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The miR-15a/16 gene cluster is located in human chromosome 13 (13q14.3) and mouse chromosome 14 (14qC3). These genes are involved in cancer development and immune regulation. Our group has previously verified the binding of the 3′-untranslated region of NKG2D gene by miR-16 through dual-luciferase reporter assay. Herein, we found that miR-16 overexpression inhibited the NKG2D expression of CD8+ T cells, and that CD8+ NKG2D+ T cell frequency increased in miR-15/16-/- mice. CD8+ NKG2D+ T cells derived of miR-15/16-/- mice displayed activatory phenotype with enhanced IFN-γ production and cytotoxicity. The transfection of lentivirus containing antago-miR-16 sequences enhanced the NKG2D expression level of CD8+ T cells. However, no significant differences in CD8+ NKG2D+ T cell frequencies existed between wild-type and miR-15/16-transgenic mice because NKG2D was not expressed on the rest CD8+ T cells. When CD8+ T cells of miR-15/16-transgenic mice were treated with IL-2 in vitro, the magnitude of NKG2D expression and activation of CD8+ T cells was lower than that of wild-type mice. miR-15/16-/- mice showed that the exacerbation of colitis induced by dextran sulfate sodium (DSS) with more CD8+ T cells accumulated in inflamed colons, whereas miR-15/16-transgenic mice ameliorated DSS-induced colitis with less infiltration of CD8+ T cells. When NKG2D+ cells were depleted with NKG2D antibody in miR-15/16-/- mice, the aggravated colitis disappeared. TAK-243 All these results demonstrated that NKG2D could be upregulated by decreased miR-16 in CD8+ T cells to mediate inflammation. Thus, gene therapy based on the overexpression of miR-16 in CD8+ T cells can be used for patients with inflammatory diseases.

Poststroke depression (PSD) is an important consequence after stroke, with a negative impact on stroke outcome. Recent evidence points to a modulatory role of Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) in depression. Herein, we evaluated the antidepressant efficacy and mechanism underlying the potent therapeutic effects of Gadd45b after cerebral ischemia.

Adult male Sprague-Dawley rats were subjected to cerebral ischemia by permanent middle cerebral artery occlusion (MCAO). The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were performed after completing MCAO to study the antidepressant-like effects. The expression of brain-derived neurotrophic factor (BDNF) and neuroinflammation were determined in the hippocampus.

We showed that Gadd45b knockdown induced depression-like behaviors after cerebral ischemia, including increased immobility time in the FST and TST and reduced sucrose preference. Gadd45b knockdown enhanced the expression of pro-inflammatory cytokines IL-6 and TNF-α, accompanying with decreased protein levels of BDNF in the hippocampus. Moreover, the levels of phosphorylated ERK and CREB, which have been implicated in events downstream of BDNF signaling, were also decreased after cerebral ischemia.

Hence, the results showed that Gadd45b is a promising drug candidate for treating PSD and possibly other nervous system diseases associated with neuroinflammation. Gadd45b may have therapeutic potential for PSD through BDNF-ERK-CREB pathway and neuroinflammation.

Hence, the results showed that Gadd45b is a promising drug candidate for treating PSD and possibly other nervous system diseases associated with neuroinflammation. Gadd45b may have therapeutic potential for PSD through BDNF-ERK-CREB pathway and neuroinflammation.

Variants in KCNQ2 and KCNQ3 may cause benign neonatal familial seizures and early infantile epileptic encephalopathy. Previous reports suggest that in silico models cannot predict pathogenicity accurately enough for clinical use. Here we sought to establish a model to accurately predict the pathogenicity of KCNQ2 and KCNQ3 missense variants based on available in silico prediction models.

ClinVar and gnomAD databases of reported KCNQ2 and KCNQ3 missense variants in patients with neonatal epilepsy were accessed and classified as benign, pathogenic, or of uncertain significance. Sensitivity, specificity, and classification accuracy for prediction of pathogenicity were determined and compared for 10 widely used prediction algorithms program. A mathematical model of the variants (KCNQ Index) was created using their amino acid location and prediction algorithm scores to improve prediction accuracy.

Using clinically characterized variants, the free online tool PROVEAN accurately predicted pathogenicity 92% of the time and the KCNQ Index had an accuracy of 96%. However, when including the gnomAD database as benign variants, only the KCNQ Index was able to predict pathogenicity with an accuracy greater than 90% (sensitivity=93% and specificity=98%). No model could accurately predict the phenotype of variants.

We show that KCNQ channel variant pathogenicity can be predicted by a novel KCNQ Index in neonatal epilepsy. However, more work is needed to accurately predict the patient’s epilepsy phenotype from in silico algorithms.

We show that KCNQ channel variant pathogenicity can be predicted by a novel KCNQ Index in neonatal epilepsy. However, more work is needed to accurately predict the patient’s epilepsy phenotype from in silico algorithms.The present work reports on the preparation of polythiol-functionalized silica particles by thermally and photo-initiated radical addition reactions using poly(3-mercaptopropyl)methylsiloxane (PMPMS) as sulfhydryl group-rich surface modification reagent. Prior to surface modification with PMPMS, the silica was vinylized with vinyl trimethoxysilane. Finally, the usefulness of the thiolated silica particles was demonstrated by their further modification for various HPLC applications such as argentation chromatography and chiral separations. Aiming at a sulfhydryl group-rich, thin PMPMS layer on the surface of the silica several factors such as quantity of PMPMS, radical starter and reaction time were investigated by a design of experiment (DoE) approach. In thermally induced polymerization reactions 2,2′-azobis(isobutyronitrile) (AIBN) was used as radical starter, in photo-induced reactions 2,2-dimethoxy-2-phenylacetophenone (DMPA) was used instead. The incorporation of PMPMS was evaluated by elemental analysis and reactive and accessible sulfhydryl groups were determined by performing a thiol-disulfide exchange reaction with 2,2′-dipyridyl disulfide (DPDS).