The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

Gastric cancer (GC) is a common cause of cancer-related death. The etiology and pathogenesis of GC remain unclear, with genetic and epigenetic factors playing an important role. Previous studies investigated the association of GC with many genetic variants in and promoter hypermethylation of E-cadherin gene (CDH1), with conflicting results reported.To clarify this inconsistency, we conducted updated meta-analyses to assess the association of genetic variants in and the promoter hypermethylation of CDH1 with GC, including C-160A (rs16260) and other less-studied genetic variants,Data sources were PubMed, Cochrane Library, Google Scholar, Web of Knowledge, and HuGE, a navigator for human genome epidemiology.Study eligibility criteria and participant details are as follows: studies were conducted on human subjects; outcomes of interest include GC; report of genotype data of individual genetic variants in (or methylation status of) CDH1 in participants with and without GC (or providing odds ratios [OR] and their variances).Study appraisal and synthesis methods included the use of OR as a measure of the association, calculated from random effects models in meta-analyses. We used I for the assessment of between-study heterogeneity, and publication bias was assessed using funnel plot and Egger test.A total of 33 studies from 30 published articles met the eligibility criteria and were included in our analyses. We found no association between C-160A and GC (OR = 0.88; 95% confidence interval [CI], 0.71-1.08; P = 0.215), assuming an additive model (reference allele C). C-160A was associated with cardia (OR = 0.21; 95% CI, 0.11-0.41; P = 2.60 × 10), intestinal (OR = 0.66; 95% CI, 0.49-0.90; P = 0.008), and diffuse GC (OR = 0.57; 95% CI, 0.40-0.82; P = 0.002). The association of C-160A with noncardia GC is of bottom line significance (OR = 0.65; 95% CI, 0.42-1.01; P = 0.054). Multiple other less-studied genetic variants in CDH1 also exhibited association with GC. Gene-based analysis indicated a significant cumulative association of genetic variants in CDH1 with GC (all Ps <10). Sensitivity analysis excluding studies not meeting Hardy-Weinberg equilibrium (HWE) yielded similar results. Analysis by ethnic groups revealed significant association of C-160A with cardia GC in both Asian and whites, significant association with noncardia GC only in Asians, and no significant association with intestinal GC in both ethnic groups. There was significant association of C160-A with diffuse GC in Asians (P = 0.011) but not in whites (P = 0.081). However, after excluding studies that violate HWE, this observed association is no longer significant (P = 0.126). We observed strong association of promoter hypermethylation of CDH1 with GC (OR = 12.23; 95% CI, 8.80-17.00; P = 1.42 × 10), suggesting that epigenetic regulation of CDH1 could play a critical role in the etiology of GC.Limitations of this study are as follows: we could not adjust for confounding factors; some meta-analyses were based on a small number of studies; sensitivity analysis was limited due to unavailability of data; we could not test publication bias for some meta-analyses due to small number of included studies.We found no significant association of the widely studied genetic variant C-160A, but identified some other genetic variants showing significant association with GC. Future studies with large sample sizes that control for confounding risk factors and/or intensively interrogate CpG sites in CDH1 are needed to validate the results found in this study and to explore additional epigenetic loci that affect GC risk.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

The actin-based myosin system is essential for the organization and dynamics of the endomembrane system and transport network in plant cells. Plants harbour two unique myosin groups, class VIII and class XI, and the latter is structurally and functionally analogous to the animal and fungal class V myosin. Little is known about myosins in grass, even though grass includes several agronomically important cereal crops. Here, we identified 14 myosin genes from the genome of maize (Zea mays). The relatively larger sizes of maize myosin genes are due to their much longer introns, which are abundant in transposable elements. Phylogenetic analysis indicated that maize myosin genes could be classified into class VIII and class XI, with three and 11 members, respectively. Apart from subgroup XI-F, the remaining subgroups were duplicated at least in one analysed lineage, and the duplication events occurred more extensively in Arabidopsis than in maize. Only two pairs of maize myosins were generated from segmental duplication. Expression analysis revealed that most maize myosin genes were expressed universally, whereas a few members (XI-1, -6, and -11) showed an anther-specific pattern, and many underwent extensive alternative splicing. We also found a short transcript at the O1 locus, which conceptually encoded a headless myosin that most likely functions at the transcriptional level rather than via a dominant-negative mechanism at the translational level. Together, these data provide significant insights into the evolutionary and functional characterization of maize myosin genes that could transfer to the identification and application of homologous myosins of other grasses.

Several studies have showed the anti-cancer efficacy of 5-FU (5-fluorouracil) on pediatric tumors. Although the delayed demyelination induced by 5-FU in adult patients has been reported, the effect of 5-FU on oligodendrocyte myelination in adolescence is still unknown. Here, we demonstrate that systemic administration with 5-FU leads to immediate demyelination in the central nervous system (CNS) of adolescent mice, which is mainly attributed to the death of OLs. Gene-chip microarray transcriptome analysis identifies that oligodendrocyte-specific factor TCF7L2 may be a toxic target of 5-FU-impaired myelination. 5-FU-decreased TCF7L2 results in disruption of the interaction between TCF7L2 and HDAC1/2. Inhibition of crucial myelination-promoting factors by 5-FU is more significantly antagonized by co-transfection of TCF7L2, HDAC1 and HDAC2 than TCF7L2 alone. Our findings reveal that 5-FU could acutely induce the severe myelin degeneration in adolescence and disruption of TCF7L2/HDAC1/HDAC2 complex is at least partially involved in 5-FU-induced demyelination.

Oxymatrine (OMT), an alkaloid derived from the traditional Chinese medicine herb Sophora flavescens Aiton, has been shown to exhibit anticancer properties on various types of cancer cells. In this study, we investigate the anticancer properties of OMT on human glioblastoma (GBM) cells and evaluate their underlying mechanisms. MTT assays were performed and demonstrated that OMT significantly inhibits the proliferation of GBM cells. Flow cytometry suggested that OMT at a concentration of 10-5 M may induce apoptosis in U251 and A172 cells. Western blot analyses demonstrated a significant increase in the expression of Bax and caspase-3 and a significant decrease in expression of Bcl-2 in both U251 and A172 cells. Additionally, OMT was found by transwell and high-content screening assays to decrease the migratory ability of the evaluated GBM cells. These findings suggest that the antitumor effects of OMT may be the result of inhibition of cell proliferation and migration and the induction of apoptosis by regulating the expression of apoptosis-associated proteins. OMT may represent a novel anticancer therapy for the treatment of GBM.

Recent reports have demonstrated that impaired barrier function and local microinflammation in the duodenal mucosa contribute to the pathogeneses of functional dyspepsia (FD). Thus, restoring normal barrier integrity becomes a potential therapeutic strategy in the treatment of FD. Sini-San (SNS) is a traditional Chinese prescription that exhibits therapeutic effects in FD, but the underlying mechanisms remain not well understood.

The aim of the present study was to explore the roles of OX40/OX40 ligand (OX40L) signaling and OX40+ T cells in ovalbumin (OVA)‑induced mouse asthma model. Asthma was induced by OVA exposure and subsequent co‑treatment with OX40L protein, neutralizing anti‑OX40L blocking antibody, OX40+ T cells or PBS. The protein expression levels of interleukin (IL)‑4, IL‑6, IL‑13, IL‑17, tumor necrosis factor (TNF)‑α and interferon (IFN)‑γ in bronchoalveolar lavage fluid (BALF) were examined using murine cytokine‑specific ELISA. Eosinophil accumulation as well as proliferation and apoptosis of T cells in BALF were detected by Cell Counting kit‑8 and flow cytometric assays. Expression of the apoptosis‑related protein cleaved caspase‑3 was examined in OX40+ T cells using western blot assay. Flow cytometric analysis revealed that OVA‑treated mice that were co‑treated with OX40L or OX40+ T cells exhibited higher eosinophil infiltration compared with control mice treated only with OVA, whereas neutralizing anti‑OX40L blocking antibody inhibited eosinophil infiltration. ELISA assays demonstrated that the expression of IL‑4, IL‑6, IL‑13, IL‑17, TNF‑α and IFN‑γ in BALF in OX40L‑treated and OX40+ T cell‑treated mice was increased compared with expression levels in control mice. Treatment with OX40L protein effectively reduced apoptosis of T cells and the expression of cleaved caspase‑3 in T cells. OX40L‑treated and OX40+ T cell‑treated mice exhibited increased asthma through OX40/OX40L signaling, which probably promoted inflammatory factor expression, eosinophil infiltration and T cell proliferation.

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. Here, we show that a dual role for Hippo effectors TAZ and YAP in SC proliferation and myelination through modulating G-protein expression and interacting with SOX10, respectively. Developmentally regulated mutagenesis indicates that TAZ/YAP are critical for SC proliferation and differentiation in a stage-dependent manner. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ/YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identify that TAZ targets and represses Gnas, encoding Gαs-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks peripheral myelination. Thus, the Hippo/TAZ/YAP and Gαs-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis.

Prolamins, the major cereal seed storage proteins, are sequestered and accumulated in the lumen of the endoplasmic reticulum (ER), and are directly assembled into protein bodies (PBs). The content and composition of prolamins are the key determinants for protein quality and texture-related traits of the grain. Concomitantly, the PB-inducing fusion system provides an efficient target to produce therapeutic and industrial products in plants. However, the proteome of the native PB and the detailed mechanisms underlying its formation still need to be determined. We developed a method to isolate highly purified and intact PBs from developing maize endosperm and conducted proteomic analysis of intact PBs of zein, a class of prolamine protein found in maize. We thus identified 1756 proteins, which fall into five major categories: metabolic pathways, response to stimulus, transport, development, and growth, as well as regulation. By comparing the proteomes of crude and enriched extractions of PBs, we found substantial evidence for the following conclusions: (i) ribosomes, ER membranes, and the cytoskeleton are tightly associated with zein PBs, which form the peripheral border; (ii) zein RNAs are probably transported and localized to the PB-ER subdomain; and (iii) ER chaperones are essential for zein folding, quality control, and assembly into PBs. We futher confirmed that OPAQUE1 (O1) cannot directly interact with FLOURY1 (FL1) in yeast, suggesting that the interaction between myosins XI and DUF593-containing proteins is isoform-specific. This study provides a proteomic roadmap for dissecting zein PB biogenesis and reveals an unexpected diversity and complexity of proteins in PBs.

The goal of the present study was to investigate the effects of TAK-242 on the gut microbiota and the TLR4/JAK2/STAT3 signaling pathway in mice with dextran sulfate sodium (DSS)-induced colitis.

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

miRNAs are expected to become potential biomarkers in the diagnosis and prognosis of Esophageal cancer (EC). Through a series of screening, miR-34a-5p, miR-148a-3p and miR-181a-5p were selected as EC-associated miRNAs. Based on AllGlo probe, a novel absolute quantitative RT-qPCR method with high sensitivity, specificity and accuracy was established for detecting miRNAs. Then the clinical significance of these 3 miRNAs was explored with 213 patients (166 cases with EC and 47 cases with benign diseases) and 170 normal controls. Compared with normal controls, the level of miR-34a-5p increased while miR-148a-3p and miR-181a-5p decreased in EC and benign patients (P < 0.001), and the level of miR-181a-5p in early EC patients was significantly lower (P < 0.001). According to logistic regression analysis, combined detection of miR-34a-5p, miR-148a-3p and Cyfra21-1 provided the highest diagnosis efficiency of 85.07% with sensitivity and specificity reaching 85.45% and 84.71%. Compared with preoperative samples, the level of miR-34a-5p decreased while miR-148a-3p and miR-181a-5p increased in postoperative samples (P < 0.001). Collectively, this first developed, novel absolute quantitative RT-qPCR method exhibits high application value in detecting miRNAs, miR-34a-5p, miR-148a-3p and miR-181a-5p may serve as potential biomarkers in the diagnosis and prognosis of EC, and miR-181a-5p probably could serve as a new biomarker for early EC.

Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, arise from neural progenitor cells in the embryonic ganglionic eminences that also generate inhibitory neurons. They are ubiquitously distributed in the central nervous system, remain proliferative through life, and generate oligodendrocytes in both gray and white matter. OPCs exhibit some lineage plasticity, and attempts have been made to reprogram them into neurons, with varying degrees of success. However, little is known about how epigenetic mechanisms affect the ability of OPCs to undergo fate switch and whether OPCs have a unique chromatin environment around neuronal genes that might contribute to their lineage plasticity. Our bioinformatic analysis of histone posttranslational modifications at interneuron genes in OPCs revealed that OPCs had significantly fewer bivalent and repressive histone marks at interneuron genes compared to astrocytes or fibroblasts. Conversely, OPCs had a greater degree of deposition of active histone modifications at bivalently marked interneuron genes than other cell types, and this was correlated with higher expression levels of these genes in OPCs. Furthermore, a significantly higher proportion of interneuron genes in OPCs than in other cell types lacked the histone posttranslational modifications examined. These genes had a moderately high level of expression, suggesting that the "no mark" interneuron genes could be in a transcriptionally "poised" or "transitional" state. Thus, our findings suggest that OPCs have a unique histone code at their interneuron genes that may obviate the need for erasure of repressive marks during their fate switch to inhibitory neurons.

More and more studies focus on the relationship between the gastrointestinal microbiome and type 2 diabetes, but few of them have actually explored the relationship between enterotypes and type 2 diabetes. Materials and Methods. We enrolled 134 patients with type 2 diabetes and 37 nondiabetic controls. The anthropometric and clinical indices of each subject were measured. Fecal samples of each subject were also collected and were processed for 16S rDNA sequencing. Multiple logistic regression analysis was used to determine the associations of enterotypes with type 2 diabetes. Multiple linear regression analysis was used to explore the relationship between lipopolysaccharide levels and insulin sensitivity after adjusting for age, BMI, TG, HDL-C, DAO, and TNF-α. The correlation analysis between factors and microbiota was identified using Spearman correlation analysis. The correlation analysis between factors was identified using partial correlation analysis.

The lack of haplotype reference panels and whole-genome sequencing resources specific to the Chinese population has greatly hindered genetic studies in the world's largest population. Here, we present the NyuWa genome resource, based on deep (26.2×) sequencing of 2,999 Chinese individuals, and construct a NyuWa reference panel of 5,804 haplotypes and 19.3 million variants, which is a high-quality publicly available Chinese population-specific reference panel with thousands of samples. Compared with other panels, the NyuWa reference panel reduces the Han Chinese imputation error rate by a margin ranging from 30% to 51%. Population structure and imputation simulation tests support the applicability of one integrated reference panel for northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes are identified, including 11,493 novel variants. These results highlight the value of the NyuWa genome resource in facilitating genetic research in Chinese and Asian populations.

The association and potential role of the protein hormone adiponectin in autoimmune diseases causing musculoskeletal disorders, including rheumatoid arthritis (RA), are controversial. Conflicting results may arise from the influences of confounding factors linked to genetic backgrounds, disease stage, disease-modifying anti-rheumatic drugs and patients' metabolic characteristics. Here, we examined serum level of adiponectin and its relationship with disease activity score 28 with erythrocytes sedimentation rate (DAS28[ESR]) and Sharp score in a treatment-naïve Han Chinese RA population. This cross-sectional study enrolled 125 RA patients. Serum level of total adiponectin was assessed by enzyme-linked immunosorbent assay (ELISA). Other important clinical and laboratory parameters were collected from the hospital database. DAS28(ESR) was calculated according to the equation previously published. Sharp score was evaluated based on hands radiographs by an independent radiologist. The correlation between serum adiponectin level and DAS28(ESR) or the Sharp score was investigated by univariate and multivariable linear regression analyses, respectively. Multiple imputation by chained equations was used to account for missing data. Univariate analyses showed a significant positive correlation between DAS28(ESR) and age or C-reactive protein (CRP) (both p = 0.003), while serum adiponectin level was negatively correlated with DAS28(ESR) (p = 0.015). The negative correlation between adiponectin level and DAS28(ESR) remained true in multivariable analyses adjusted for confounders. In addition, the univariate analyses revealed positive correlations of Sharp score to disease duration (p < 0.001), CRP (p = 0.023) and ESR (p < 0.001). In the multivariable model adjusted for confounders, adiponectin was negatively correlated with Sharp score (p = 0.013). In this single-institution cross-sectional study, serum adiponectin level in treatment-naive RA patients is negatively correlated with DAS28(ESR) and the Sharp score after adjustment for prominent identified confounders. Serum adiponectin may be potentially useful for assessing disease activity and radiographic progression of RA.

Purpose: Choroidal neovascularization (CNV) is the main pathogenic process and a leading cause of severe vision loss in neovascular age-related macular degeneration (AMD). We investigated the antiangiogenic efficacy of dihydroartemisinin (DHA) in an experimental laser-induced CNV mouse model. Methods: After fluorescein angiography confirmed that CNV was induced by laser photocoagulation in C57BL/6J mice, DHA or vehicle was given by intragastric administration once a day. On day 6 and day 12, fluorescein angiography, optic coherence tomography, and flat-mounting analysis were performed to grade CNV leakage, measure CNV thickness and evaluate CNV areas, respectively. Immunofluorescence staining and Western blot analysis were performed to evaluate the expression of NF-κB, VEGF, and VEGFR2. To confirm the safety of intragastric DHA application, changes in retinal morphology and neural cell apoptosis were tested by histopathological examination and TUNEL assay, and retinal function was determined by electroretinogram (ERG). Results: Intragastric administration of DHA significantly suppressed CNV leakage and CNV formation in both thickness and area. Immunofluorescence showed that DHA suppressed VEGFR2 and NF-κB p65 expression in laser-induced lesions. Compared to the normal group, the protein expression of VEGF, VGFER2, NF-κB p65, and NF-κB1 p50 increased significantly in the vehicle group after laser photocoagulation, while it was profoundly inhibited by DHA treatment. In addition, histopathological examination, TUNEL analysis, and ERG test showed no obvious evidence of retinal toxicity caused by DHA. Conclusion: Systemic administration of DHA can effectively inhibit laser-induced CNV formation in mice, which might be due to the suppression of the classic NF-κB signaling pathway and downregulation of VEGFR2 and VEGF expression. The current results suggest that DHA could be a natural potential alternative therapeutic strategy for neovascular AMD.

A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.

Potato (Solanum tuberosum L.) is one of the world's most important crops, the cultivated potato is frost-sensitive, and low-temperature severely influences potato production. However, the mechanism by which potato responds to low-temperature stress is unclear. In this research, we apply a combination of second-generation sequencing and third-generation sequencing technologies to sequence full-length transcriptomes in low-temperature-sensitive cultivars to identify the important genes and main pathways related to low-temperature resistance.