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Found 35417 matches. Displaying 1-10
Su LL, Wang ZH, Xie ST, Hu DH, Cheng YC, Mruk DD, Guan YJ
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Testin regulates the blood-testis barrier via disturbing occludin/ZO-1 association and actin organization

The blood-testis barrier (BTB) separates the seminiferous epithelium into the apical and basal compartments. The BTB has to operate timely and accurately to ensure the correct migration of germ cells, meanwhile maintaining the immunological barrier. Testin was first characterized from primary Sertoli cells, it is a secretory protein and a sensitive biomarker to monitor junctions between Sertoli and germ cells. Till now, the functions of testin on BTB dynamics and the involving mechanisms are unknown. Herein, testin acts as a regulatory protein on BTB integrity. In vitro testin knockdown by RNAi caused significant damage to the Sertoli cell barrier with no apparent changes in the protein levels of several major tight junction (TJ), adhesion junction, and gap junction proteins. Also, testin RNAi caused the diffusion of two TJ structural proteins, occludin and ZO-1, diffusing away from the Sertoli cell surface into the cytoplasm. Association and colocalization between ZO-1 and occludin were decreased after testin RNAi, examined by Co-IP and coimmunofluorescent staining, respectively. Furthermore, testin RNAi induced a dramatic disruption on the arrangement of actin filament bundles and a reduced F-actin/G-actin ratio. The actin regulatory protein ARP3 appeared at the Sertoli cell interface after testin RNAi without its protein level change, whereas overexpressing testin in Sertoli cells showed no effect on TJ barrier integrity. The above findings suggest that besides as a monitor for Sertoli-germ cell junction integrity, testin is also an essential molecule to maintain Sertoli-Sertoli junctions.
Edri Y, Meron E, Yochelis A
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Spatial asymmetries of resonant oscillations in periodically forced heterogeneous media

PHYSICA D-NONLINEAR PHENOMENA 2020 SEP; 410(?):? Article 132501
Spatially localized oscillations in periodically forced systems are intriguing phenomena. They may occur in spatially homogeneous media (oscillons), but quite often emerge in heterogeneous media, such as the auditory system, where localized oscillations are believed to play an important role in frequency discrimination of incoming sound waves. In this paper, we use an amplitude-equation approach to study the spatial profile of the oscillations and the factors that affect it. More specifically, we use a variant of the forced complex Ginzburg-Landau (FCGL) equation to describe an oscillatory system below the Hopf bifurcation with space-dependent Hopf frequency, subject to both parametric and additive forcing. We show that spatial heterogeneity, combined with bistability of system states, results in spatial asymmetry of the localized oscillations. We further identify parameters that control that asymmetry, and characterize the spatial profile of the oscillations in terms of maximum amplitude, location, width and asymmetry. Our results bear qualitative similarities to empirical observation trends that have found in the auditory system. (C) 2020 Elsevier B.V. All rights reserved.
Morganstern I, Gulati G, Leibowitz SF
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Role of melanin-concentrating hormone in drug use disorders

BRAIN RESEARCH 2020 AUG 15; 1741(?):? Article 146872
Melanin-concentrating hormone (MCH) is a neuropeptide primarily transcribed in the lateral hypothalamus (LH), with vast projections to many areas throughout the central nervous system that play an important role in motivated behaviors and drug use. Anatomical, pharmacological and genetic studies implicate MCH in mediating the intake and reinforcement of commonly abused substances, acting by influencing several systems including the mesolimbic dopaminergic system, glutamatergic as well as GABAergic signaling and being modulated by inflammatory neuroimmune pathways. Further support for the role of MCH in controlling behavior related to drug use will be discussed as it relates to cerebral ventricular volume transmission and intracellular molecules including cocaine- and amphetamine-regulated transcript peptide, dopamine- and cAMP-regulated phosphoprotein 32 kDa. The primary goal of this review is to introduce and summarize current literature surrounding the role of MCH in mediating the intake and reinforcement of commonly abused drugs, such as alcohol, cocaine, amphetamine, nicotine and opiates.
Liu XS, Zhao XL, Wang Y, Hong JB, Shi M, Pfaff D, Guo LX, Tang HW
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Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain

CHEMOSPHERE 2020 AUG; 252(?):? Article 126470
Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNIF-alpha) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored. (C) 2020 Elsevier Ltd. All rights reserved.
Page KM, Suarez-Farinas M, Suprun M, Zhang WD, Garcet S, Fuentes-Duculan J, Li X, Scaramozza M, Kieras E, Banfield C, Clark JD, Fensome A, Krueger JG, Peeva E
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Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis

The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3(+)/CD8(+) (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.
Kazak L, Cohen P
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Creatine metabolism: energy homeostasis, immunity and cancer biology

Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease. Creatine is well known to have a key role in energy buffering; however, new work is showing that creatine also has roles in diverse cell types and physiological conditions that are distinct from this classic role. This Review discusses the role of creatine in adipocyte thermogenesis, immunity and cancer cell survival.
Fadlallah J, Chentout L, Boisson B, Pouliet A, Masson C, Morin F, Durandy A, Casanova JL, Oksenhendler E, Kracker S
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From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years

JOURNAL OF PEDIATRICS 2020 AUG; 223(?):207-211.e1
The genetic investigation of a family presenting with a dominant form of hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense mutation in activation-induced cytidine deaminase. This report illustrates the progress made over 6 decades in the characterization of primary immunodeficiencies, from immunochemistry to whole-exome sequencing.
Frew JW
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Primary imputation methods impact efficacy results in hidradenitis suppurativa clinical trials

Rahman N, Bubnys A, Kandel H, Le Moene O, Vaughan R, Kow LM, Tabansky I, Pfaff D
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Equation representing the dark-entrained transition from inaction to action in male and female mice

BEHAVIOURAL BRAIN RESEARCH 2020 AUG 17; 392(?):? Article 112673
The activation of behaviour in a daily rhythm governed by the light cycle is a universal phenomenon among humans, laboratory mammals and other vertebrates. For mice, the active period is during the dark. We have quantified the increase in activity when the lights shut off (Light to Dark, L to D) using a generalized CNS arousal assay with 20 ms resolution, rather than traditional running wheels. Data analysis yielded the rare demonstration of an equation which precisely tracks this behavioural transition and, surprisingly, its reverse during D to L. This behavioural dynamic survives in constant darkness (experiment 2) and is hormone-sensitive (experiment 3). Finally (experiment 4), mice on a light schedule analogous to one which proved troublesome for U.S. Navy sailors, had dysregulated activity bursts which did not conform to the transitions between D and L. These experiments show the lawfulness of a behavioural phase transition and the consequence of deviating from that dynamic pattern. And, in a new way, they bring mathematics to the realm of behavioural neuroscience.
Kong XF, Worley L, Rinchai D, Bondet V, Jithesh PV, Goulet M, Nonnotte E, Rebillat AS, Conte M, Mircher C, Gurtler N, Liu LY, Migaud M, Elanbari M, Habib T, Ma CS, Bustamante J, Abel L, Ravel A, Lyonnet S, Munnich A, Duffy D, Chaussabel D, Casanova JL, Tangye SG, Boisson-Dupuis S, Puel A
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Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes:IFNAR1,IFNAR2,IFNGR2, andIL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF)STAT1mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-alpha R1, IFN-alpha R2, and IFN-gamma R2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-alpha- and IFN-gamma-stimulated monocytes from DS patients but lower than those in patients with GOFSTAT1mutations. Following stimulation with IFN-alpha or -gamma, but not with IL-6 or IL-21, pSTAT1 and IFN-gamma activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients withSTAT1GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-alpha- and IFN-gamma-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOFSTAT1mutations. Unlike patients with GOFSTAT1mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8(+)T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.