 3-Kinases, MESH: RNA, Messenger

الوصف: International audience ; Background: Pollution, including polyaromatic hydrocarbons (PAH), may contribute to increased

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/25860963; hal-03002029; https://hal.science/hal-03002029Test; https://hal.science/hal-03002029/documentTest; https://hal.science/hal-03002029/file/Ple%202015%20PlosOne2.pdfTest; PUBMED: 25860963; PUBMEDCENTRAL: PMC4393221

الإتاحة: https://doi.org/10.1371/journal.pone.0122372Test
https://hal.science/hal-03002029Test
https://hal.science/hal-03002029/documentTest
https://hal.science/hal-03002029/file/Ple%202015%20PlosOne2.pdfTest

المؤلفون: Jan B. Koenderink, Frans G. M. Russel, Ron H.J. Mathijssen, Marcel M. Verbeek, Laurens F. M. Verscheijden, Saskia N. de Wildt, Carlijn H. C. Litjens

المساهمون: Medical Oncology, Pediatric Surgery

المصدر: Plos Computational Biology, 17
Plos Computational Biology, 17, 3
PLoS Computational Biology, 17(3):e1008786. Public Library of Science
PLoS Computational Biology
PLoS Computational Biology, Vol 17, Iss 3, p e1008786 (2021)

مصطلحات موضوعية: Male, Central Nervous System, Physiology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Pharmacology, 030226 pharmacology & pharmacy, Nervous System, Pediatrics, 0302 clinical medicine, Cerebrospinal fluid, Extracellular fluid, Medicine and Health Sciences, Medicine, Biology (General), Child, Cerebrospinal Fluid, education.field_of_study, Analgesics, Ecology, Morphine, Pharmaceutics, Age Factors, Brain, Drugs, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Body Fluids, Analgesics, Opioid, Computational Theory and Mathematics, Blood-Brain Barrier, Modeling and Simulation, Child, Preschool, Female, Anatomy, medicine.drug, Research Article, Adult, QH301-705.5, Population, Analgesic, Pain, Models, Biological, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dose Prediction Methods, Signs and Symptoms, Pharmacokinetics, Genetics, Humans, Pain Management, ATP Binding Cassette Transporter, Subfamily B, Member 1, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Active metabolite, Morphine Derivatives, business.industry, Infant, Newborn, Computational Biology, Biology and Life Sciences, Opioids, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Pharmacodynamics, Analgesia, Clinical Medicine, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business, 030217 neurology & neurosurgery

الوصف: Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.
Author summary Developmental processes in children can affect pharmacokinetics: “what the body does to the drug” as well as pharmacodynamics: “what the drug does to the body”. A typical example is morphine, of which the analgesic response is variable and particularly neonates suffer more often from respiratory depression, even when receiving doses corrected for differences in elimination. One way to mathematically incorporate developmental processes is by employing physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) models, where physiological differences between individuals are incorporated. In this study, we developed a morphine PB-PK/PD model to predict brain drug disposition as well as analgesic response in adults and children, as both processes could potentially contribute to developmental variability in the effect of morphine. We found that age-related variation in BBB expression of the main morphine efflux transporter P-glycoprotein was not responsible for differences in brain exposure. In contrast, pharmacodynamic modelling suggested an increased sensitivity to morphine in neonates.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d5e0339be4b1c10a3d1579ecfc73dc1Test
https://pure.eur.nl/en/publications/f9227b4f-11c2-4bb0-880f-f0a785a324b5Test

المؤلفون: Hiroki Morishita, Kozue Okawa, Kentaro Yano, Kenta Mizoi, Takuo Ogihara, Misaki Ishii, Hiroshi Arakawa, Masaaki Ito

المصدر: PLoS ONE
PLoS ONE, Vol 15, Iss 10, p e0232438 (2020)

مصطلحات موضوعية: Side effect, Swine, Science, Aripiprazole, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Pimozide, Sertraline, medicine, Animals, Humans, Drug Interactions, ATP Binding Cassette Transporter, Subfamily B, Member 1, P-glycoprotein, Gastrointestinal tract, Multidisciplinary, biology, Chemistry, Biological Transport, Gastrointestinal Absorption, biology.protein, Medicine, LLC-PK1 Cells, Efflux, Caco-2 Cells, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug, Research Article

الوصف: Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate (Jmax) and half-saturation concentration (Kt) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23d5183a21cdd62f59f9796a2915ca8eTest
http://europepmc.org/articles/PMC7595425Test

المؤلفون: Francisco Callejas-Hernández, Jesús Osuna-Pérez, Konstantinos Stamatakis, María C. Maza, Carlos Chillón-Marinas, Cristina Poveda, Núria Gironès, Jossela Calderón, Manuel Fresno, Alfonso Herreros-Cabello

المساهمون: Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Red de Investigación Cooperativa en Enfermedades Tropicales (España)

المصدر: PLoS Neglected Tropical Diseases
Digital.CSIC. Repositorio Institucional del CSIC
instname
PLoS Neglected Tropical Diseases, Vol 14, Iss 9, p e0008608 (2020)

مصطلحات موضوعية: 0301 basic medicine, CD4-Positive T-Lymphocytes, RC955-962, Gene Expression, CD8-Positive T-Lymphocytes, Parasite load, Parasite Load, White Blood Cells, Mice, 0302 clinical medicine, Medical Conditions, Mathematical and Statistical Techniques, Signaling Lymphocytic Activation Molecule Family Member 1, Animal Cells, Arctic medicine. Tropical medicine, Gene expression, Chlorocebus aethiops, Medicine and Health Sciences, Receptor, Protozoans, Trypanosoma Cruzi, Mice, Knockout, Principal Component Analysis, Mice, Inbred BALB C, NADPH oxidase, biology, Statistics, Eukaryota, Heart, Infectious Diseases, Physical Sciences, NADPH Oxidase 2, Disease Susceptibility, Public aspects of medicine, RA1-1270, Cellular Types, Anatomy, Research Article, Trypanosoma, Immune Cells, 030231 tropical medicine, Immunology, Research and Analysis Methods, Parasite Replication, Proinflammatory cytokine, Cell Line, 03 medical and health sciences, Immune system, Parasitic Diseases, Genetics, Animals, Humans, Chagas Disease, Statistical Methods, Trypanosoma cruzi, Vero Cells, Blood Cells, Macrophages, Myocardium, Public Health, Environmental and Occupational Health, Organisms, Biology and Life Sciences, Cell Biology, Dendritic Cells, biology.organism_classification, Molecular biology, Parasitic Protozoans, Gastrointestinal Tract, 030104 developmental biology, HEK293 Cells, Multivariate Analysis, biology.protein, Cardiovascular Anatomy, Parasitology, Reactive Oxygen Species, Digestive System, CD8, Mathematics

الوصف: The receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethal Trypanosoma cruzi Y strain. To elucidate whether genetic diversity of the parasite was related with disease susceptibility, we further analyzed the role of SLAMF1 using 6 different Trypanosoma cruzi strains including Y. The interaction of SLAMF1 receptor with T. cruzi was evidenced by fluorescence microscopy, flow cytometry and quantitative PCR. All the strains, except VFRA, showed a decrease in parasite load in infected macrophages in Slamf1-/- compared to BALB/c. In macrophages gene expression NADPH oxidase (NOX2), and reactive oxygen species (ROS) production increased in Slamf1-/- compared to BALB/c in 5 out of 6 strains. However, Slamf1-/-macrophages infected with VFRA strain exhibited a divergent behavior, with higher parasite load, lower NOX2 expression and ROS production compared to BALB/c. Parasitological and immunological studies in vivo with Y strain showed that in the absence of SLAMF1 the immune response protected mice from the otherwise lethal Y infection favoring a proinflammatory response likely involving CD4, CD8, dendritic cells and classically activated macrophages. In the case of VFRA, no major changes were observed in the absence of SLAMF1. Thus, the results suggest that the T. cruzi affects SLAMF1-dependent ROS production, controlling parasite replication in macrophages and affecting survival in mice in a strain-dependent manner. Further studies will focus in the identification of parasite molecules involved in SLAMF1 interaction to explain the immunopathogenesis of the disease.
Author summary Chagas disease, caused by Trypanosoma cruzi, is characterized by an acute phase, with low mortality, and after many years without any sign of disease, patients develop a symptomatic chronic phase, characterized by cardiomyopathy and/or digestive mega syndromes. These differences have been attributed to the high genetic variability of this parasite. We have shown that the receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethal T. cruzi Y strain. Here we studied in detail the immunopathogenic role of SLAMF1 using 6 genetically diverse strains of T. cruzi using in vitro and in vivo approaches. Our results indicate an important role of SLAMF1 in T. cruzi infection which is parasite strain-dependent. We found that parasites interact with SLAMF1 in macrophages affecting NADPH oxidase (NOX2) expression and reactive oxygen species (ROS) production 5 out of 6 strains tested. Y and VFRA strains showed a divergent behavior in vitro and the role of SLAMF1 in the in vivo infection was also strikingly different. The Y strain caused 70% mortality in BALB/c mice but not in Slamf1-/- mice. The proinflammatory response was stronger in the last, suggesting that SLAMF1 was repressing protective immune responses of mice infected with the Y strain. In contrast, for VFRA, SLAMF1 deficiency resulted in 100% survival of BALB/c mice, without major changes in the immune response in the absence of SLAMF1. Thus, the results indicate that SLAMF1 receptor interacts with T. cruzi, affecting parasite replication and ROS production in macrophages as well as the adaptive immune response in mice in a parasite strain-dependent manner. Future studies will focus in understanding the immunopathogenic role of SLAMF1 during T. cruzi infection.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5e57a7358b0bf107123032e6ad1382c0Test
http://europepmc.org/articles/PMC7515593Test

المؤلفون: Eung Kweon Kim, Heejei Yoon, Young Hyeh Ko

المصدر: PLoS ONE
PLoS ONE, Vol 15, Iss 9, p e0238791 (2020)

مصطلحات موضوعية: 0301 basic medicine, Cell signaling, Herpesvirus 4, Human, B Cells, Apoptosis, Artificial Gene Amplification and Extension, Signal transduction, medicine.disease_cause, Polymerase Chain Reaction, Pathogenesis, White Blood Cells, 0302 clinical medicine, Spectrum Analysis Techniques, Signaling Lymphocytic Activation Molecule Family Member 1, Animal Cells, Medicine and Health Sciences, Tumor Cells, Cultured, Cell Cycle and Cell Division, AKT signaling cascade, Fluorescence-Activated Cell Sorting, B-Lymphocytes, Multidisciplinary, Cell Death, Signaling cascades, Cell cycle, medicine.anatomical_structure, Cell Processes, Spectrophotometry, 030220 oncology & carcinogenesis, Medicine, Cytophotometry, Cellular Types, Research Article, Cell Survival, Science, Immune Cells, Immunology, Biology, Research and Analysis Methods, 03 medical and health sciences, medicine, Humans, Antibody-Producing Cells, Molecular Biology Techniques, Molecular Biology, B cell, Cell Proliferation, Blood Cells, Akt/PKB signaling pathway, Cell growth, Biology and Life Sciences, Cell Biology, Epstein–Barr virus, 030104 developmental biology, Cell culture, Cancer research, Proto-Oncogene Proteins c-akt, Cloning

الوصف: SLAMF1 is often overexpressed in Epstein Barr virus (EBV)-infected B cell tumors. However, its role in the pathogenesis of EBV-infected B cell tumors remains largely unknown. Here, we generated SLAMF1-deficient EBV+ tumor cells and examined the effect of its deficiency on cell proliferation and cell survival. There were no significant differences in cell proliferation and cell cycle distribution for short periods between the SLAMF1-deficient and wild-type cells. However, the deficient cells were more resistant to an AKT inhibitor (MK-2206). When the both cells were co-cultured and repeatedly exposed to the limitations in nutrition and growth factors, the SLAMF1-deficient cells were gradually decreased. We observed that levels of phospho-AKT were differentially regulated according to the nutritional status between the SLAMF1-deficient and wild-type cells. A decrease in phospho-AKT was observed in SLAMF1-deficient cells as well as an increase in pro-apoptotic Bim just before cell passage, which may have been due to the loss of SLAMF1 under poor growth condition. Overall, SLAMF1 is not a strong survival factor, but it seems to be necessary for cell survival in unfavorable growth condition.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34ee62949623d299d6f7eccfb679aa94Test
http://europepmc.org/articles/PMC7473542Test

المؤلفون: Sudha Seshadri, John Hardy, Wolfgang Maier, Janet C Harwood, Emily Baker, Carol Brayne, Julie Williams, Lesley Jones, Gerard D. Schellenberg, Reinhard Heun, Frank Jessen, Valentina Escott-Price, Matthew Hill, Oliver Peters, John Powell, Dobril Ivanov, Peter Passmore, Martin Dichgans, Lutz Frölich, Alfredo Ramirez, Aura Frizzati, Alison Goate, Kevin Morgan, Paul Morgan, Carlos Cruchaga, Ganna Leonenko, Gianfranco Spalletta, Paola Bossù, Michael Gill, Clive Holmes, Simon Mead, Detelina Grozeva, Peter Holmans, Philippe Amouyel, Rebecca Sims, Nicholas D. Allen

المساهمون: Baker, Emily [0000-0001-5691-597X], Grozeva, Detelina [0000-0003-3239-8415], Brayne, Carol [0000-0001-5307-663X], Mead, Simon [0000-0002-4326-1468], Ramirez, Alfredo [0000-0003-4991-763X], Ivanov, Dobril [0000-0001-6271-6301], Hill, Matthew [0000-0001-6776-8709], Holmans, Peter [0000-0003-0870-9412], Schellenberg, Gerard D [0000-0003-1115-2475], Apollo - University of Cambridge Repository, van Duijn, Cornelia [0000-0002-2374-9204], Williams, Julie [0000-0002-4069-0259]

المصدر: PLoS ONE
PLoS ONE, Vol 14, Iss 7, p e0218111 (2019)
PLOS ONE 14(7), e0218111 (2019). doi:10.1371/journal.pone.0218111

مصطلحات موضوعية: 0301 basic medicine, Male, DNA Repair, Gene Expression, Social Sciences, genetics [Alzheimer Disease], genetics [Cholesterol], Genome-wide association study, Alzheimer's Disease, Biochemistry, IGAP consortia, pathology [Centrosome], pathology [Alzheimer Disease], 0302 clinical medicine, Sociology, metabolism [Centrosome], Consortia, Medicine and Health Sciences, genetics [Amyloid beta-Peptides], Genetics, Regulation of gene expression, metabolism [Inflammation], Multidisciplinary, biology, metabolism [Proteins], Neurodegenerative Diseases, Nuclear Receptor Subfamily 1, Group F, Member 1, Genomics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Circadian Rhythm, Circadian Rhythms, Cholesterol, Neurology, Medicine, Female, metabolism [Alzheimer Disease], Research Article, medicine.medical_specialty, genetics [Circadian Rhythm], Amyloid beta, Science, Lipoproteins, metabolism [Amyloid beta-Peptides], Single-nucleotide polymorphism, genetics [Energy Metabolism], Polymorphism, Single Nucleotide, GERAD Consortium, Apolipoprotein Genes, Molecular Genetics, genetics [Inflammation], 03 medical and health sciences, Alzheimer Disease, genetics [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], Molecular genetics, Mental Health and Psychiatry, medicine, Genome-Wide Association Studies, GERAD/PERADES, Dementia, Humans, genetics [DNA Damage], Gene Regulation, ddc:610, genetics [DNA Repair], Gene, Molecular Biology, EADI Consortium, pathology [Inflammation], Centrosome, Inflammation, Amyloid beta-Peptides, Genome, Human, Biology and Life Sciences, Proteins, Computational Biology, Human Genetics, metabolism [Cholesterol], medicine.disease, Genome Analysis, ADGC Consortium, genetics [Proteins], 030104 developmental biology, metabolism [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], CHARGE Consortium, biology.protein, Energy Metabolism, Chronobiology, 030217 neurology & neurosurgery, genetics [Nuclear Receptor Subfamily 1, Group F, Member 1], metabolism [Nuclear Receptor Subfamily 1, Group F, Member 1], DNA Damage, Genome-Wide Association Study

الوصف: A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

وصف الملف: application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::caad960b1629d3f30b5bbfa303783204Test
http://europepmc.org/articles/PMC6613773Test

المؤلفون: Claudia Joppert, Madeeha Froze Mughal, Evgeny Bisk, Kara M. Ryan, Rana Said, Kathryn C. Asalone, Annastelle L. Cohen, Deborah J. George, Metin Toksoz-Exley, William G. Farmer, John R. Bracht, Kaitlyn Kim, Maryam Yamadi

المصدر: PLoS Computational Biology
PLoS Computational Biology, Vol 16, Iss 7, p e1008104 (2020)

مصطلحات موضوعية: 0301 basic medicine, Heredity, Nematoda, Proteome, Sequence assembly, Genome, Infographics, Loss of heterozygosity, Database and Informatics Methods, Contig Mapping, 0302 clinical medicine, Biology (General), Data Management, Likelihood Functions, Heterozygosity, Ecology, Gene Ontologies, High-Throughput Nucleotide Sequencing, Phylogenetic Analysis, Genome project, Genomics, Phylogenetics, Computational Theory and Mathematics, Modeling and Simulation, Sequence Analysis, Graphs, Algorithms, Research Article, Computer and Information Sciences, Heterozygote, QH301-705.5, Bioinformatics, Gene prediction, Sequence alignment, Computational biology, Biology, Research and Analysis Methods, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetics, Animals, Evolutionary Systematics, ATP Binding Cassette Transporter, Subfamily B, Member 1, Gene Prediction, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Sequence (medicine), Taxonomy, Evolutionary Biology, Genome, Helminth, Data Visualization, Biology and Life Sciences, Computational Biology, Molecular Sequence Annotation, Sequence Analysis, DNA, Genome Analysis, Genome Annotation, 030104 developmental biology, Sequence Alignment, 030217 neurology & neurosurgery

الوصف: High levels of heterozygosity present a unique genome assembly challenge and can adversely impact downstream analyses, yet is common in sequencing datasets obtained from non-model organisms. Here we show that by re-assembling a heterozygous dataset with variant parameters and different assembly algorithms, we are able to generate assemblies whose protein annotations are statistically enriched for specific gene ontology categories. While total assembly length was not significantly affected by assembly methodologies tested, the assemblies generated varied widely in fragmentation level and we show local assembly collapse or expansion underlying the enrichment or depletion of specific protein functional groups. We show that these statistically significant deviations in gene ontology groups can occur in seemingly high-quality assemblies, and result from difficult-to-detect local sequence expansion or contractions. Given the unpredictable interplay between assembly algorithm, parameter, and biological sequence data heterozygosity, we highlight the need for better measures of assembly quality than N50 value, including methods for assessing local expansion and collapse.
Author summary In the genomic era, genomes must be reconstructed from fragments using computational methods, or assemblers. How do we know that a new genome assembly is correct? This is important because errors in assembly can lead to downstream problems in gene predictions and these inaccurate results can contaminate databases, affecting later comparative studies. A particular challenge occurs when a diploid organism inherits two highly divergent genome copies from its parents. While it is widely appreciated that this type of data is difficult for assemblers to handle properly, here we show that the process is prone to more errors than previously appreciated. Specifically, we document examples of regional expansion and collapse, affecting downstream gene prediction accuracy, but without changing the overall genome assembly size or other metrics of accuracy. Our results suggest that assembly evaluation methods should be altered to identify whether regional expansions and collapses are present in the genome assembly.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e58e9f8279b456aafc509b8f04041b8Test
http://europepmc.org/articles/PMC7423139Test

المؤلفون: Yuanhai Li, Zeyong Yang, Shuguang Yu, Dengfeng Huang, Jie He, Haifang Wang, Xingxing Li, Jun Yan

المصدر: PLoS Biology
PLoS Biology, Vol 18, Iss 3, p e3000435 (2020)

مصطلحات موضوعية: Embryo, Nonmammalian, Cell, Circadian clock, Artificial Gene Amplification and Extension, Pineal Gland, Biochemistry, Polymerase Chain Reaction, Animals, Genetically Modified, Pineal gland, Single-cell analysis, Medicine and Health Sciences, Biology (General), Promoter Regions, Genetic, Zebrafish, photoperiodism, General Neuroscience, Methods and Resources, Brain, Eukaryota, Animal Models, Cell biology, Circadian Rhythm, CLOCK, Circadian Oscillators, Circadian Rhythms, medicine.anatomical_structure, Experimental Organism Systems, Osteichthyes, Vertebrates, Genetic Oscillators, Single-Cell Analysis, Anatomy, General Agricultural and Biological Sciences, QH301-705.5, Imaging Techniques, Fish Biology, Photoperiod, Endocrine System, Biology, Research and Analysis Methods, Time-Lapse Imaging, General Biochemistry, Genetics and Molecular Biology, Model Organisms, Bacterial Proteins, Circadian Clocks, Fluorescence Imaging, medicine, Fish Physiology, Genetics, Animals, Animal Physiology, Circadian rhythm, Molecular Biology Techniques, Molecular Biology, General Immunology and Microbiology, Organisms, Correction, Biology and Life Sciences, biology.organism_classification, Vertebrate Physiology, Luminescent Proteins, Fish, Nuclear Receptor Subfamily 1, Group D, Member 1, Animal Studies, Chronobiology, Zoology

الوصف: The circadian clock is a cell-autonomous time-keeping mechanism established gradually during embryonic development. Here, we generated a transgenic zebrafish line carrying a destabilized fluorescent protein driven by the promoter of a core clock gene, nr1d1, to report in vivo circadian rhythm at the single-cell level. By time-lapse imaging of this fish line and 3D reconstruction, we observed the sequential initiation of the reporter expression starting at photoreceptors in the pineal gland, then spreading to the cells in other brain regions at the single-cell level. Even within the pineal gland, we found heterogeneous onset of nr1d1 expression, in which each cell undergoes circadian oscillation superimposed over a cell type–specific developmental trajectory. Furthermore, we found that single-cell expression of nr1d1 showed synchronous circadian oscillation under a light–dark (LD) cycle. Remarkably, single-cell oscillations were dramatically dampened rather than desynchronized in animals raised under constant darkness, while the developmental trend still persists. It suggests that light exposure in early zebrafish embryos has significant effect on cellular circadian oscillations.
A transgenic zebrafish line, nr1d1-VNP, enables the monitoring of single-cell circadian rhythms in live zebrafish; using this fish line, the authors find that light exposure in early development initializes rather than synchronizes single-cell oscillators.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6654c31a06c7e5acb074f30c56aee08fTest
http://europepmc.org/articles/PMC7069618Test

المؤلفون: Ishaque Pulikkal Kadamberi, Seong C. Kim, Asoka Banno, Sowmya P. Lakshmi, Raju C. Reddy, Shantanu Krishna Jadhav, Aravind T. Reddy

المصدر: PLoS ONE
PLoS ONE, Vol 15, Iss 2, p e0229256 (2020)

مصطلحات موضوعية: 0301 basic medicine, Threonine, Pulmonology, Physiology, Social Sciences, Gene Expression, Pathology and Laboratory Medicine, Epithelium, Habits, Mice, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Animal Cells, Immune Physiology, Smoke, Medicine and Health Sciences, Smoking Habits, Nuclear Receptor Subfamily 4, Group A, Member 1, Medicine, Psychology, Phosphorylation, Immune Response, Lung, COPD, Innate Immune System, Multidisciplinary, Transcriptional Control, Animal Models, respiratory system, 3. Good health, medicine.anatomical_structure, Experimental Organism Systems, 030220 oncology & carcinogenesis, Cytokines, Signal transduction, medicine.symptom, Cellular Types, Anatomy, Research Article, Nerve growth factor IB, Science, Chronic Obstructive Pulmonary Disease, Inflammatory Diseases, Immunology, Down-Regulation, Inflammation, Mouse Models, Research and Analysis Methods, 03 medical and health sciences, Signs and Symptoms, Model Organisms, Downregulation and upregulation, In vivo, Diagnostic Medicine, Tobacco, Genetics, Animals, Humans, Gene Regulation, Behavior, business.industry, Wild type, Biology and Life Sciences, Epithelial Cells, Cell Biology, Molecular Development, medicine.disease, respiratory tract diseases, 030104 developmental biology, Biological Tissue, Immune System, Animal Studies, business, Developmental Biology

الوصف: Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-κB signaling pathway. Because it is unknown if Nur77's anti-inflammatory role modulates COPD, we assessed if and how Nur77 expression and activity are altered in CS-induced airway inflammation. In lung tissues and bronchial epithelial cells from COPD patients, we found Nur77 was downregulated. In a murine model of CS-induced airway inflammation, CS promoted lung inflammation and also reduced Nur77 activity in wild type (WT) mice, whereas lungs of Nur77-deficient mice showed exaggerated CS-induced inflammatory responses. Our findings in in vitro studies of human airway epithelial cells complemented those in vivo data in mice, together showing that CS induced threonine-phosphorylation of Nur77, which is known to interfere with its anti-inflammatory functions. In summary, our findings point to Nur77 as an important regulator of CS-induced inflammatory responses and support the potential benefits of Nur77 activation for COPD treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6953f788d7531ae9dc7038fcf272b4faTest
http://europepmc.org/articles/PMC7034866Test

المصدر: PLoS ONE

مصطلحات موضوعية: Adult, Male, Research Validity, ATP Binding Cassette Transporter, Subfamily B, Adolescent, Gene Expression, Research and Analysis Methods, Hematologic Cancers and Related Disorders, Phosphatidylinositol 3-Kinases, Young Adult, Antigens, CD, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemias, Medicine and Health Sciences, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Small Interfering, Child, Aged, Gene Expression Regulation, Leukemic, Cancers and Neoplasms, Hematology, Research Assessment, Middle Aged, Drug Resistance, Multiple, Sialyltransferases, Retraction, Leukemia, Myeloid, Acute, Oncology, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Female, Multidrug Resistance-Associated Proteins, K562 Cells, Proto-Oncogene Proteins c-akt

الوصف: β-Galactoside α2, 6-sialyltransferse gene (ST6GAL) family has two members, which encode corresponding enzymes ST6Gal I and ST6Gal II. The present atudy was to investigate whether and how ST6GAL family involved in multidrug resistance (MDR) in human leukemia cell lines and bone marrow mononuclear cells (BMMC) of leukemia patients. Real-time PCR showed a high expression level of ST6GAL1 gene in both MDR cells and BMMCs (*P0.05). Alternation of ST6GAL1 levels had a significant impact on drug-resistant phenotype changing of K562 and K562/ADR cells both in vitro and in vivo. However, no significant changes were observed of ST6GAL2 gene. Further data revealed that manipulation of ST6GAL1 modulated the activity of phosphoinositide 3 kinase (PI3K)/Akt signaling and consequently regulated the expression of P-glycoprotein (P-gp, *P0.05) and multidrug resistance related protein 1 (MRP1, *P0.05), which are both known to be associated with MDR. Therefore we postulate that ST6GAL1 is responsible for the development of MDR in human leukemia cells probably through medicating the activity of PI3K/Akt signaling and the expression of P-gp and MRP1.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::36536c1f795ce3650031896cc3949beaTest
http://europepmc.org/articles/PMC6797186Test