Engineering the interfacial orientation of MoS2/Co9S8 bidirectional catalysts with highly exposed active sites for reversible Li-CO2 batteries.

Sluggish CO2 reduction reaction (CO2RR) and evolution reaction (CO2ER) kinetics at cathodes seriously hamper the applications of Li-CO2 batteries, which have attracted vast attention as one kind of promising carbon-neutral technology. Two-dimensional transition metal dichalcogenides (TMDs) have shown great potential as the bidirectional catalysts for CO2 redox, but how to achieve a high exposure of dual active sites of TMDs with CO2RR/CO2ER activities remains a challenge. Herein, a bidirectional catalyst that vertically growing MoS2 on Co9S8 supported by carbon paper (V-MoS2/Co9S8@CP) has been designed with abundant edge as active sites for both CO2RR and CO2ER, improves the interfacial conductivity, and modulates the electron transportation pathway along the basal planes. As evidenced by the outstanding energy efficiency of 81.2% and ultra-small voltage gap of 0.68 V at 20 µA cm-2, Li-CO2 batteries with V-MoS2/Co9S8@CP show superior performance compared with horizontally growing MoS2 on Co9S8 (H-MoS2/Co9S8@CP), MoS2@CP, and Co9S8@CP. Density functional theory calculations help reveal the relationship between performance and structure and demonstrate the synergistic effect between MoS2 edge sites and Co9S8. This work provides an avenue to understand and realize rationally designed electronic contact of TMDs with specified crystal facets, but more importantly, provides a feasible guide for the design of high-performance cathodic catalyst materials in Li-CO2 batteries.

Pseudorabies virus usurps non-muscle myosin heavy chain IIA to dampen viral DNA recognition by cGAS for antagonism of host antiviral innate immunity.

Alphaherpesvirus pseudorabies virus (PRV) causes severe economic losses to the global pig industry and has garnered increasing attention due to its broad host range including humans. PRV has developed a variety of strategies to antagonize host antiviral innate immunity. However, the underlying mechanisms have not been fully elucidated. In our previous work, we demonstrated that non-muscle myosin heavy chain IIA (NMHC-IIA), a multifunctional cytoskeleton protein, attenuates innate immune responses triggered by RNA viruses. In the current study, we reported a previously unrecognized role of NMHC-IIA in counteracting PRV-induced cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) production. Mechanistically, PRV infection led to an elevation of NMHC-IIA, strengthening the interaction between poly (ADP-ribose) polymerase 1 (PARP1) and cGAS. This interaction impeded cGAS recognition of PRV DNA and hindered downstream signaling activation. Conversely, inhibition of NMHC-IIA by Blebbistatin triggered innate immune responses and enhanced resistance to PRV proliferation both in vitro and in vivo. Taken together, our findings unveil that PRV utilizes NMHC-IIA to antagonize host antiviral immune responses via impairing DNA sensing by cGAS. This in-depth understanding of PRV immunosuppression not only provides insights for potential PRV treatment strategies but also highlights NMHC-IIA as a versatile immunosuppressive regulator usurped by both DNA and RNA viruses. Consequently, NMHC-IIA holds promise as a target for the development of broad-spectrum antiviral drugs.IMPORTANCECyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in counteracting alphaherpesvirus infections. Alphaherpesviruses exploit various strategies for antagonizing cGAS-STING-mediated antiviral immune responses. However, limited examples of pseudorabies virus (PRV)-caused immunosuppression have been documented. Our findings reveal a novel role of non-muscle myosin heavy chain IIA (NMHC-IIA) in suppressing PRV-triggered innate immune responses to facilitate viral propagation both in vitro and in vivo. In detail, NMHC-IIA recruits poly (ADP-ribose) polymerase 1 (PARP1) to augment its interaction with cGAS, which impairs cGAS recognition of PRV DNA. Building on our previous demonstration of NMHC-IIA's immunosuppressive role during RNA virus infections, these findings indicate that NMHC-IIA acts as a broad-spectrum suppressor of host antiviral innate immunity in response to both DNA and RNA viruses. Therefore, NMHC-IIA will be a promising target for the development of comprehensive antiviral strategies.

Liposomal STAT3-Degrading PROTAC Prodrugs Promote Anti-Hepatocellular Carcinoma Immunity via Chemically Reprogramming Cancer Stem Cells.

Cancer stem cells (CSCs) with hyperactivated signal transducer and activator of transcription 3 (STAT3) are a major driver of hepatocellular carcinoma (HCC). Herein, we report a nanointegrative proteolysis-targeting chimera (PROTAC)-based STAT3 degradation strategy that enables efficient chemical reprogramming of HCC-associated CSCs, which potently inhibits CSC growth while evoking anti-HCC immune responses. The PROTAC prodrug was synthesized by conjugating the STAT3 binding domain (inS3) with a thioketal-caged E3 ligase ligand (VL-TK) via an oligo(ethylene glycol) linker (OEG) with tuned length and flexibility and encapsulating it in cRGD-modified cationic liposomes for CSC-targeted delivery while facilitating their lysosomal escape. The PROTAC prodrugs were activated by the upregulated ROS levels in CSCs and efficiently degraded STAT3 for chemical reprogramming, which would not only impair their stemness features but also remodel the immunosuppressive TME into an immunosupportive state to boost anti-HCC immunity. This strategy provides an approach for improving HCC treatment in clinics.

Preparation of cellulose acetate based flexible separator and its application in zinc-air batteries.

Flexible solid-state zinc-air batteries as a wearable energy storage device with great potential, and their separators, which control ion permeability, inhibit zinc dendrite generation, and regulate catalytic active sites, have been developed as gel electrolyte separators with high retention of electrolyte uptake. However, the gel electrolyte separator still has problems such as poor affinity with the electrolyte and poor ionic conductivity, which limits its further application. In order to further improve the electrolyte absorption, ionic conductivity and mechanical strength of cellulose acetate(CA)/polyvinyl alcohol (PVA) nanofibers, TiO2was added to CA/PVA to increase the porosity, and glutaraldehyde (GA) was used to modify the CA/PVA/TiO2separator by acetal reaction with CA and PVA to make the molecules closely linked. The results shows that the optimal mass fractions of TiO2and GA were 2% and 5%, respectively. At this time, the porosity and absorption rate of the separator increased from 48% to 68.2% and 142.4% to 285.3%, respectively. The discharge capacity reached 179 mA cm-3, and the cycle stability rate was 89% after 7 stable constant current charge/discharge cycles.

Biomaterial-enabled therapeutic modulation of cGAS-STING signaling for enhancing antitumor immunity.

cGAS-STING signaling is a central component in the therapeutic action of most existing cancer therapies. The accumulated knowledge of tumor immunoregulatory network in recent years has spurred the development of cGAS-STING agonists for tumor treatment as an effective immunotherapeutic strategy. However, the clinical translation of these agonists is thus far unsatisfactory because of the low immunostimulatory efficacy and unrestricted side effects under clinically relevant conditions. Interestingly, the rational integration of biomaterial technology offers a promising approach to overcome these limitations for more effective and safer cGAS-STING-mediated tumor therapy. Herein, we first outline the cGAS-STING signaling axis and generally discuss its association with tumors. We then symmetrically summarize the recent progress in those biomaterial-based cGAS-STING agonism strategies to generate robust antitumor immunity, categorized by the chemical nature of those cGAS-STING stimulants and carrier substrates. Finally, a perspective is provided to discuss the existing challenges and potential opportunities in cGAS-STING modulation for tumor therapy.

Combined effects of polystyrene nanoplastics and lipopolysaccharide on testosterone biosynthesis and inflammation in mouse testis.

Microplastics (MPs)/nanoplastics (NPs), as a source and vector of pathogenic bacteria, are widely distributed in the natural environments. Here, we investigated the combined effects of polystyrene NPs (PS-NPs) and lipopolysaccharides (LPS) on testicular function in mice for the first time. 24 male mice were randomly assigned into 4 groups, control, PS-NPs, LPS, and PS-NPs + LPS, respectively. Histological alterations of the testes were observed in mice exposed to PS-NPs, LPS or PS-NPs + LPS. Total sperm count, the levels of testosterone in plasma and testes, the expression levels of steroidogenic acute regulatory (StAR) decreased more remarkable in testes of mice treated with PS-NPs and LPS than the treatment with LPS or PS-NPs alone. Compared with PS-NPs treatment, LPS treatment induced more sever inflammatory response in testes of mice. Moreover, PS-NPs combined with LPS treatment increased the expression of these inflammatory factors more significantly than LPS treatment alone. In addition, PS-NPs or LPS treatment induced oxidative stress in testes of mice, but their combined effect is not significantly different from LPS treatment alone. These results suggest that PS-NPs exacerbate LPS-induced testicular dysfunction. Our results provide new evidence for the threats to male reproductive function induced by both NPs and bacterial infection in human health.

Acute exposure to polystyrene nanoplastics induces unfolded protein response and global protein ubiquitination in lungs of mice.

Inhaling microplastics (MPs) and nanoplastics (NPs) in the air can damage lung function. Xenobiotics in the body can cause endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) activation alleviates ER stress. Degradation of unfolded or misfolded proteins is an important pathway for recovering cellular homeostasis. The UPR and protein degradation induced by MPs/NPs in lung tissues are not well understood. Here, we investigated the UPR and protein ubiquitination in the lungs of mice exposed to polystyrene (PS)-NPs and their possible molecular mechanisms leading to protein ubiquitination. Mice were intratracheally administered with 5.6, 17, and 51 mg/kg PS-NPs once for 24 h. Exposure to PS-NPs elevated protein ubiquitination in the lungs of mice in a dose-dependent manner. PS-NPs activated three branches of UPR including inositol-requiring protein 1α (IRE1α), eukaryotic translation initiator factor 2α (eIF2α), and activating transcription factor 6α (ATF6α) in the lungs of mice. However, activated IRE1α did not trigger X-box binding protein 1 (XBP1) mRNA splicing. Exposure to PS-NPs induced an increase in the levels of E3 ubiquitin ligase hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (HRD1) and carboxy terminus of Hsc70 interacting protein (CHIP) in the lungs of mice and BEAS-2B cells. ATF6α siRNA inhibited the levels of HRD1 and CHIP proteins induced by PS-NPs in BEAS-2B cells. These results suggest that ATF6α plays a critical role in increasing ubiquitination of unfolded or misfolded proteins by alleviating PS-NPs induced ER stress through UPR to achieve ER homeostasis in the lungs of mice.

Multi-Attack Intrusion Detection for In-Vehicle CAN-FD Messages.

As an enhanced version of standard CAN, the Controller Area Network with Flexible Data (CAN-FD) rate is vulnerable to attacks due to its lack of information security measures. However, although anomaly detection is an effective method to prevent attacks, the accuracy of detection needs further improvement. In this paper, we propose a novel intrusion detection model for the CAN-FD bus, comprising two sub-models: Anomaly Data Detection Model (ADDM) for spotting anomalies and Anomaly Classification Detection Model (ACDM) for identifying and classifying anomaly types. ADDM employs Long Short-Term Memory (LSTM) layers to capture the long-range dependencies and temporal patterns within CAN-FD frame data, thus identifying frames that deviate from established norms. ACDM is enhanced with the attention mechanism that weights LSTM outputs, further improving the identification of sequence-based relationships and facilitating multi-attack classification. The method is evaluated on two datasets: a real-vehicle dataset including frames designed by us based on known attack patterns, and the CAN-FD Intrusion Dataset, developed by the Hacking and Countermeasure Research Lab. Our method offers broader applicability and more refined classification in anomaly detection. Compared with existing advanced LSTM-based and CNN-LSTM-based methods, our method exhibits superior performance in detection, achieving an improvement in accuracy of 1.44% and 1.01%, respectively.

Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders.

A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development and function of oligodendrocytes (OLs) and interneurons. OLs are the myelin-forming cells in the central nervous system (CNS), while interneurons are important neural types gating the function of excitatory neurons. These two types of cells are of great significance for the establishment and function of neural circuits, and they share similar developmental origins and transcriptional architectures, and interact with each other in multiple ways during development. In this review, we compare the similarities and differences in these two cell types, providing an important reference and further revealing the pathogenesis of related brain disorders.

A Review of the Role of Tendon Stem Cells in Tendon-Bone Regeneration.

Tendon-bone injuries are a prevalent health concern associated with sports and other physically demanding activities. These injuries have a limited innate healing ability, often leading to the formation of scar tissue rather than the regeneration of healthy tendon tissue. This scar tissue results from excessive fibrosis during the early healing process and often leads to reduced tendon function and an increased risk of reinjury. Traditionally, surgical reconstruction has been the primary treatment for tendon-bone injuries. However, restoring the natural structure and mechanical properties of tendons after surgical reconstruction presents a considerable challenge. Recently, the potential of stem cell therapy has been explored as an alternative treatment approach. In particular, a new type of pluripotent stem cell known as tendon stem cells (TDSCs) has been identified within tendon tissue. These cells exhibit the potential for self-renewal and multidirectional differentiation, meaning they can differentiate into fibroblasts and chondrocytes. These differentiated cells can aid in the repair and regeneration of new tissues by producing collagen and other matrix molecules that provide structural support. TDSCs have become a focal point in research for treating tendon-bone injuries and related conditions. The potential use of these cells provides a basis for both basic research and clinical applications, particularly in understanding the tendon-bone healing process and identifying factors that affect the ability of TDSCs to promote this healing. This review article aims to analyze the role of TDSCs in tendon-bone healing, understanding their therapeutic potential and contributing to the development of effective treatment strategies for tendon-bone injuries.

Exploring the Mitogenomes of Mantodea: New Insights from Structural Diversity and Higher-Level Phylogenomic Analyses.

The recently reorganized classification of Mantodea has made significant progress in resolving past homoplasy problems, although some relationships among higher taxa remain uncertain. In the present study, we utilized newly sequenced mitogenomes and nuclear gene sequences of 23 mantid species, along with published data of 53 mantises, to perform familial-sampling structural comparisons of mantodean mitogenomes and phylogenomic studies. Our rstructural analysis revealed generally conserved mitogenome organizations, with a few cases of tRNA gene rearrangements, including the detection of trnL2 duplication for the first time. In our phylogenetic analysis, we found a high degree of compositional heterogeneity and lineage-specific evolutionary rates among mantodean mitogenomes, which frequently corresponded to several unexpected groupings in the topologies under site-homogeneous models. In contrast, the topologies obtained using the site-heterogeneous mixture model fit the currently accepted phylogeny of Mantodea better. Topology tests and four-cluster likelihood mapping analyses further determined the preferred topologies. Our phylogenetic results confirm the monophyly of superfamilial groups Schizomantodea, Amerimantodea, Heteromantodea, Promantidea, and Mantidea and recover the early-branching relationships as (Mantoidoidea + (Amerimantodea + (Metallyticoidea + Cernomantodea))). Additionally, the results suggest that the long-unresolved phylogenetic position of Majangidae should be placed within Mantidea, close to Mantoidea, rather than within Epaphroditoidea. Our findings contribute to understanding the compositional and structural diversity in mantodean mitogenomes, underscore the importance of evolutionary model selection in phylogenomic studies, and provide new insights into the high-level phylogeny of Mantodea.

Designing Electrophilic and Nucleophilic Dual Centers in the ReS2 Plane toward Efficient Bifunctional Catalysts for Li-CO2 Batteries.

Two-dimensional transition metal dichalcogenides (TMDCs) show great potential as efficient catalysts for Li-CO2 batteries. However, the basal plane engineering on TMDCs toward bifunctional catalysts for Li-CO2 batteries is still poorly understood. In this work, density functional theory calculations reveal that nucleophilic N dopants and electrophilic S vacancies in the ReS2 plane tailor the interactions with Li atoms and C/O atoms in intermediates, respectively. The electrophilic and nucleophilic dual centers show suitable adsorption with all intermediates during discharge and charge, resulting in a small energy barrier for the rate-determining step. Thus, an efficient bifunctional catalyst is produced toward Li-CO2 batteries. As a result, the optimal catalyst achieves an ultrasmall voltage gap of 0.66 V and an ultrahigh energy efficiency of 81.1% at 20 µA cm-2, which is superior to those of previous catalysts under similar conditions. The introduction of electrophilic and nucleophilic dual centers provides new avenues for designing excellent bifunctional catalysts for Li-CO2 batteries.

Black phosphorous nanomaterials as a new paradigm for postoperative tumor treatment regimens.

Surgery is currently a mainstream treatment modality for various solid tumor indications. However, aggressive resection of tumor tissues frequently causes postoperative complications, which severely undermine the well-being of patients. Moreover, the residue tumor cells may substantially increase the risk of local and distant tumor relapse. The recent development in black phosphorus (BP)-based nanomaterials offers a promising opportunity to address these clinical challenges. BP is an emerging nanomaterial with excellent biocompatibility and versatile functionality, which has already demonstrated great potential for a variety of biomedical applications including tumor therapy and tissue engineering. In this review, the recent advances in BP-based nanobiomaterials for the post-surgery treatment of solid tumor have been summarized, while specific emphasis was placed on their capability to continuously inhibit residue tumor growth at the surgery site as well as stimulating various healing mechanisms, aiming to preventing tumor relapse while promoting the healing of surgery-induced traumatic soft/hard tissue injuries. It is anticipated that the nanoengineered BP-based materials may open new avenues to tackle those clinical challenges in surgical treatment of solid tumors.

A synthetic biscoumarin suppresses lung cancer cell proliferation and induces cell apoptosis by increasing expression of RIP1.

Coumarin has a variety of biological activities and widely exists in plants. Biscoumarin, derived from coumarin, their synthetic methods and bioactivities of biscoumarins is the hotspot of the current research. In this study, we evaluated for the first time the anticancer of a synthetic biscoumarin (3,3'-(4-chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one, C3) on lung cancer cells and explored the related mechanism. C3 was simply prepared by 4-hydroxycoumarin and 4-chlorobenzaldehyde under ethanol. The structure of C3 was elucidated by various spectroscopic analyses. The antiproliferation effect of C3 was evaluated by the cell counting kit-8 assay. Cell cycle and apoptosis analysis were detected by flow cytometry. The expression of correlated proteins was determined using Western blotting. The result showed that C3 displayed a strong cytostatic effect on Lewis lung cancer (LLC) cells. C3 inhibited the proliferation of LLC cells, and induced G2/M phase cell cycle arrest. In addition, C3 possessed a significant reduction on cell apoptosis by increasing of RIP1 expression. Our data showed that C3 suppresses lung cancer cell proliferation and induces cell apoptosis, which is possibly involved with the RIP1.

Exploring the Role and Mechanism of Adipose Derived Mesenchymal Stem Cells on Reversal of Pigmentation Model Effects.

Interventions for extrinsic aging can be implemented, but these must address photoaging, which is the primary cause of extrinsic aging. Pigmentation due to photoaging depends on the duration and intensity of sun exposure. This study investigated the relationship between adipose-derived mesenchymal stem cells (ASCs) and photoaging pigmentation, and the underlying mechanism of action by establishing a photoaging pigmentation model using various treatments and exposure options in a guinea pigs. The energy dose of each UVB irradiation was 120 mJ/cm2 and the total dose of irradiation was 360 mJ/cm2. After successfully establishing the photoaging model, ASCs (1×106) in an balanced salt solution (0.9 ml), balanced salt solution (0.9 ml), and bFGF (9 µg) mixed with an balanced salt solution (0.9 ml) were injected intradermally in ten guinea pigs. ELISA, macroscopic skin and histological observations, and Masson-Fontana staining were done. At 2 and 4 weeks post-injection, noticeable changes were observed. Guinea pigs receiving ASCs injections displayed significantly lower visible skin scores while the melanin content continued to decrease. Somewhat improved histopathological morphology, including epidermal thinning, dermal thickening, and little inflammatory cell infiltration was observed immediately after and up to 4 weeks of ASCs injection. Melanocortin 1 receptor (MC1R) and alpha-melanocyte test hormone (alpha-MSH) levels reduced significantly, and basic fibroblast growth factor (bFGF) levels increased significantly immediately after and up to 4 weeks of ASCs injection. The MC1R and alpha-MSH levels reduced significantly immediately after and up to 4 weeks of bFGF injection. Briefly, intradermal ASCs injection can notably eliminate pigmentation in a guinea pig photoaging pigmentation model. This may be related to the fact that bFGF secreted by ASCs lowers MC1R and alpha-MSH levels, blocks the cAMP signalling pathway, and inhibits melanin synthesis. This finding may present new options for treating photoaging pigmentation.Level of Evidence: N/A.

New Insights into TETs in Psychiatric Disorders.

Psychiatric disorders are complex and heterogeneous disorders arising from the interaction of multiple factors based on neurobiology, genetics, culture, and life experience. Increasing evidence indicates that sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Over the past decade, the critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Here, we review the progress of studies designed to provide a better understanding of how profiles of TET proteins and 5hmC are powerful mechanisms by which to explain neuronal plasticity and long-term behaviors, and impact transcriptional programs operative in the brain that contribute to psychiatric disorders.

Infrared-Visible Image Fusion Based on Semantic Guidance and Visual Perception.

Infrared-visible fusion has great potential in night-vision enhancement for intelligent vehicles. The fusion performance depends on fusion rules that balance target saliency and visual perception. However, most existing methods do not have explicit and effective rules, which leads to the poor contrast and saliency of the target. In this paper, we propose the SGVPGAN, an adversarial framework for high-quality infrared-visible image fusion, which consists of an infrared-visible image fusion network based on Adversarial Semantic Guidance (ASG) and Adversarial Visual Perception (AVP) modules. Specifically, the ASG module transfers the semantics of the target and background to the fusion process for target highlighting. The AVP module analyzes the visual features from the global structure and local details of the visible and fusion images and then guides the fusion network to adaptively generate a weight map of signal completion so that the resulting fusion images possess a natural and visible appearance. We construct a joint distribution function between the fusion images and the corresponding semantics and use the discriminator to improve the fusion performance in terms of natural appearance and target saliency. Experimental results demonstrate that our proposed ASG and AVP modules can effectively guide the image-fusion process by selectively preserving the details in visible images and the salient information of targets in infrared images. The SGVPGAN exhibits significant improvements over other fusion methods.

Suppression of Sox4 protects against myocardial ischemic injury by reduction of cardiac apoptosis in mice.

Sox4 participates in the progression of embryo development and regulation of apoptosis in tumors. However, the effect and mechanism of Sox4 in myocardial infarction (MI) remains unclear. Therefore, we aimed at examining the role and molecular mechanism of Sox4 in the process of cardiomyocytes apoptosis during MI. The expression of Sox4 were obviously increased both in MI mice and in neonatal mouse cardiomyocytes treated with H2 O2 . Overexpression of Sox4 promoted cardiomyocyte apoptosis with or without H2 O2 , whereas knocking down of Sox4 alleviated H2 O2 -induced apoptosis in cardiomyocytes. Furthermore, silencing Sox4 by AAV-9 carried short hairpin RNA targeting Sox4 (AAV-9-sh-Sox4) markedly decreased cardiac infarct area, imprfoved cardiac dysfunction, and reversed apoptosis in MI mice. Mechanistically, there is a potential Sox4-binding site in the promoter region of Bim, and forced expression of Sox4 significantly promoted Bim expression in cultured cardiomyocytes with or without H2 O2 , whereas knocking down of Sox4 inhibited the expression of Bim. Further studies showed that silencing Bim attenuated Sox4-induced apoptosis in cardiomyocytes, indicating that Sox4 promoted cardiomyocytes apoptosis through regulation of Bim expression, which can be used as a potential therapeutic target for MI.

Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthritis.

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for osteoporosis (OP) and rheumatoid arthritis (RA), individually, however, a large proportion of the total trait heritability remains unexplained. Previous studies demonstrated that these two diseases may share some common genetic determination and risk factors, but they were generally focused on individual trait and failed to identify the common variants that play key functional roles in the etiology of these two diseases. Here, we performed a conditional false discovery rate (cFDR) analysis to identify novel pleiotropic variants shared between them by integrating two independent GWASs with summary statistics for total body bone mineral density (TB-BMD, a major risk factor for osteoporosis) (n = 66,628) and RA (n = 58,284). A fine-mapping approach was also applied to identify the most probable causal variants with biological effects on both TB-BMD and RA. As a result, we found 47 independent pleiotropic SNPs shared between TB-BMD and RA, and 40 of them were validated in heel ultrasound estimated BMD (eBMD), femoral neck BMD (FN-BMD) or lumbar spine (LS-BMD). We detected one SNP (rs13299616) was novel and not identified by previous BMD or RA-related studies. Combined with fine-mapping and GWAS-eQTL colocalization analyses, our results suggested that locus 1p13.2 (including PTPN22, MAGI3, PHTF1, and RSBN1) was an important region to regulate TB-BMD and RA simultaneously. These findings provide new insights into the shared biological mechanisms and functional genetic determinants between OP and RA, and novel potential targets for treatment development.

Arsenic trioxide induces expression of BCL-2 expression via NF-κB and p38 MAPK signaling pathways in BEAS-2B cells during apoptosis.

Inorganic arsenic compounds are environmental toxicants that are widely distributed in air, water, and food. B-cell lymphoma 2 (BCL-2) is an oncogene having anti-apoptotic function. In this study, we clarify that BCL-2, as a pro-apoptotic factor, participates in As2O3-induced apoptosis in BEAS-2B cells. Specifically, As2O3 stimulated the expression of BCL-2 mRNA and protein in a dose-dependent manner which was highly accumulated in the nucleus of BEAS-2B cell together with chromatin condensation and DNA fragmentation during apoptosis. Mechanistically, the process described above is mediated through the NF-κB and p38 MAPK signaling pathways, which can be abated by corresponding inhibitors, such as BAY11-7082 and SB203580, respectively. Additionally, BAY11-7082, actinomycin D, and cycloheximide have inhibitory effects on As2O3-induced expression of BCL-2 mRNA and protein, and restore the cell viability of BEAS-2B cells. Suppression of BCL-2 protein activation by ABT-199 also restored viability of BEAS-2B cell in As2O3-induced apoptosis. Furthermore, As2O3 increased the level of BCL-2 phosphorylation. These results suggest that in BEAS-2B cells, As2O3-induced apoptosis is mainly dominated by BCL-2 upregulation, nuclear localization and phosphorylation. The study presented here provides a novel insight into the molecular mechanism of BCL-2-induced apoptosis.