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Found 34492 matches. Displaying 41-50
Okamato M, Gray JD, Larson CS, Kazim SF, Soya H, McEwen BS, Pereira AC
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Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease (vol 8, 153, 2018)

TRANSLATIONAL PSYCHIATRY 2019 FEB 4; 9(?):? Article 61
Li HL, O'Donnell ME
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DNA replication from two different worlds

SCIENCE 2019 FEB 22; 363(6429):814-815
Seki T, Liu JY, Brutkiewicz RR, Tsuji M
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A Potent CD1d-binding Glycolipid for iNKT-Cell-based Therapy Against Human Breast Cancer

ANTICANCER RESEARCH 2019 FEB; 39(2):549-555
Background/Aim: Invariant natural killer T-cells (iNKT) stimulated by CD1d-binding glycolipids have been shown to exert antitumor effects by a number of studies in a mouse model. Breast cancer is a devastating disease, with different types of breast cancer recurring locally or distant as metastatic/advanced disease following initial treatment. The aim of this study was to examine the tumoricidal effect of a CD1d-binding glycolipid, called 7DW8-5, against a highly invasive human breast cancer cell line both in vitro and in vivo. Materials and Methods: Parental MDA-MB-231 cells and MDA-MB-231 cells transduced with human CD1d were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE), followed by loading with glycolipids. After co-culturing with human iNKT cells, the cells were permeabilized and stained with Alexa Flour 647-conjugated antibody to active caspase-3, and analyzed using a BD LSR II. For the in vivo tumoricidal effect, MDA-MB-231 cells transduced with human CD1d and luciferase genes were injected into the mammary fat pad of female NOD/SCID/IL2r gamma null (NSG) mice, followed by the injection of human iNKT cells with or without 7DW8-5, and the levels of luminescence were analyzed with whole-body imaging. Results: Human iNKT cells could kill CD1d-expressing human breast cancer cells in vitro in the presence of 7DW8-5, but not a-GalCer. As for in vivo, the adoptive transfer of human iNKT cells into tumor-challenged NSG mice significantly inhibited the growth of CD1d+ MDA-MB-231 human breast cancer cells in the presence of 7DW8-5. Conclusion: CD1d-binding, glycolipid-based iNKT-cell therapy is suggested as a potent and effective treatment against breast cancer in humans.
Capalbo A, Chokoshvili D, Dugoff L, Franasiak J, Gleicher N, Pennings G, Simon C
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Should the reproductive risk of a couple aiming to conceive be tested in the contemporary clinical context?

FERTILITY AND STERILITY 2019 FEB; 111(2):229-238
Veale DJ, McGonagle D, McInnes IB, Krueger JG, Ritchlin CT, Elewaut D, Kanik KS, Hendrikx T, Berstein G, Hodge J, Telliez JB
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The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

RHEUMATOLOGY 2019 FEB; 58(2):197-205
The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.
Zhang HX, Chaudhury D, Nectow AR, Friedman AK, Zhang S, Juarez B, Liu H, Pfau ML, Aleyasin H, Jiang C, Crumiller M, Calipari ES, Ku SM, Morel C, Tzavaras N, Montgomery SE, He M, Salton SR, Russo SJ, Nestler EJ, Friedman JM, Cao JL, Han MH
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alpha(1)- and beta(3)-Adrenergic Receptor-Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice

BIOLOGICAL PSYCHIATRY 2019 FEB 1; 85(3):226-236
BACKGROUND: Homeostatic plasticity in mesolimbic dopamine ( DA) neurons plays an essential role in mediating resilience to social stress. Recent evidence implicates an association between stress resilience and projections from the locus coeruleus ( LC) to the ventral tegmental area (VTA) ( LC/VTA) DA system. However, the precise circuitry and molecular mechanisms of the homeostatic plasticity in mesolimbic DA neurons mediated by the LC/VTA circuitry, and its role in conferring resilience to social defeat stress, have not been described. METHODS: In a well-established chronic social defeat stress model of depression, using projection-specific electrophysiological recordings and optogenetic, pharmacological, and molecular profiling techniques, we investigated the functional role and molecular basis of an LC/VTA circuit in conferring resilience to social defeat stress. RESULTS: We found that LC neurons projecting to the VTA exhibit enhanced firing activity in resilient, but not susceptible, mice. Optogenetically mimicking this firing adaptation in susceptible mice reverses their depressionrelated behaviors, and induces reversal of cellular hyperactivity and homeostatic plasticity in VTA DA neurons projecting to the nucleus accumbens. Circuit-specific molecular profiling studies reveal that alpha(1)-and beta(3)-adrenergic receptors are highly expressed in VTA/nucleus accumbens DA neurons. Pharmacologically activating these receptors induces similar proresilient effects at the ion channel and cellular and behavioral levels, whereas antagonizing these receptors blocks the proresilient effect of optogenetic activation of LC/VTA circuit neurons in susceptible mice. CONCLUSIONS: These findings reveal a key role of the LC/VTA circuit in mediating homeostatic plasticity in stress resilience and reveal alpha(1)-and beta(3)-adrenergic receptors as new molecular targets for therapeutically promoting resilience.
Klinge S, Woolford JL
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Ribosome assembly coming into focus

In the past 25 years, genetic and biochemical analyses of ribosome assembly in yeast have identified most of the factors that participate in this complex pathway and have generated models for the mechanisms driving the assembly. More recently, the publication of numerous cryo-electron microscopy structures of yeast ribosome assembly intermediates has provided near-atomic resolution snapshots of ribosome precursor particles. Satisfyingly, these structural data support the genetic and biochemical models and provide additional mechanistic insight into ribosome assembly. In this Review, we discuss the mechanisms of assembly of the yeast small ribosomal subunit and large ribosomal subunit in the nucleolus, nucleus and cytoplasm. Particular emphasis is placed on concepts such as the mechanisms of RNA compaction, the functions of molecular switches and molecular mimicry, the irreversibility of assembly checkpoints and the roles of structural and functional proofreading of pre-ribosomal particles.
Jakkamsetti V, Marin-Valencia I, Ma Q, Good LB, Terrill T, Rajasekaran K, Pichumani K, Khemtong C, Hooshyar MA, Sundarrajan C, Patel MS, Bachoo RM, Malloy CR, Pascual JM
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Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency

SCIENCE TRANSLATIONAL MEDICINE 2019 FEB 20; 11(480):? Article eaan0457
Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neuro-transmitters glutamate and gamma-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. One such prototypic disorder is pyruvate dehydrogenase (PDH) deficiency (PDHD). PDH is central to metabolism because it steers most of the glucose-derived flux into the TCA cycle. To better understand the pathophysiology of PDHD, we generated mice with brain-specific reduced PDH activity that paralleled salient human disease features, including cerebral hypotrophy, decreased amplitude electroencephalogram (EEG), and epilepsy. The mice exhibited reductions in cerebral TCA cycle flux, glutamate content, spontaneous, and electrically evoked in vivo cortical field potentials and gamma EEG oscillation amplitude. Episodic decreases in gamma oscillations preceded most epileptiform discharges, facilitating their prediction. Fast-spiking neuron excitability was decreased in brain slices, contributing to in vivo action potential burst prolongation after whisker pad stimulation. These features were partially reversed after systemic administration of acetate, which augmented cerebral TCA cycle flux, glutamate-dependent synaptic transmission, inhibition and gamma oscillations, and reduced epileptiform discharge duration. Thus, our results suggest that dysfunctional excitability in PDHD is consequent to reduced oxidative flux, which leads to decreased neuronal activation and impaired inhibition, and can be mitigated by an alternative metabolic substrate.
Galea S, Vaughan RD
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Making Decisions That Narrow, or Widen, Health Gaps: A Public Health of Consequence, February 2019

Saito Y, Yuan Y, Zucker-Scharff I, Fak JJ, Jereb S, Tajima Y, Licatalosi DD, Darnell RB
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Differential NOVA2-Mediated Splicing in Excitatory and Inhibitory Neurons Regulates Cortical Development and Cerebellar Function

NEURON 2019 FEB 20; 101(4):707-720.e5
RNA-binding proteins (RBPs) regulate genetic diversity, but the degree to which they do so in individual cell types in vivo is unknown. We developed NOVA2 cTag-crosslinking and immunoprecipitation (CLIP) to generate functional RBP-RNA maps from different neuronal populations in the mouse brain. Combining cell type datasets from Nova2-cTag and Nova2 conditional knockout mice revealed differential NOVA2 regulatory actions on alternative splicing (AS) on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons, where we find NOVA2 is required for, respectively, development of laminar structure, motor coordination, and synapse formation. We also find that NOVA2-regulated AS is coupled to NOVA2 regulation of intron retention in hundreds of transcripts, which can sequester the trans-acting splicing factor PTBP2. In summary, cTag-CLIP complements single-cell RNA sequencing (RNA-seq) studies by providing a means for understanding RNA regulation of functional cell diversity.