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.

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.

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.

Immune-mediated necrotizing myopathy: A comprehensive review of the pathogenesis, clinical features, and treatments.

Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.

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.

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.

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.

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.

Soluble LILRA3 is aberrantly expressed in antiphospholipid syndrome (APS) and is a potential marker of thrombotic APS.

OBJECTIVE: Leucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with APS. We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis. METHODS: Two independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic aPL carriers and 150 healthy controls (HCs) from Peking University People's Hospital. The second included 99 APS patients, 25 aPL carriers and 40 HCs from United States APS centres. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes. RESULTS: Both positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort. CONCLUSION: Our study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.

Thermal-mechanical-photo-activation effect on silica micro/nanofiber surfaces: origination, reparation and utilization.

The exploration relevant to the surface changes on optical micro- and nanofibers (MNFs) is still in infancy, and the reported original mechanisms remain long-standing puzzles. Here, by recognizing the combined interactions between fiber heating, mechanically tapering, and high-power pulsed laser guiding processes in MNFs, we establish a general thermal-mechanical-photo-activation mechanism that can explain the surface changes on MNFs. Our proposed activation mechanism can be well supported by the systematical experimental results using high-intensity nanosecond/femtosecond pulsed lasers. Especially we find large bump-like nanoscale cavities on the fracture ends of thin MNFs. Theoretically, on the basis of greatly increased bond energy activated by the fiber heating and mechanically tapering processes, the energy needed to break the silicon-oxygen bond into dangling bonds is significantly reduced from its intrinsic bandgap of ∼9 eV to as low as ∼4.0 eV, thus high-power pulsed lasers with much smaller photon energy can induce obvious surface changes on MNFs via multi-photon absorption. Finally, we demonstrate that using surfactants can repair the MNF surfaces and exploit them in promising applications ranging from sensing and optoelectronics to nonlinear optics. Our results pave the way for future preventing the performances from degradation and enabling the practical MNF-based device applications.

Utility of autoantibody against an UCH-L1 epitope as a serum diagnostic marker for neuropsychiatric systemic lupus erythematosus.

OBJECTIVES: Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most serious complications of systemic lupus erythematosus (SLE), lacking efficient diagnostic biomarkers. Previous studies have shown that anti-ubiquitin carboxyl hydrolase L1(UCH-L1) autoantibody is a promising cerebrospinal fluid (CSF) biomarker for NPSLE diagnosis. The purpose of this study is to explore the serum autoantibodies against different UCH-L1 epitopes and investigate the potential diagnostic value of serum autoantibodies against different UCH-L1 epitopes in NPSLE. METHODS: The epitopes of UCH-L1 protein were predicted in DNAStar software. The serum levels of different UCH-L1 epitope autoantibodies in 40 NPSLE patients, 32 SLE patients without neuropsychiatric symptoms and 21 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). Data were analysed using Pearson correlation analysis, ROC curve analysis, nonparametric Mann-Whitney test, t-test and χ2 test. RESULTS: We screened three candidate epitopes of UCH-L1 protein. The autoantibody against amino acid 58 to 69 of UCH-L1 (UCH58-69) showed highest diagnostic power in distinguishing NPSLE patients from SLE patients without neuro-psychiatric symptoms (p=0.0038). The ROC analysis showed that the specificity and sensitivity of anti-UCH58-69 were 92.3% and 37.5%, respectively. In addition, increased serum anti-UCH58-69 levels were associated with increased SLEDAI, CSF microprotein, CSF leukocyte count, ESR, AnuA, anti-dsDNA, IgG and IgM but with decrease of C3 in SLE patients. CONCLUSIONS: The serum levels of anti-UCH58-69 significantly increased in NPSLE patients compared with SLE patients without neuropsychiatric symptoms and were correlated with disease severity. Anti-UCH58-69 autoantibody may become a novel serum biomarker for NPSLE non-invasive diagnosis, which might be applicable for NPSLE early screening and diagnosis.

Long noncoding RNA LINC00511 induced by SP1 accelerates the glioma progression through targeting miR-124-3p/CCND2 axis.

Mounting evidence suggests the vital roles of long noncoding RNA (lncRNAs) in the glioma. However, the role of LINC00511 in gliomagenesis is still uncovered. Here, in this study, we aim to investigate the effects of LINC00511 on the glioma cancer phenotype and its deepgoing mechanism. Results indicated that LINC00511 was up-regulated in glioma tissues and cell lines, moreover its overexpression positively correlated with the poor prognosis and advanced pathological stages. For the upstream regulation, LINC00511 was epigenetically up-regulated by transcription factor specificity protein 1 (SP1). Gain and loss of functional experiments demonstrated that LINC00511 promoted the proliferation and invasion of glioma cells in vitro. The knockdown of LINC00511 repressed the tumour growth in vivo. Mechanistically, LINC00511 positively regulated the CCND2 expression via competitively sponging with miR-124-3p. Overall, our finding illuminates that LINC00511 is induced by SP1 and accelerates the glioma progression through targeting miR-124-3p/CCND2 axis, constructing the SP1/LINC00511/miR-124-3p/CCND2 axis.

PUM2 Promotes Glioblastoma Cell Proliferation and Migration via Repressing BTG1 Expression.

PUM2, an RNA binding protein, is known to promote stem cell proliferation via repressing expressions of cell cycle genes. Similar with stem cells, malignant cells are characterized by unlimited proliferation and remote migration. However, roles of PUM2 in cancer development are controversial. Here, we investigated PUM2's role in glioblastoma development and its relationship with the cell cycle regulator BTG1. Immunoblotting and RT-qPCR were used to evaluate protein expression level and transcript level, respectively. ShRNAs were designed to knock down PUM2 and BTG1 expression. CCK-8 assay was used to evaluate cell viability. Cell migration assay and evasion assay were used to evaluate metastatic capability of glioblastoma cell. RNA pull-down assay and RNA immunoprecipitation assay were used to test the interaction between PUM2 and BTG1 3'UTR. PUM2 expression is elevated in glioblastoma tumor tissues as well as glioblastoma cell lines. PUM2 knockdown remarkably suppresses glioblastoma cell proliferation and migration. In addition, PUM2 knockdown increases BTG1 expression. RNA pull-down assay and RNA immunoprecipitation assay show PUM2 binds to BTG1 3'UTR directly. Furthermore, knockdown of BTG1 reverses the effect of PUM2 knockdown on glioblastoma cell proliferation and migration. Our results suggest that PUM2 promote glioblastoma development via repressing BTG1 expression.Key words: PUM2, BTG1, glioblastoma, cell proliferation, metastasis.

Long noncoding RNA CASC9/miR-519d/STAT3 positive feedback loop facilitate the glioma tumourigenesis.

Emerging evidence have illustrated the vital roles of long noncoding RNAs (lncRNAs) in glioma. Nevertheless, the majority of their roles and mechanisms in gliomagenesis are still largely unclear. In this study, we investigate the roles of lncRNA CASC9 on glioma tumourigenesis and authenticate its potential mechanisms. Results manifested that CASC9 was highly expressed in glioma specimens and cells, moreover, the ectopic overexpression was correlated with glioma patients' clinic. Functional studies found that siRNA-mediated CASC9 silencing inhibited the proliferative ability, invasion in vitro, and impaired the tumour growth in vivo. Mechanical studies revealed that miR-519d both targeted the 3'-UTR of CASC9 and STAT3 mRNA, which was identified by luciferase reporter assay and RNA immunoprecipitation (RIP). Moreover, chromatin immunoprecipitation (ChIP) and luciferase reporter assay revealed that STAT3, an oncogenic transcription factor, could bind with the promoter of CASC9 and activate its transcriptional level. In conclusion, our results concluded that CASC9 promotes STAT3 expression via sponging miR-519d, in return, STAT3 activate CASC9 transcription, forming a positive feedback loop of CASC9/miR-519d/STAT3. The novel finding provides a potential therapeutic target for glioma.

Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis.

Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1α regulates interactions between RASFs and T cells and B cells. We report here that HIF-1α promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-α, and IL-1ß, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1α perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-γ, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1α perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1α may provide new therapeutic strategies for overcoming this persistent disease.

Downregulation of ZMYND11 induced by miR-196a-5p promotes the progression and growth of GBM.

ZMYND11 (zinc finger MYND-type containing 11) has been widely regarded to be involved in a variety of cancers as a potential suppressor. However, the biological role and mechanism of ZMYND11 in glioblastoma multiform (GBM) remain unknown. In this study, we found that ZMYND11 expression was remarkably decreased in GBM tissues from 20 cases and cell line (U87) compared to normal brain tissue from 10 cases (P < 0.001). Furthermore, we explored that ZMYND11 upregulation significantly suppressed U87 cells proliferation and invasion, induced cell cycle arrest and apoptosis in vitro. Subsequently, we identified increased ZMYND11 inhibited the tumor growth using tumor cells xenograft experiment on rude mice. Moreover, we explored that ZMYND11 was a new direct and functional target of miR-196a-5p in U87 via luciferase reporter assay. In addition, we confirmed the negative correlation between miR-196a-5p and ZMYND11 in GBM tissue and U87 cells by changing the expression level of miR-196a-5p with lentivirus and plasmid vector. Furthermore, we demonstrated that decreased ZMYND11 could reverse suppressive effect of downregulated miR-196a-5p on U87 by rescue experiment. Taken together, ZMYND11 was demonstrated to be a potential and extremely promising suppressor of GBM, while miRNA-196a-5p was quite an important target of treatment of GBM.

Pathogenic conversion of regulatory B10 cells into osteoclast-priming cells in rheumatoid arthritis.

Regulatory B10 cells were functionally impaired in rheumatoid arthritis (RA), yet the mechanisms were unclear. B cells are recently recognized as important participants in osteoclastogenesis by producing RANKL. In this study, we investigated whether regulatory B10 cells could convert into RANKL-producing cells, thus impairing their immunosuppressive functions in RA and exacerbating the disease progression. Our results showed that human regulatory B10 cells could ectopically express RANKL. Under RA circumstance, RANKL-producing B10 cells expanded dramatically, partially induced by TNF-α. The frequencies of these cells were positively correlated with RA patient disease activities and tender joint counts, but negatively correlated with the frequencies of regulatory B10 cells. Strikingly, RANKL-producing B10 cells from RA patients, but not healthy individuals significantly promoted osteoclast differentiation and bone erosion in a paracrine and cell-cell contact-dependent manner. Moreover, these pathogenic RANKL-producing B10 cells declined while regulatory IL-10-producing B10 cells increased in RA patients with disease remission after therapy. Collectively, these results showed that in RA, regulatory B10 cells demonstrated the potential of converting into RANKL-producing cells, thus exacerbating osteoclast formation, bone destruction and disease progression. Modulating the status of B10 cells might provide novel therapeutic strategies for RA.

One-Dimensional Zinc-Based Coordination Polymer as a Higher Capacity Anode Material for Lithium Ion Batteries.

A zinc-based one-dimensional (1D) coordination polymer ([Zn(H2mpca)2(tfbdc)(H2O)], Zn-ODCP) has been synthesized and characterized by spectroscopic and physicochemical methods, single-crystal X-ray diffraction, and thermogravimetric analysis (H2mpca = 3-methyl-1H-pyrazole-4-carboxylic acid; H2tfbdc = 2,3,5,6-tetrafluoroterephthalic acid). Zn-ODCP shows blue luminescence in the solid state. When Zn-ODCP acts as an anode material for lithium ion batteries, it exhibits a good cyclic stability and a higher reversible capacity of 300 mAh g-1 at 50 mA g-1 after 50 cycles. The higher capacity may be mainly ascribed to the metal ion and ligand all taking part in lithium storage. Searching for electrode materials of lithium ion batteries from 1D metal coordination polymers is a new route.

Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis.

OBJECTIVES: Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA. METHODS: The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions. RESULTS: MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1ß, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells. CONCLUSIONS: Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.