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Found 34832 matches. Displaying 121-130
Matthews BJ
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Aedes aegypti

TRENDS IN GENETICS 2019 JUN; 35(6):470-471
Spalinger MR, Atrott K, Baebler K, Schwarzfischer M, Melhem H, Peres DR, Lalazar G, Rogler G, Scharl M, Frey-Wagner I
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Administration of the Hyper-immune Bovine Colostrum Extract IMM-124E Ameliorates Experimental Murine Colitis

JOURNAL OF CROHNS & COLITIS 2019 JUN; 13(6):785-797
Background and Aims Inflammatory bowel disease [IBD] is accompanied by lesions in the epithelial barrier, which allow translocation of bacterial products from the gut lumen to the host's circulation. IMM-124E is a colostrum-based product containing high levels of anti-E.coli-LPS IgG, and might limit exposure to bacterial endotoxins. Here, we investigated whether IMM-124E can ameliorate intestinal inflammation. Methods Acute colitis was induced in WT C57Bl/6J mice by administration of 2.5% dextran sodium sulphate [DSS] for 7 days. T cell transfer colitis was induced via transfer of 0.5 x 10(6) naive T cells into RAG2(-/-) C57Bl/6J mice. IMM-124E was administered daily by oral gavage, either preventively or therapeutically. Results Treatment with IMM-124E significantly ameliorated colitis in acute DSS colitis and in T cell transfer colitis. Maximum anti-inflammatory effects were detected at an IMM-124E concentration of 100 mg/kg body weight, whereas 25 mg/kg and 500 mg/kg were less effective. Histology revealed reduced levels of infiltrating immune cells and less pronounced mucosal damage. Flow cytometry revealed reduced numbers of effector T helper cells in the intestine, whereas levels of regulatory T cells were enhanced. IMM-124E treatment reduced the DSS-induced increase of serum levels of lipopolysaccharide [LPS]-binding protein, indicating reduced systemic LPS exposure. Conclusions Our results demonstrate that oral treatment with IMM-124E significantly reduces intestinal inflammation, via decreasing the accumulation of pathogenic T cells and concomitantly increasing the induction of regulatory T cells. Our study confirms the therapeutic efficacy of IMM-124E in acute colitis and suggests that administration of IMM-124E might represent a novel therapeutic strategy to induce or maintain remission in chronic colitis.
Meeske AJ, Nakandakari-Higa S, Marraffini LA
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Cas13-induced cellular dormancy prevents the rise of CRISPR-resistant bacteriophage

NATURE 2019 JUN 13; 570(7760):241-245
Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci in prokaryotes are composed of 30-40-base-pair repeats separated by equally short sequences of plasmid and bacteriophage origin known as spacers(1-3). These loci are transcribed and processed into short CRISPR RNAs (crRNAs) that are used as guides by CRISPR-associated (Cas) nucleases to recognize and destroy complementary sequences (known as protospacers) in foreign nucleic acids(4,5). In contrast to most Cas nucleases, which destroy invader DNA(4-7), the type VI effector nuclease Cas13 uses RNA guides to locate complementary transcripts and catalyse both sequence-specific cis-and non-specific trans-RNA cleavage(8). Although it has been hypothesized that Cas13 naturally defends against RNA phages(8), type VI spacer sequences have exclusively been found to match the genomes of double-stranded DNA phages(9,10), suggesting that Cas13 can provide immunity against these invaders. However, whether and how Cas13 uses its cis- and/or trans-RNA cleavage activities to defend against double-stranded DNA phages is not understood. Here we show that trans-cleavage of transcripts halts the growth of the host cell and is sufficient to abort the infectious cycle. This depletes the phage population and provides herd immunity to uninfected bacteria. Phages that harbour target mutations, which easily evade DNA-targeting CRISPR systems(11-13), are also neutralized when Cas13 is activated by wild-type phages. Thus, by acting on the host rather than directly targeting the virus, type VI CRISPR systems not only provide robust defence against DNA phages but also prevent outbreaks of CRISPR-resistant phage.
Funabiki H
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Correcting aberrant kinetochore microtubule attachments: a hidden

For equal chromosome segregation, a pair of kinetochores on each
Zaidi N, Quezada SA, Kuroiwa JMY, Zhang L, Jaffee EM, Steinman RM, Wang B
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Anti-CTLA-4 synergizes with dendritic cell-targeted vaccine to promote IL-3-dependent CD4(+) effector T cell infiltration into murine pancreatic tumors

One successful class of cancer immunotherapies, immune checkpoint inhibitory antibodies, disrupts key pathways that regulate immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These agents unleash the potency of antigen-experienced T cells that have already been induced as a consequence of the existing tumor. But only 20% of cancers naturally induce T cells. For most cancers, vaccines are require to induce and mobilize T effector cells (T-effs) to traffick into tumors. We evaluated the effects of anti-CTLA-4 given in combination with an antigen-specific dendritic cell vaccine on intratumoral T-effs in a murine pancreatic cancer model. The dendritic cell-targeted tumor antigen plus anti-CTLA-4 significantly increased the number of vaccine-induced CD4(+) T-effs within the tumor. This increase was accompanied by a reduction in the size of the peripheral CD4(+) T-eff pool. We also found that IL-3 production by activated CD4(+) T cells was significantly increased with this combination. Importantly, the CD4(+) T-eff response was attenuated in Il3(-/-) mice, suggesting mediation of the effect by IL-3. Finally, the induced T cell infiltration was associated with activation of the tumor endothelium by T cell-derived IL-3. Our findings collectively provide a new insight into the mechanism driving T-eff infiltration and vascular activation in a murine pancreatic cancer model, specifically identifying a new role for IL-3 in the anticancer immune response.
Background Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. Methods We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. Results Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. Conclusion The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.
Czarnowicki T, He H, Leonard A, Kim HJ, Kameyama N, Pavel AB, Li R, Estrada Y, Wen HC, Kimmel GW, Kim HJ, Chima M, Lebwohl M, Krueger JG, Guttman-Yassky E
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Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases

Background: Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)(+) T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. Objective: We sought to measure cytokine production by circulating skin-homing (CLA(+)) versus systemic (CLA(-)) "polar'' CD4(+)/CD8(+) ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. Methods: Flow cytometry was used to measure levels of the cytokines IFN-gamma, IL-13, IL-9, IL-17, and IL-22 in CD4(+)/CD8(+) T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. Results: Patients with Vitiligo showed the highest CLA(+)/CLA(-) T(H)1/type 1 cytotoxic T-cell polarization, with parallel T(H)2/T(H)9/T(H)17/T(H)22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P < .05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P < .001). Vitiligo severity correlated with levels of multiple cytokines (P < .1), whereas duration was linked with IFN-gamma and IL-17 levels (P < .04). Patients and control subjects grouped into separate clusters based on blood biomarkers. Conclusions: Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation.
Abel GJ, Cohen JE
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Bilateral international migration flow estimates for 200 countries

SCIENTIFIC DATA 2019 JUN 17; 6(?):? Article 82
Data on stocks and flows of international migration are necessary to understand migrant patterns and trends and to monitor and evaluate migration-relevant international development agendas. Many countries do not publish data on bilateral migration flows. At least six methods have been proposed recently to estimate bilateral migration flows between all origin-destination country pairs based on migrant stock data published by the World Bank and United Nations. We apply each of these methods to the latest available stock data to provide six estimates of five-year bilateral migration flows between 1990 and 2015. To assess the resulting estimates, we correlate estimates of six migration measures from each method with equivalent reported data where possible. Such systematic efforts at validation have largely been neglected thus far. We show that the correlation between the reported data and the estimates varies widely among different migration measures, over space, and over time. We find that the two methods using a closed demographic accounting approach perform consistently better than the four other estimation approaches.
Varble A, Marraffini LA
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Three New Cs for CRISPR: Collateral, Communicate, Cooperate

TRENDS IN GENETICS 2019 JUN; 35(6):446-456
Clustered regularly interspaced short palindromic repeats (CRISPR) loci and their associated (cas) genes provide protection against invading phages and plasmids in prokaryotes. Typically, short sequences are captured from the genome of the invader, integrated into the CRISPR locus, and transcribed into short RNAs that direct RNA-guided Cas nucleases to the nucleic acids of the invader for their degradation. Recent work in the field has revealed unexpected features of the CRISPR-Cas mechanism: (i) collateral, nonspecific, cleavage of host nucleic acids; (ii) secondary messengers that amplify the immune response; and (iii) immunosuppression of CRISPR targeting by phage-encoded inhibitors. Here, we review these new and exciting findings.
Suresh S
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Poring over chromosomes: mitotic nuclear pore complex segregation

Eukaryotic cells rely on flux of macromolecules between the nucleus and