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Deep learning for the earth sciences : a comprehensive approach to remote sensing, climate science and geosciences
DEEP LEARNING FOR THE EARTH SCIENCES Explore this insightful treatment of deep learning in the field of earth sciences, from four leading voices Deep learning is a fundamental technique in modern Artificial Intelligence and is being applied to disciplines across the scientific spectrum; earth science is no exception.
eBook
Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone
Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934
Journal Article
Short O-GlcNAcase Is Targeted to the Mitochondria and Regulates Mitochondrial Reactive Oxygen Species Level
O-GlcNAcylation is a reversible post-translational modification involved in the regulation of cytosolic, nuclear, and mitochondrial proteins. Only two enzymes, OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase), control the attachment and removal of O-GlcNAc on proteins, respectively. Whereas a variant OGT (mOGT) has been proposed as the main isoform that O-GlcNAcylates proteins in mitochondria, identification of a mitochondrial OGA has not been performed yet. Two splice variants of OGA (short and long isoforms) have been described previously. In this work, using cell fractionation experiments, we show that short-OGA is preferentially recovered in mitochondria-enriched fractions from HEK-293T cells and RAW 264.7 cells, as well as mouse embryonic fibroblasts. Moreover, fluorescent microscopy imaging confirmed that GFP-tagged short-OGA is addressed to mitochondria. In addition, using a Bioluminescence Resonance Energy Transfer (BRET)-based mitochondrial O-GlcNAcylation biosensor, we show that co-transfection of short-OGA markedly reduced O-GlcNAcylation of the biosensor, whereas long-OGA had no significant effect. Finally, using genetically encoded or chemical fluorescent mitochondrial probes, we show that short-OGA overexpression increases mitochondrial ROS levels, whereas long-OGA has no significant effect. Together, our work reveals that the short-OGA isoform is targeted to the mitochondria where it regulates ROS homoeostasis.
Journal Article
سيرة ألبرت هيرشمان الفكرية
يفتش هذا الكتاب في حياة عالم بارز من علماء الاجتماع في القرن العشرين، ويلخص لك فكره وعقله وعمله وجوانب كثيرة من حياته ابتداء من أعماله في التنمية الاقتصادية وخاصة في أمريكا اللاتينية إلى مساهماته التي عقبت ذلك في الاقتصاد السياسي والنظريات الاجتماعية. وفيه يقص علينا مؤلفه ميشيل الاسيفيتش مبادئ حياة هيرشيمان التي ارتكز عليها، ويبين لنا أثره في العلوم الاجتماعية المعاصرة بتتبع سيرته من أولها إلى آخرها، وبتفحص خبراته وتجاربه في العلوم والآداب والحياة، إن هذا الكتاب له شأن في بابه، ولكل أحد يود أن ينظر في أفكار هيرشمان وأثرها في علوم الناس الاجتماعية، وهو مع هذا مرجع غني من مصادر المعرفة للمنشغلين في أبواب علوم الفكر والاقتصاد والاجتماع والسياسة.
Book
ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials
Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study (
NCT03248882
) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study (
NCT03776175
) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging–proton density fat fraction. Dose-dependent reductions in liver fat reached 50–65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was −7.2 (−13.9, 0.0), −17.1 (−22.7, −11.1), −49.9 (−53.3, −46.2), −55.9 (−59.0, −52.4) and −64.8 (−67.5, −62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) −44.6% (−54.8, −32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was −44.5% (−55.0, −31.7) and −35.4% (−47.4, −20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.
Two phase 2a trials demonstrate the efficacy of a new ACC inhibitor (PF 05221304) for reducing liver fat in patients with NAFLD, with co-administration of a DGAT2 inhibitor (PF-06865571) mitigating ACC inhibitor-mediated increases in serum triglycerides.
Journal Article
Dopamine, Locus of Control, and the Exploration-Exploitation Tradeoff
Whether to continue to exploit a source of reward, or to search for a new one of potentially greater value, is a fundamental and underconstrained decision. Recent computational studies of this exploration-exploitation tradeoff have found that variability in exploration across individuals is influenced by a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene, whose protein product degrades synaptically released dopamine. However, these and other genotype-phenotype associations have rarely been causally tested. To directly test this association and to evaluate additional behavioral characteristics, including perceived locus of control (LOC), here we used the COMT inhibitor tolcapone in a randomized, double-blind, counterbalanced, within-subject study of 66 subjects genotyped for the Val158Met allele to assess the hypothesis that reducing COMT enzymatic activity interacts with genotype to increase uncertainty-driven exploration. In keeping with our initial hypothesis, tolcapone led to an increase in exploratory, but not exploitative, behavior in Met/Met rather than Val/Val subjects. Independent of genotype, those subjects with a more external LOC also showed increases in uncertainty-driven exploration on tolcapone relative to placebo. However, we did not replicate our previous finding that Met/Met subjects show greater exploration at baseline. Together these findings support a model in which exploration is hypothesized to have a dopaminergic basis. Moreover, in keeping with findings in other behavioral and cognitive domains, the response to an increase in presumptively frontal dopamine is dependent upon baseline dopamine tone.
Journal Article