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Label-Free, Color-Indicating, Polarizer-Free Dye-Doped Liquid Crystal Microfluidic Polydimethylsiloxane Biosensing Potato chips with regard to Sensing Albumin.
These studies have stimulated increasing interest in the role of lipophagy in the pathogenesis and treatment of cancer and other human diseases.Upon vascular injury, vascular smooth muscle cells (VSMCs) change from a contractile phenotype to a synthetic phenotype, thereby leading to atherogenesis and arterial restenosis. Trichostatin A manufacturer Myocardin (MYOCD) is essential for maintaining the contractile phenotype of VSMCs. Deletion of MYOCD in VSMCs triggers autophagy. However, the molecular mechanism underlying the effect of MYOCD on autophagy is not clear. In this study, knockdown of MYOCD in human aortic VSMCs (HA-VSMCs) triggered autophagy and diminished the expression of SMC contractile proteins. Inhibition of autophagy in MYOCD-knockdown cells restored the expression of contractile proteins. MYOCD activated the transcription of miR-30a by binding to the CArG box present in its promoter, as confirmed by luciferase reporter and chromatin immune coprecipitation assays, while miR-30a decreased the expression of autophagy protein-6 (ATG6, also known as beclin1) by targeting its 3'UTR. Restoring the expression of miR-30a in MYOCD-knockdown cells upregulated the levels of contractile proteins. Treatment of VSMCs with platelet-derived growth factor type BB (PDGF-BB) resulted in the transformation of VSMCs to a proliferative phenotype. A low level of miR-30a was observed in PDGF-BB-treated HA-VSMCs, and re-expression of miR-30a led to a decrease in proliferative marker expression. Furthermore, using a wire injury mouse model, we found that miR-30a expression was significantly downregulated in the arterial tissues of mice and that restoration of miR-30a expression at the injured site abolished neointimal formation. Herein, MYOCD could inhibit autophagy by activating the transcription of miR-30a and that miR-30a-mediated autophagy defects could inhibit intimal hyperplasia in a carotid arterial injury model.The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic β-cell mass as a result of improved β-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of β-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced β-cell mass and improved insulin secretion without changes in insulin sensitivity. Metabolic and morphological data suggest that normalization of blood glucose and insulin secretion, islet architecture, and β-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved β-cell survival and proliferation establishing MST1 as potent regulator of physiological β-cell turnover.We set out to identify novel protein associations with potential as clinically viable biomarkers for bipolar disorder. To this end, we used proximity extension assay to analyze 201 unique proteins in blood serum from two independent cohorts comprising patients with bipolar disorder and healthy controls (total n = 493). We identified 32 proteins significantly associated with bipolar disorder in both case-control cohorts after adjusting for relevant covariates. Twenty-two findings are novel to bipolar disorder, but 10 proteins have previously been associated with bipolar disorder chitinase-3-like protein 1, C-C motif chemokine 3 (CCL3), CCL4, CCL20, CCL25, interleukin 10, growth/differentiation factor-15, matrilysin (MMP-7), pro-adrenomedullin, and TNF-R1. Next, we estimated the variance in serum protein concentrations explained by psychiatric drugs and found that some case-control associations may have been driven by psychiatric drugs. The highest variance explained was observed between lithium use and MMP-7, and in post-hoc analyses and found that the serum concentration of MMP-7 was positively associated with serum lithium concentration, duration of lithium therapy, and inversely associated with estimated glomerular filtration rate in an interaction with lithium. This is noteworthy given that MMP-7 has been suggested as a mediator of renal tubulointerstitial fibrosis, which is characteristic of lithium-induced nephropathy. Finally, we used machine learning to evaluate the classification performance of the studied biomarkers but the average performance in unseen data was fair to moderate (area under the receiver operating curve = 0.72). Taken together, our serum biomarker findings provide novel insight to the etiopathology of bipolar disorder, and we present a suggestive biomarker for lithium-induced nephropathy.DNA methylation is a reversible process catalyzed by the ten-eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with glioblastoma (GBM) stem cells and correlates with poor survival of GBM patients. We further identify a SOX2miR-10b-5pTET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels, and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P  less then  0.001, area under the curve [AUC] was 0.797), especially for the first episode patients (P  less then  0.001, AUC was 0.872). We identified two loci located within genes related to mitochondrial function and cell growth and differentiation, which were both associated with schizophrenia and heart function. The combination of PRS and clinical data could predict whether patients with schizophrenia have the side effect of QTc interval prolongation, which could fundamentally guide the choice of antipsychotic in patients with schizophrenia, especially for the first-episode patients.Recent studies reported that Methyl-CpG-binding domain protein 2 (MBD2) promoted M2 macrophages accumulation to increase bleomycin-induced pulmonary fibrosis. However, the role and mechanism of action of MBD2 in macrophages differentiation and renal fibrosis remain largely unknown. In the current study, MBD2 not only promoted the differentiation of resting M0 macrophages to polarized M2 macrophages, but also induced them to polarized M1 macrophages and the transition of M2 to M1 macrophages. ChIP analysis demonstrated that MBD2 physically interacted with the promoter region of the CpG islands of G0S2 genes, and then activated their expression by inducing hypomethylation of the promoter region. Interestingly, the data demonstrated that the role of G0S2 in macrophages differentiation is consistent with MBD2. Furthermore, Co-culture of activated M1 macrophages and murine embryonic NIH 3T3 fibroblasts indicated that MBD2 mediated the M1-induction of ECM production by embryonic NIH 3T3 fibroblasts via promotion of G0S2. In addition, we also found that inhibition of MBD2 suppressed LPS induced the expression of p53 as well as activation and expression of stat3 in RAW264.7 macrophages. In vivo, MBD2 LysMcre attenuated unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R)-induced renal fibrosis via downregulation of G0S2, which was demonstrated by the downregulation of fibronectin (FN), collagen I and IV, α-SMA, G0S2. These data collectively demonstrated that MBD2 in macrophages contributed to UUO and I/R-induced renal fibrosis through the upregulation of G0S2, which could be a target for treatment for chronic kidney disease.The use of the BRAF inhibitor vemurafenib exhibits drug resistance in the treatment of thyroid cancer (TC), and finding more effective multitarget combination therapies may be an important solution. In the present study, we found strong correlations between Ref-1 high expression and BRAF mutation, lymph node metastasis, and TNM stage. The oxidative stress environment induced by structural activation of BRAF upregulates the expression of Ref-1, which caused intrinsic resistance of PTC to vemurafenib. Combination inhibition of the Ref-1 redox function and BRAF could enhance the antitumor effects of vemurafenib, which was achieved by blocking the action of Ref-1 on BRAF proteins. Furthermore, combination treatment could cause an overload of autophagic flux via excessive AMPK protein activation, causing cell senescence and cell death in vitro. And combined administration of Ref-1 and vemurafenib in vivo suppressed PTC cell growth and metastasis in a cell-based lung metastatic tumor model and xenogeneic subcutaneous tumor model. Collectively, our study provides evidence that Ref-1 upregulation via constitutive activation of BRAF in PTC contributes to intrinsic resistance to vemurafenib. Combined treatment with a Ref-1 redox inhibitor and a BRAF inhibitor could make PTC more sensitive to vemurafenib and enhance the antitumor effects of vemurafenib by further inhibiting the MAPK pathway and activating the excessive autophagy and related senescence process.Pathological anxiety typically emerges during preadolescence and has been linked to alterations in white matter (WM) pathways. Because myelination is critical for efficient neuronal communication, characterizing associations between WM microstructure and symptoms may provide insights into pathophysiological mechanisms associated with childhood pathological anxiety. This longitudinal study examined 182 girls enrolled between the ages of 9-11 that were treatment-naïve at study entry healthy controls (n = 49), subthreshold-anxiety disorders (AD) (n = 82), or meeting DSM-5 criteria for generalized, social, and/or separation ADs (n = 51), as determined through structured clinical interview. Anxiety severity was assessed with the Clinical Global Impression Scale and Screen for Child Anxiety and Related Emotional Disorders (SCARED). Participants (n = 182) underwent clinical, behavioral, and diffusion tensor imaging (DTI) assessments at study entry, and those with pathological anxiety (subthreshold-AD and AD, n = 133) were followed longitudinally for up to 3 additional years.
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