YTHDF2-Mediated m6A methylation inhibition by miR27a as a protective mechanism against hormonal osteonecrosis in BMSCs.

BACKGROUND: With the increasing incidence of steroid-induced necrosis of the femoral head (SNFH), numerous scholars have investigated its pathogenesis. Current evidence suggests that the imbalance between lipogenesis and osteoblast differentiation in bone marrow mesenchymal stem cells (BMSCs) is a key pathological feature of SNFH. MicroRNAs (miRNAs) have strong gene regulatory effects and can influence the direction of cell differentiation. N6-methyladenosine (m6A) is a prevalent epigenetic modification involved in diverse pathophysiological processes. However, knowledge of how miRNAs regulate m6A-related factors that affect BMSC differentiation is limited. OBJECTIVE: We aimed to investigate the role of miR27a in regulating the expression of YTHDF2 in BMSCs. METHODS: We compared miR27a, YTHDF2, and total m6A mRNA levels in SNFH-affected and control BMSCs. CCK-8 and TUNEL assays were used to assess BMSC proliferation and apoptosis. Western blotting and qRT‒PCR were used to measure the expression of osteogenic (ALP, RUNX2, and OCN) and lipogenic (PPARγ and C/EBPα) markers. Alizarin Red and Oil Red O staining were used to quantify osteogenic and lipogenic differentiation, respectively. miR27a was knocked down or overexpressed to evaluate its impact on BMSC differentiation and its relationship with YTHDF2. Bioinformatics analyses identified YTHDF2 as a differentially expressed gene in SNFH (ROC analysis) and revealed potential signaling pathways through GSEA. The effects of YTHDF2 silencing on the lipogenic and osteogenic functions of BMSCs were assessed. RESULTS: miR27a downregulation and YTHDF2 upregulation were observed in the SNFH BMSCs. miR27a knockdown/overexpression modulated YTHDF2 expression, impacting BMSC differentiation. miR27a silencing decreased m6A methylation and promoted osteogenic differentiation, while YTHDF2 silencing exerted similar effects. GSEA suggested potential signaling pathways associated with YTHDF2 in SNFH. CONCLUSION: miR27a regulates BMSC differentiation through YTHDF2, affecting m6A methylation and promoting osteogenesis. This finding suggests a potential therapeutic target for SNFH.

Detection and Analysis of Genes Affecting the Number of Thoracic Vertebrae in Licha Black Pigs.

The number of thoracic vertebrae (NTV) in pigs is an important economic trait that significantly influences pork production. While the Licha black pig is a well-known Chinese pig breed with multiple thoracic vertebrae, the genetic mechanism is still unknown. Here, we performed a selective signal analysis on the genome of Licha black pigs, comparing individuals with 15 NTV versus those with 16 NTV to better understand functional genes associated with NTV. A total of 2265 selection signal regions were detected across the genome, including 527 genes and 1073 QTL that overlapped with the selection signal regions. Functional enrichment analysis revealed that LRP5 and SP5 genes were involved in biological processes such as bone morphogenesis and Wnt protein binding. Furthermore, three genes, LRP8, DEF6, and SCUBE3, associated with osteoblast differentiation and bone formation, were located within or close to the QTL related to bone development and vertebrae number. These five genes were hypothesized to be potential candidates for regulating the NTV trait in Licha black pigs. Our findings revealed several candidate genes that play crucial roles in NTV regulation and provide a theoretical foundation to understand the genetic mechanism of the NTV trait in pig breeding.

Predictive modeling of co-infection in lupus nephritis using multiple machine learning algorithms.

This study aimed to analyze peripheral blood lymphocyte subsets in lupus nephritis (LN) patients and use machine learning (ML) methods to establish an effective algorithm for predicting co-infection in LN. This study included 111 non-infected LN patients, 72 infected LN patients, and 206 healthy controls (HCs). Patient information, infection characteristics, medication, and laboratory indexes were recorded. Eight ML methods were compared to establish a model through a training group and verify the results in a test group. We trained the ML models, including Logistic Regression, Decision Tree, K-Nearest Neighbors, Support Vector Machine, Multi-Layer Perceptron, Random Forest, Ada boost, Extreme Gradient Boosting (XGB), and further evaluated potential predictors of infection. Infected LN patients had significantly decreased levels of T, B, helper T, suppressor T, and natural killer cells compared to non-infected LN patients and HCs. The number of regulatory T cells (Tregs) in LN patients was significantly lower than in HCs, with infected patients having the lowest Tregs count. Among the ML algorithms, XGB demonstrated the highest accuracy and precision for predicting LN infections. The innate and adaptive immune systems are disrupted in LN patients, and monitoring lymphocyte subsets can help prevent and treat infections. The XGB algorithm was recommended for predicting co-infection in LN.

Macrophage-derived mir-100-5p orchestrates synovial proliferation and inflammation in rheumatoid arthritis through mTOR signaling.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, causing substantial disability and reducing life quality. While macrophages are widely appreciated as a master regulator in the inflammatory response of RA, the precise mechanisms underlying the regulation of proliferation and inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS) remain elusive. Here, we provide extensive evidence to demonstrate that macrophage contributes to RA microenvironment remodeling by extracellular vesicles (sEVs) and downstream miR-100-5p/ mammalian target of rapamycin (mTOR) axis. RESULTS: We showed that bone marrow derived macrophage (BMDM) derived-sEVs (BMDM-sEVs) from collagen-induced arthritis (CIA) mice (cBMDM-sEVs) exhibited a notable increase in abundance compared with BMDM-sEVs from normal mice (nBMDM-sEVs). cBMDM-sEVs induced significant RA-FLS proliferation and potent inflammatory responses. Mechanistically, decreased levels of miR-100-5p were detected in cBMDM-sEVs compared with nBMDM-sEVs. miR-100-5p overexpression ameliorated RA-FLS proliferation and inflammation by targeting the mTOR pathway. Partial attenuation of the inflammatory effects induced by cBMDM-sEVs on RA-FLS was achieved through the introduction of an overexpression of miR-100-5p. CONCLUSIONS: Our work reveals the critical role of macrophages in exacerbating RA by facilitating the transfer of miR-100-5p-deficient sEVs to RA-FLS, and sheds light on novel disease mechanisms and provides potential therapeutic targets for RA interventions.

A GITRL-mTORC1-GM-CSF Positive Loop Promotes Pathogenic Th17 Response in Primary Sjögren Syndrome.

OBJECTIVE: Glucocorticoid-induced tumor necrosis factor receptor superfamily-related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell-mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS). METHODS: Patients with pSS and healthy controls were recruited. Serum GITRL and Th17-related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno-associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. RESULTS: Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17-related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte-macrophage colony-stimulating factor positive (GM-CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM-CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL-mTORC1-GM-CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice. CONCLUSION: Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL-mTORC1-GM-CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS.

Transplantation of human umbilical cord blood mononuclear cells promotes functional endometrium reconstruction via downregulating EMT in damaged endometrium.

Introduction: Cell transplantation is an emerging and effective therapeutic approach for enhancing uterine adhesions caused by endometrial damage. Currently, human umbilical cord blood mononuclear cells (HUCBMCs) have been extensively for tissue and organ regeneration. However, their application in endometrial repair remains unexplored. Our investigation focuses on the utilization of HUCBMCs for treating endometrial injury. Methods: The HUCBMCs were isolated from health umbilical cord blood, and co-cultured with the injured endometrial stromal cells and injured endometrial organoids. The cell proliferation and apoptosis were measured by cck8 assays and flow cytometry. Western blotting was used to detect the expression of PTEN, AKT and p-AKT. Immunofluorescence assay revealed expression levels of epithelial-mesenchymal transition (EMT) -related markers such as E-cadherin, N-cadherin, and TGF-ß1. The endometrial thickness, fibrosis level, and glandular number were examined after the intravenous injection of HUCBMCs in mouse endometrial models. Immunohistochemistry was employed to assess changes in growth factors vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) as well as fibrosis markers α-SMA and COL1A1. Additionally, expressions of EMT-related proteins E-cadherin and N-cadherin were evaluated. Results: HUCBMCs significantly improved the proliferation and reduced the apoptosis of damaged endometrial stromal cells (ESCs), accompanied by up-regulation of phospho-AKT expression. HUCBMCs increased endometrial thickness and glandular count while decreasing fibrosis and EMT-related markers in mouse endometrial models. Furthermore, EMT-related markers of ESCs and endometrial organoids were significantly decreased. Conclusions: Our findings suggest that HUCBMCs plays a pivotal role in mitigating endometrial injury through the attenuation of fibrosis. HUCBMCs may exert a reverse effect on the EMT process during the endometrium reconstruction.

Applications of single­cell omics and spatial transcriptomics technologies in gastric cancer (Review).

Gastric cancer (GC) is a prominent contributor to global cancer-related mortalities, and a deeper understanding of its molecular characteristics and tumor heterogeneity is required. Single-cell omics and spatial transcriptomics (ST) technologies have revolutionized cancer research by enabling the exploration of cellular heterogeneity and molecular landscapes at the single-cell level. In the present review, an overview of the advancements in single-cell omics and ST technologies and their applications in GC research is provided. Firstly, multiple single-cell omics and ST methods are discussed, highlighting their ability to offer unique insights into gene expression, genetic alterations, epigenomic modifications, protein expression patterns and cellular location in tissues. Furthermore, a summary is provided of key findings from previous research on single-cell omics and ST methods used in GC, which have provided valuable insights into genetic alterations, tumor diagnosis and prognosis, tumor microenvironment analysis, and treatment response. In summary, the application of single-cell omics and ST technologies has revealed the levels of cellular heterogeneity and the molecular characteristics of GC, and holds promise for improving diagnostics, personalized treatments and patient outcomes in GC.

Phase separation of YAP-MAML2 differentially regulates the transcriptome.

Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS-induced formation of several transcriptional factor (TF) condensates that are transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show that the oncogenic TF fusion Yes-associated protein 1-Mastermind like transcriptional coactivator 2 (YAP-MAML2) undergoes PS and forms liquid-like condensates that bear the hallmarks of transcriptional activity. Furthermore, we examined the contribution of PS to YAP-MAML2-mediated gene expression by developing a chemogenetic tool that dissolves TF condensates, allowing us to compare phase-separated and non-phase-separated conditions at identical YAP-MAML2 protein levels. We found that a small fraction of YAP-MAML2-regulated genes is further affected by PS, which include the canonical YAP target genes CTGF and CYR61, and other oncogenes. On the other hand, majority of YAP-MAML2-regulated genes are not affected by PS, highlighting that transcription can be activated effectively by diffuse complexes of TFs with the transcriptional machinery. Our work opens new directions in understanding the role of PS in selective modulation of gene expression, suggesting differential roles of PS in biological processes.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune condition marked by inflammation of the joints, degradation of the articular cartilage, and bone resorption. Recent studies found the absolute and relative decreases in circulating regulatory T cells (Tregs) in RA patients. Tregs are a unique type of cells exhibiting immunosuppressive functions, known for expressing the Foxp3 gene. They are instrumental in maintaining immunological tolerance and preventing autoimmunity. Increasing the absolute number and/or enhancing the function of Tregs are effective strategies for treating RA. This article reviews the studies on the mechanisms and targeted therapies related to Tregs in RA, with a view to provide better ideas for the treatment of RA.

Hypouricemia as a novel predictor of mortality in anti-MDA5 positive dermatomyositis patients with ILD: A retrospective cohort study.

OBJECTIVE: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is a unique subtype of idiopathic inflammatory myopathy (IIM) that is associated with rapidly progressive interstitial lung disease (RPILD) and high mortality. This retrospective study aimed to identify predictors of mortality and discover novel easily detectable indicators. METHODS: We retrospectively reviewed 183 MDA5+ DM-ILD patients who were from West China Hospital of Sichuan University myositis cohort, the largest single-center cohort of southwest China, from January 2016 to October 2021. Clinical characteristics were reviewed, and risk factors for mortality were determined by univariate and multivariable Cox regression analyses. RESULTS: Of the 183 MDA5+ DM-ILD patients, 59 were presented with RP-ILD, and 53 died during the follow-up period. Compared with the survived patients, deceased patients had higher rates of dyspnea, higher concentrations of CRP, and LDH, but lower rates of heliotrope sign, lower quantity of lymphocyte and lower levels of serum uric acid (SUA). Notably, patients with hypouricemia (SUA <154 µmol/L) had higher concentrations of CRP and LDH, higher neutrophil counts, lower lymphocyte counts and higher mortality rate when compared with the non-hypouricemia group. Multivariate Cox regression analyses confirmed that hypouricemia, smoking, RPILD, high HRCT score, elevated LDH, and lymphopenia were independent risk factors for mortality in MDA5+ DM-ILD patients. Moreover, patients with hypouricemia had significantly lower survival rates than non-hypouricemia patients. CONCLUSION: Our study identified hypouricemia as a non-redundant promising prognostic factor for the mortality of MDA5+ DM-ILD patients, which may hopefully provide insight into the prevention and pathogenesis study.

Using live videography observation and Bayesian isotope mixing model to identify food composition and dietary contribution to inorganic mercury and methylmercury intake by songbird nestlings.

Mercury (Hg) exposure is increasing in terrestrial birds; however, studies on its sources are scarce. In the present study, we elucidated the food composition of green-backed tit nestlings from three urban forest parks (CPL, AHL, and LCG) using live videography observation (LVO). Furthermore, the daily dietary intakes of inorganic Hg (IHg) (MDIIHg) and methylmercury (MeHg) (MDIMeHg) were determined using the Bayesian isotope mixing model (BIMM) to uncover the nestlings' specific dietary Hg contribution. Both LVO and BIMM indicated that Lepidoptera (primarily caterpillar) constituted the primary food source for the nestlings in the three forests, accounting for approximately 60% of their diet in all three forest parks. The estimated MDI of Hg revealed that lepidopterans and spiders primarily contributed to IHg exposure, with a co-contribution ratio of 71.8%-97.7%. Unexpectedly, dietary MeHg was mostly derived from spiders; the highest contribution ratio of 93.6% was recorded at CPL, followed by another peak ratio of 92.9% at LCG. However, the dietary exposure was primarily IHg, accounting for 69.8% (AHL), 62.0% (LCG), and 61.3% (CPL) of the nestlings. Our study findings highlight the importance of dietary IHg transfer in evaluating the effects of Hg in nestlings. LVO, coupled with BIMM, is an effective tool for determining the food compositions of songbird nestlings and estimating the contribution of specific diets.

Comprehensive transcriptomic analysis and machine learning reveal unique gene expression profiles in patients with immune-mediated necrotizing myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness and muscle fiber necrosis, yet its pathogenesis remains unclear. So far, there are few bioinformatics studies on underlying pathogenic genes and infiltrating immune cell profiles of IMNM. Therefore, we aimed to characterize differentially expressed genes (DEGs) and infiltrating cells in IMNM muscle biopsy specimens, which may be useful for elucidating the pathogenesis of IMNM. METHODS: Three datasets (GSE39454, GSE48280 and GSE128470) of gene expression profiling related to IMNM were obtained from the Gene Expression Omnibus database. Data were normalized, and DEG analysis was performed using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using clusterProfiler. The CIBERSORT algorithm was performed to identify infiltrating cells. Machine learning algorithm and gene set enrichment analysis (GSEA) were performed to find distinctive gene signatures and the underlying signaling pathways of IMNM. RESULTS: DEG analysis identified upregulated and downregulated in IMNM muscle compared to the gene expression levels of other groups. GO and KEGG analysis showed that the pathogenesis of IMNM was notable for the under-representation of pathways that were important in dermatomyositis and inclusion body myositis. Three immune cells (M2 macrophages, resting dendritic cells and resting natural killer cells) with differential infiltration and five key genes (NDUFAF7, POLR2J, CD99, ARF5 and SKAP2) in patients with IMNM were identified through the CIBERSORT and machine learning algorithm. The GSEA results revealed that the key genes were remarkably enriched in diverse immunological and muscle metabolism-related pathways. CONCLUSIONS: We comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.

Autonomous nanorobots with powerful thrust under dry solid-contact conditions by photothermal shock.

Nanorobotic motion on solid substrates is greatly hindered by strong nanofriction, and powerful nanomotors‒the core components for nanorobotic motion‒are still lacking. Optical actuation addresses power and motion control issues simultaneously, while conventional technologies with small thrust usually apply to fluid environments. Here, we demonstrate micronewton-thrust nanomotors that enable the autonomous nanorobots working like conventional robots with precise motion control on dry surfaces by a photothermal-shock technique. We build a pulsed laser-based actuation and trapping platform, termed photothermal-shock tweezers, for general motion control of metallic nanomaterials and assembled nanorobots with nanoscale precision. The thrust-to-weight ratios up to 107 enable nanomotors output forces to interact with external micro/nano-objects. Leveraging machine vision and deep learning technologies, we assemble the nanomotors into autonomous nanorobots with complex structures, and demonstrate multi-degree-of-freedom motion and sophisticated functions. Our photothermal shock-actuation concept fundamentally addresses the nanotribology challenges and expands the nanorobotic horizon from fluids to dry solid surfaces.

Functional characterization of Alzheimer's disease genetic variants in microglia.

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

Fast and Reversible Quasi-Solid-State Anion Exchange in Highly Luminescent CsPbX3 Perovskite Nanocrystals for Dual-Mode Encryption-Decryption.

Solid-state anion exchange method is easy to handle and beneficial to improve stability of CsPbX3 (X = Cl, Br, I) perovskites nanocrystals (NCs) with respect to anion exchange in liquid phase. However, the corresponding exchange rate is rather slow due to the limited diffusion rate of anions from solid phases, resulting in mixed-halide perovskite NCs. Herein,  a fast and reversible post-synthetic quasi-solid-state anion exchange method in CsPbX3 NCs with inorganic potassium halide KX salts/polyvinylpyrrolidone (PVP) thin film is firstly reported. Original morphology of the exchanged NCs is well-preserved for all samples. Complete anion exchange from Br- to Cl- or I- is successfully achieved in CsPbX3 NCs within ≈20 min through possible vacancies-assisted ion exchange mechanism, under ambient conditions and vice versa. Particularly, Br- -exchanged CsPbCl3 and CsPbI3 NCs exhibit improved optical properties. Encouraged by the attractive fluorescence and persistent luminescence as well as good stability of the resulted CsPbX3 NCs, an effective dual-mode information storage-reading application is demonstrated.  It is believed that this method can open a new avenue for the synthesis of other direct-synthesis challenging quantum-confined perovskite NCs/nanoplates/nanodisks or CsSnX3 NCs/thin film and provide an opportunity for advanced information storage compatible for practical applications.

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics.

BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.

A one-dimensional cobalt-based coordination polymer as a cathode material of lithium-ion batteries.

For obtaining high-performance lithium-ion batteries, it is important to develop new cathode materials with high capacity. Herein, a one-dimensional coordination polymer [Co(4-DTBPT) (DMF)2(H2O)2] (4-DTBPT) (C10H4O8) (Co-DTBPT) (4-DTBPT = 2,7-di(4H-1,2,4-triazol-4yl)benzo[lmn][3,8] phenanthroline-1,3,6,8-(2H,7H)-tetraone; DMF = dimethylformamide) was synthesized and its electrochemical performance as the cathode material of lithium-ion batteries was first investigated. The Co-DTBPT electrode showed better cycling stability and a specific capacity of 55 mA h g-1 at 50 mA g-1 after 50 cycles, and the coulombic efficiency was close to 100%. The capacity contribution of the Co-DTBPT electrode may be ascribed to the redox reaction of the Co(II) ion and the 4-DTBPT ligand in the process of charge and discharge. Our work proves once again that using one-dimensional coordination polymers as cathode materials for lithium-ion batteries is a feasible way.

Pyloric stenosis secondary to peptic ulcer disease in pediatric patients: A case report and review of the literature.

RATIONALE: Pediatric pyloric obstruction is a condition characterized by complete or incomplete obstruction of the distal stomach caused by obstructive lesions of the distal stomach, pyloric duct, or proximal duodenum. Congenital hypertrophic pyloric stenosis is the most common cause of pediatric pyloric obstruction, whereas acquired pyloric stenosis is comparatively rare, with peptic ulcer disease being the most common cause. PATIENT CONCERNS: We describe a case of a 5-year-old girl who had peptic ulcer disease and developed scarring pyloric stenosis. We also give comprehensive details of the diagnosis and course of treatment. DIAGNOSIS: Intraoperative findings revealed ulcerative, scarring pyloric obstruction. INTERVENTIONS: Conservative treatment failed and surgery was subsequently performed. OUTCOMES: No further vomiting symptoms occurred after surgery. And 3 months after surgery, the patient had gained weight on average and had no further complaints. LESSONS: Although scarring pediatric pyloric blockage due to peptic ulcer is less common, emphasis should be placed on rapid diagnosis by accurate gastroscopy, barium meal of the gastrointestinal tract, or ultrasonography. Depending on the patient's condition, conservative treatment or surgery should be chosen carefully selected.

Genetically encoded chemical crosslinking of RNA in vivo.

Protein-RNA interactions regulate RNA fate and function, and defects can lead to various disorders. Such interactions have mainly been studied by nucleoside-based UV crosslinking methods, which lack broad in vivo compatibility and the ability to resolve specific amino acids. In this study we genetically encoded latent bioreactive unnatural amino acids into proteins to react with bound RNA by proximity-enabled reactivity and demonstrated genetically encoded chemical crosslinking of proteins with target RNA (GECX-RNA) in vivo. Applying GECX-RNA to the RNA chaperone Hfq in Escherichia coli identified target RNAs with amino acid specificity. Combining GECX-RNA with immunoprecipitation and high-throughput sequencing of an N6-methyladenosine reader protein in mammalian cells allowed the in vivo identification of unknown N6-methyladenosine on RNA with single-nucleotide resolution throughout the transcriptome. GECX-RNA thus affords resolution at the nucleotide and amino acid level for interrogating protein-RNA interactions in vivo. It also enables the precise engineering of covalent linkages between a protein and RNA, which will inspire innovative solutions for RNA-related research and therapeutics.