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Abstract Background Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. Methods To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. Results Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). Conclusions Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity. Graphical Abstract

Abstract Clamping bushing structure is an internode connection mechanism designed for the standard section of tubular truss tower. In this paper, the clamping bushing structure of the connecting mechanism of super-large tower crane is taken as the research object, a three-dimensional model of clamping bushing structure is established and imported into ABAQUS, and its multi-body contact model is further constructed to study the contact and bearing relationship of the structure under multiple working conditions, and the accuracy of the calculation results of the model is verified by the experimental stress test under tensile working conditions. In addition, this study is based on the control variable method, and through the design of orthogonal test table, the influence degree of five variable parameters of clamping bushing on the bearing capacity of the structure is investigated. Finally, through the range analysis, the optimal horizontal combination of variables and parameters of clamping bushing structure is obtained, and the optimal matching relationship between the shape of the tower connecting mechanism and the bearing capacity is obtained. The results show that, compared with the original model, the stress concentration at the most dangerous section of the optimized joint and the bushing is obviously alleviated, in which the stress peaks of the upper and lower joints are kept below 500 MPa, and the stress peaks of the bushing groove are also reduced to between 573 and 722 MPa. Moreover, the designed and optimized lower joint can reduce the maximum equivalent plastic strain of the joint root circumference by 56.05% under the original maximum tensile condition, and the overall distribution trend of equivalent plastic strain is more uniform, and a more reliable structural design is obtained, which plays an important guiding role in the design, optimization and analysis of the connecting mechanism of the tower body of large tower crane.

Abstract Background Environmental factors play an important role in developing mental disorders. This study aimed to investigate the associations of metal and nonmetal elements in drinking water with the risk of depression and anxiety and to assess whether diets modulate these associations. Methods We conducted a prospective cohort study including 24,285 participants free from depression and anxiety from the Yinzhou Cohort study in the 2016–2021 period. The exposures were measured by multiplying metal and nonmetal element concentrations in local pipeline terminal tap water samples and total daily drinking water intakes. Cox regression models adjusted for multi-level covariates were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (95%CIs). Results During an average follow-up period of 4.72 and 4.68 years, 773 and 1334 cases of depression and anxiety were identified, respectively. A 1 standard deviation (SD) increase in manganese exposure reduced the incidence of depression by 8% (HR 0.92, 95%CI 0.88 to 0.97). In contrast, with a 1 SD increase in copper and cadmium exposure, the incidence of depression increased by 6% (HR 1.06, 95%CI 1.01 to 1.11) and 8% (HR 1.08, 95%CI 1.00 to 1.17), respectively. The incidence of anxiety increased by 39% (HR 1.39, 95%CI 1.20 to 1.62), 33% (HR 1.33, 95%CI 1.03 to 1.71), and 14% (HR 1.14, 95%CI 1.03 to 1.25) respectively for a 1 SD increase in manganese, iron, and selenium exposure. Diets have a moderating effect on the associations of metal and nonmetal elements with the risk of anxiety. Stronger associations were observed in older, low-income groups and low-education groups. Conclusions We found significant associations between exposure to metal and nonmetal elements and depression and anxiety. Diets regulated the associations to some extent.

Abstract To evaluate the possible thermal risks associated with the storage of octogen (HMX), non-isothermal differential scanning calorimetry (DSC) experiments were conducted in order to ascertain the kinetic model and parameters governing its thermal decomposition. DSC measurements indicate that HMX underwent a crystal transformation prior to thermal decomposition. A kinetic model for the autocatalytic thermal decomposition process was developed through the analysis of its primary exothermic peaks. Subsequently, numerical simulations were performed using the aforementioned kinetic model to assess the potential thermal explosion hazard of HMX under two distinct storage conditions. The comparison was made between the models of HMX autocatalytic decomposition temperature and thermal explosion critical temperature under two distinct storage conditions. The prediction of the influence of ambient temperature on the critical temperature of thermal explosion is conducted simultaneously. Finally, the thermal hazard parameters of HMX under different package quality are given.

Abstract Background Sepsis is a life-threatening organ dysfunction caused by abnormal immune responses to various, predominantly bacterial, infections. Different bacterial infections lead to substantial variation in disease manifestation and therapeutic strategies. However, the underlying cellular heterogeneity and mechanisms involved remain poorly understood. Methods Multiple bulk transcriptome datasets from septic patients with 12 types of bacterial infections were integrated to identify signature genes for each infection. Signature genes were mapped onto an integrated large single-cell RNA (scRNA) dataset from septic patients, to identify subsets of cells associated with different sepsis types, and multiple omics datasets were combined to reveal the underlying molecular mechanisms. In addition, an scRNA dataset and spatial transcriptome data were used to identify signaling pathways in sepsis-related cells. Finally, molecular screening, optimization, and de novo design were conducted to identify potential targeted drugs and compounds. Results We elucidated the cellular heterogeneity among septic patients with different bacterial infections. In Escherichia coli (E. coli) sepsis, 19 signature genes involved in epigenetic regulation and metabolism were identified, of which DRAM1 was demonstrated to promote autophagy and glycolysis in response to E. coli infection. DRAM1 upregulation was confirmed in an independent sepsis cohort. Further, we showed that DRAM1 could maintain survival of a pro-inflammatory monocyte subset, C10_ULK1, which induces systemic inflammation by interacting with other cell subsets via resistin and integrin signaling pathways in blood and kidney tissue, respectively. Finally, retapamulin was identified and optimized as a potential drug for treatment of E. coli sepsis targeting the signature gene, DRAM1, and inhibiting E. coli protein synthesis. Several other targeted drugs were also identified in other types of sepsis, including nystatin targeting C1QA in Neisseria sepsis and dalfopristin targeting CTSD in Streptococcus viridans sepsis. Conclusion Our study provides a comprehensive overview of the cellular heterogeneity and underlying mechanisms in septic patients with various bacterial infections, providing insights to inform development of stratified targeted therapies for sepsis.

Abstract Background Epidemiology is considered to be the fundamental science of public health and plays an important role in clinical competence and professional development. The objective of this study is to evaluate the effectiveness of a short-term course for the teaching of epidemiology, which was designed as a community-based class for medical students. Method This course was designed according to Kern’s six-step approach to curriculum development. A total of 75 undergraduates were recruited. Forty-one students were assigned to an experimental group engaged in theoretical teaching and practical courses, while 34 students were assigned to the control group only taking theoretical courses. All participants were asked to complete a pre- and post-course survey and to take a test after completing the course. The scores between the experimental and control groups were compared using the Wilcoxon test. Result The experimental group showed significantly higher self-assessment scores in course understanding (p = 0.0126) and clinical practice skills (p = 0.0005) after completing the course, while no significant difference was observed in the control group. In addition, students in the experimental group reported significantly higher interest (p = 0.0015), stronger learning motivation (p = 0.0113) and a better mastery of epidemiology (p = 0.0167) after completing the course than those in the control group. However, test scores (p = 0.0859) and pass rates (p = 0.1755) demonstrated no statistical significance between the two groups. Conclusion The short-term practical course in epidemiology exerted significantly positive effects on the improvement of student learning enthusiasm, course understanding and clinical practice skills. These findings provide new ideas and statistical evidence for the development of epidemiological instruction. Future studies should explore how to more widely and optimally apply community-based courses to the teaching of epidemiology.

Abstract The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90β, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.

Abstract Background Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1). Methods Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined. Results Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3−, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6−Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase. Conclusions Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

Abstract With an increase in tunnel construction and retention, traditional waterproofing and drainage systems have been unable to meet the needs of tunnels in heavy rainfall areas, and disasters such as tunnel lining cracking, leakage, and even collapse, occur frequently. In order to ensure the safe operation and maintenance of tunnels, this paper analyses the characteristics of the traditional waterproofing and drainage system, and puts forward a new drainage structure through numerical simulation and indoor testing. This structure removes the circular drainage blind pipe and adds a convex shell drainage plate between the waterproof board and the secondary lining. The research shows that the new drainage system greatly decreases the water pressure in the easily blocked area of the drainage structure. With the special surface discharge model, the external water pressure of the lining far away from the blocked area can quickly fall back to the normal level. In addition, the drainage capacity of different waterproof and drainage boards is different. With an increase in support pressure, the drainage capacity decreases; the geotextile decreases the most, followed by the capillary drainage board and then the convex shell drainage board. At the same time, after the muddy water drainage test of the three materials, it is found that the convex shell type drainage plate has the best anti-sludge performance. The research in this paper provides a beneficial attempt for the design of waterproofing and drainage structure of a water-rich karst tunnel, and provides a guarantee for the safe operation and maintenance of the tunnel.

Abstract Background Psoriasis is a chronic inflammatory dermatosis with an unclear pathogenesis. Mast cells (MCs) can serve as a bridge between innate and adaptive immunity and are involved in the regulation of the inflammatory state and immune homeostasis in diseases. MCs constitutively express interleukin-33 receptor T1/ST2 (IL-33R). IL-33 is a potent MCs activator that is actively secreted by keratinocytes in psoriasis. However, the regulatory role of MCs in psoriasis remains uncertain. Therefore, we hypothesised that IL-33 could promote MC activation to regulate psoriasis development. Methods We performed experiments on wild-type (WT) and MC-deficient (Kit Wsh/Wsh) mice, established psoriasis-like mouse models using imiquimod (IMQ), and performed RNA sequencing and transcriptomic analysis of skin lesions. Exogenous administration was performed using recombinant IL-33. Validation and evaluation were performed using PSI scoring, immunofluorescence, immunohistochemistry, and qPCR. Results We observed an upregulation in the number and activation of MCs in patients with psoriasis and in IMQ-induced psoriasis-like dermatitis. Deficiency of MCs ameliorates IMQ-induced psoriatic dermatitis at an early stage. IL-33 is increased and co-localized with MCs in the dermis of psoriasis-like lesions using immunofluorescence. Compared to WT mice, IMQ-induced KitWsh/Wsh mice demonstrated a delayed response to exogenous IL-33. Conclusions MCs are activated by IL-33 in the early stages of psoriasis and exacerbate psoriasis-associated skin inflammation. The regulation of MC homeostasis may be a potential therapeutic strategy for psoriasis. Video Abstract

Background Postmenopausal osteoporosis and osteoporosis-related fractures are world-wide serious public health problem. Recent studies demonstrated that inhibiting caveolin-1 leads to osteoclastogenesis suppression and protection against OVX-induced osteoporosis. This study aimed to explore the mechanism of caveolin-1 mediating bone loss and the potential therapeutic target. Methods Thirty C57BL/6 female mice were allocated randomly into three groups: sham or bilateral ovariectomy (OVX) surgeries were performed for mice and subsequently daidzein or vehicle was administrated to animals (control, OVX + vehicle and OVX + daidzein). After 8-week administration, femurs were harvested for Micro-CT scan, histological staining including H&E, immunohistochemistry, immunofluorescence, TRAP. Bone marrow endothelial cells (BMECs) were cultured and treated with inhibitors of caveolin-1 (daidzein) or EGFR (erlotinib) and then scratch wound healing and ki67 assays were performed. In addition, cells were harvested for western blot and PCR analysis. Results Micro-CT showed inhibiting caveolin-1with daidzein alleviated OVX-induced osteoporosis and osteogenesis suppression. Further investigations revealed H-type vessels in cancellous bone were decreased in OVX-induced mice, which can be alleviated by daidzein. It was subsequently proved that daidzein improved migration and proliferation of BMECs hence improved H-type vessels formation through inhibiting caveolin-1, which suppressed EGFR/AKT/PI3K signaling in BMECs. Conclusions This study demonstrated that daidzein alleviates OVX-induced osteoporosis by promoting H-type vessels formation in cancellous bone, which then promotes bone formation. Activating EGFR/AKT/PI3K signaling could be the critical reason.

Bone marrow stromal cells (BMSCs) have emerged as a potential therapy for sepsis, yet the underlying mechanisms remain unclear. In this study, we investigated the effects of BMSCs on serum inflammatory cytokines in a rat model of lipopolysaccharide (LPS)-induced sepsis. Sepsis was induced by intravenous injection of LPS, followed by transplantation of BMSCs. We monitored survival rates for 72 h and evaluated organ functions, histopathological changes, and cytokines expression. Sepsis rats showed decreased levels of white blood cells, platelets, lymphocyte ratio, and oxygen partial pressure, along with increased levels of neutrophil ratio, carbon dioxide partial pressure, lactic acid, alanine aminotransferase, and aspartate aminotransferase. Histologically, lung, intestine, and liver tissues exhibited congestion, edema, and infiltration of inflammatory cells. However, after BMSCs treatment, there was improvement in organ functions, histopathological injuries, and survival rates. Protein microarray analysis revealed significant changes in the expression of 12 out of 34 inflammatory cytokines. These findings were confirmed by enzyme-linked immunosorbent assay. Pro-inflammatory factors, such as interleukin-1β (IL-1β), IL-1α, tumor necrosis factor-α (TNF-α), tissue inhibitor of metal protease 1 (TIMP-1), matrix metalloproteinase 8 (MMP-8), Leptin, and L-selectin were upregulated in sepsis, whereas anti-inflammatory and growth factors, including IL-4, β-nerve growth factor (β-NGF), ciliary neurotrophic factor (CNTF), interferon γ (IFN-γ), and Activin A were downregulated. BMSCs transplantation led to a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory and growth factors. We summarized relevant molecular signaling pathways that resulted from cytokines in BMSCs for treating sepsis. Our results illustrated that BMSCs could promote tissue repair and improve organ functions and survival rates in sepsis through modulating cytokine networks.

Abstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. Methods A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. Results In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (P trend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. Conclusions In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Abstract Background Some occult hepatitis B virus (HBV) infections are resulted from PreS mutations that reduce secretion of envelope protein (HBsAg). We investigated the ceramide amounts and species in hepatocytes infected with PreS variants that were isolated from HBsAg-seronegative patients with hepatocellular carcinoma (HCC) and the ceramide effects on autochthonous HCC development in murine models. Methods HBV PreS/S regions from 35 HBsAg-seronegative HCC patients were sequenced. Hepatocyte cell lines and male C57BL/6J mouse livers were transfected with two PreS variant representatives. The ceramides with variated lengths of fatty acyl chains were quantified. Tumour development was examined in the HBV-transfected mice fed different diet types. Results In HBsAg-seronegative HCC patients, nonneoplastic liver tissues harboured HBsAg and replication-competent HBV. The most frequently detected PreS/S variants carried mutations of altered amino acid properties in HBsAg compared with an isolate from one HBsAg-seronegative HCC patient. Hepatocyte infection with PreS variants caused HBsAg retention within the endoplasmic reticulum and generated more amounts of ceramides with C16:0 ceramide elevated the highest. Saturated fatty acids aggravated the PreS variant-infected hepatocytes to generate abnormal amounts and species of ceramides, which with HBV proteins synergistically activated NLRP3 inflammasome in liver inflammatory macrophages. Liver tumours were only detected in HBV-transfected mice fed high-fat diet, with higher tumour loads in the PreS variant-transfected, associated with abnormal ceramide generation. Conclusions HBV PreS mutations which altered amino acid properties of envelope proteins inhibited HBsAg secretion. Hepatocyte infection with PreS variants generated abnormal ceramides which with HBV proteins coactivated NLRP3 inflammasome in liver macrophages to promote autochthonous HCC development.

Abstract RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma (HCC), pancreatic cancer and colon cancer. ZCCHC4 promotes chemoresistance of HCC cells to DNA-damage agent (DDA) both in vitro and in vivo. HCC cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDA-induced antitumor effect. Mechanistically, ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA (lncRNA) AL133467.2 to hamper its pro-apoptotic function. Also, ZCCHC4 blocks the interaction between AL133467.2 and γH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and γH2AX interaction for enhancing chemosensitivity in HCC cells. Together, our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects, providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.

Abstract Sepsis is caused by an uncontrolled inflammatory response, whose underlying mechanisms are not fully understood. It is well known that the majority of human genes can be expressed as alternative isoforms. While isoform switching is implicated in many diseases and is particularly prominent in cancer, it has never been reported in the context of sepsis. Patients presented to the emergency department of three tertiary care hospitals from January 2020 to December 2020 were enrolled. Clinical variables and genome-wide transcriptome of peripheral blood mononuclear cells (PBMC) were obtained. Isoform switching analysis were performed to identify significant isoform switches and relevant biological consequences. A total of 48 subjects with sepsis, involving 42 survivors and 6 non-survivors, admitted to the emergency department of three tertiary care hospitals were enrolled in this study. PBMCs were extracted for RNA sequencing (RNA-seq). Patients (n = 4) with mild stroke or acute coronary syndrome without infection were enrolled in this study as controls. The most frequent functional changes resulting from isoform switching were changes affecting the open reading frame, protein domains and intron retention. Many genes without differences in gene expression showed significant isoform switching. Many genes with significant isoform switches ( $$|dIF|$$ | d I F | > 0.1) were associated with higher mortality risk, including PIGS, CASP3, LITAF, HBB and RUVBL2. The study for the first time described the landscape of isoform switching in sepsis, including differentially expressed isoform fractions between patients with and without sepsis and survivors and nonsurvivors. The biological consequences of isoform switching, including protein domain loss, signal peptide gain, and intron retention, were identified.

Summary: Background: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8+ T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8+ T cells in SLE remain to be identified. Methods: Single-cell RNA sequencing (scRNA-seq) of PBMCs from a SLE family pedigree (including 3 HCs and 2 SLE patients) was performed to identify the SLE-associated CD8+ T cell subsets. Flow cytometry analysis of a SLE cohort (including 23 HCs and 33 SLE patients), qPCR analysis of another SLE cohort (including 30 HCs and 25 SLE patients) and public scRNA-seq datasets of autoimmune diseases were employed to validate the finding. Whole-exome sequencing (WES) of this SLE family pedigree was used to investigate the genetic basis in dysregulation of CD8+ T cell subsets identified in this study. Co-culture experiments were performed to analyze the activity of CD8+ T cells. Findings: We elucidated the cellular heterogeneity of SLE and identified a new highly cytotoxic CD8+ T cell subset, CD161−CD8+ TEMRA cell subpopulation, which was remarkably increased in SLE patients. Meanwhile, we discovered a close correlation between mutation of DTHD1 and the abnormal accumulation of CD161−CD8+ TEMRA cells in SLE. DTHD1 interacted with MYD88 to suppress its activity in T cells and DTHD1 mutation promoted MYD88-dependent pathway and subsequently increased the proliferation and cytotoxicity of CD161−CD8+ TEMRA cells. Furthermore, the differentially expressed genes in CD161−CD8+ TEMRA cells displayed a strong out-of-sample prediction for case–control status of SLE. Interpretation: This study identified DTHD1-associated expansion of CD161−CD8+ TEMRA cell subpopulation is critical for SLE. Our study highlights genetic association and cellular heterogeneity of SLE pathogenesis and provides a mechanistical insight into the diagnosis and treatment of SLE. Fundings: Stated in the Acknowledgements section of the manuscript.

Abstract We calculate the single-particle excitation spectrum and the Landau liquid parameters for the archetypal model of solids, the three-dimensional uniform electron gas, with the variational diagrammatic Monte Carlo method, which gives numerically controlled results without systematic error. In the metallic range of density, we establish benchmark values for the wave-function renormalization factor Z, the effective mass $$m^*/m$$ m ∗ / m , and the Landau parameters $$F_0^s$$ F 0 s and $$F_0^a$$ F 0 a with unprecedented accuracy, and we resolve the long-standing puzzle of non-monotonic dependence of mass on density. We also exclude the possibility that experimentally measured large reduction of bandwidth in Na metal can originate from the charge and spin fluctuations contained in the model of the uniform electron gas.

ObjectivePreventing suicide in US youth is of paramount concern, with rates increasing over 50% between 2007 and 2018. Statistical modeling using electronic health records may help identify at-risk youth before a suicide attempt. While electronic health records contain diagnostic information, which are known risk factors, they generally lack or poorly document social determinants (e.g., social support), which are also known risk factors. If statistical models are built incorporating not only diagnostic records, but also social determinants measures, additional at-risk youth may be identified before a suicide attempt.MethodsSuicide attempts were predicted in hospitalized patients, ages 10-24, from the State of Connecticut's Hospital Inpatient Discharge Database (HIDD; N = 38943). Predictors included demographic information, diagnosis codes, and using a data fusion framework, social determinants features transferred or fused from an external source of survey data, The National Longitudinal Study of Adolescent to Adult Health (Add Health). Social determinant information for each HIDD patient was generated by averaging values from their most similar Add Health individuals (e.g., top 10), based upon matching shared features between datasets (e.g., Pearson's r). Attempts were then modelled using an elastic net logistic regression with both HIDD features and fused Add Health features.ResultsThe model including fused social determinants outperformed the conventional model (AUC = 0.83 v. 0.82). Sensitivity and positive predictive values at 90 and 95% specificity were almost 10% higher when including fused features (e.g., sensitivity at 90% specificity = 0.48 v. 0.44). Among social determinants variables, the perception that their mother cares and being non-religious appeared particularly important to performance improvement.DiscussionThis proof-of-concept study showed that incorporating social determinants measures from an external survey database could improve prediction of youth suicide risk from clinical data using a data fusion framework. While social determinant data directly from patients might be ideal, estimating these characteristics via data fusion avoids the task of data collection, which is generally time-consuming, expensive, and suffers from non-compliance.

Abstract In view of the problems of low straw decomposition rates and reduced soil fertility in southern Liaoning, China, we investigated the effects of no-tillage mode (NT), deep loosening + deep rotary tillage mode (PT), rotary tillage mode (RT) and the addition of decomposing agent (the next is called a decomposer) (NT + S, PT + S, RT + S) on the decomposition proportion of straw, respectively, by using the nylon net bag method in combination with 365-day field plot experiments. The decomposition rules of cellulose, hemicellulose and lignin as well as the dynamics of soil organic carbon (SOC), soil microbial biomass carbon (MBC) and soil dissolved organic carbon (DOC) in straw returned to the field for 15, 35, 55, 75, 95, 145 and 365 days were analyzed. The results showed that in the short term, the decomposition of straw was better in both the rotray tillage and deep loosening + deep rotary modes than in the no-tillage mode, and the addition of decomposer significantly promoted the decomposition of straw and the release of carbon from straw, among them, the RT + S treatment had the highest straw decomposition proportion and carbon release proportion in all sampling periods. After a one year experimental cycle, the RT + S treatment showed the highest proportion of cellulose, hemicellulose and lignin decomposition with 35.49%, 84.23% and 85.50%, respectively, and soil SOC, MBC and DOC contents were also higher than the other treatments with an increase of 2.30 g kg−1, 14.22 mg kg−1 and 25.10 mg kg−1, respectively, compared to the pre-experimental soil. Our results show that in the short term, to accelerate the decomposition rate of returned straw and increase the content of various forms of carbon in soil, rotary tillage can be used to return the straw to the field, while also spraying straw decomposer on its surface. This experiment used a new straw decomposer rich in a variety of microorganisms, combined with the comparison of a variety of straw return modes, and in-depth study of straw decomposition effects of cellulose, hemicellulose and lignin. Thus, a scheme that can effectively improve the decomposition rate of straw and the content of various forms of organic carbon in soil within a short period of time was explored to provide theoretical support for the southern Liaoning.

Abstract Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.

Summary: Background: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. Methods: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. Findings: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. Interpretation: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

BackgroundSuicides and opioid overdose deaths are among the most pressing public health concerns in the US. However direct evidence for the association between opioid use and suicidal behavior is limited. The objective of this article is to examine the association between frequency and dose of prescription opioid use and subsequent suicide attempts.Methods and findingsThis retrospective cohort study analyzed 4 years of statewide medical claims data from the Connecticut All-Payer Claims Database. Commercially insured adult patients in Connecticut (n = 842,773) who had any medical claims beginning in January 2012 were followed through December 2015. The primary outcome was suicide attempt identified using International Classification of Diseases (ICD 9) diagnosis codes. Primary predictor variables included frequency of opioid use, which was defined as the number of months with claims for prescription opioids per year, and strength of opioid dose, which was standardized using morphine milligram equivalent (MME) units. We also controlled for psychiatric and medical comorbidities using ICD 9 codes. We used Cox proportional hazards regression to examine the association between frequency, dose, and suicide attempts, adjusting for medical and psychiatric comorbid conditions. Interactions among measures of opioid use and comorbid conditions were analyzed. In this cohort study with follow-up time up to 4 years (range = 2-48 months, median = 46 months), the hazard ratios (HR) from the time-to-event analysis indicated that patients prescribed opioid medications for at least 6 months during the past year and at 20-50 MME levels or higher had 4.44 (95% CI: [3.71, 5.32]) to 7.23 (95% CI: [6.22, 8.41]) times the risk of attempted suicide compared to those not prescribed opioids. Risk of suicide attempt was sharply elevated among patients with psychiatric conditions other than anxiety who were prescribed more frequent and higher opioid doses. In contrast, more frequent and higher doses of prescription opioids were associated with lower risk of suicide attempts among patients with medical conditions necessitating pain management. This study is limited by its exclusive focus on commercially insured patients and does not include patients covered by public insurance. It is also limited to patients' receipt of prescription opioids and does not take into account opioids obtained through other means, nor does it include measures of actual patient opioid use.ConclusionsThis analysis provides evidence of a complex relationship among prescription opioids, mental health, pain and other medical comorbidities, and suicide risk. Findings indicate the need for proactive suicide surveillance among individuals diagnosed with affective or psychotic disorders who are receiving frequent and high doses of opioids. However, appropriate opioid treatment may have significant value in reducing suicide risk for those without psychiatric comorbidities.

Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased post-AMI survival. Through a series of bone marrow transplantation studies and leukocyte depletion experiments, we further clarified that excessive bone marrow–derived and GSDMD-dependent early neutrophil production and mobilization (24 hours after AMI) contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection after AMI through a reduction in scar size and enhancement of heart function. Our study provides mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.

Abstract Background Foxp3+CD4+ regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells. Methods The CD3+T cell and Foxp3+CD4+ regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation assays, Luciferase assay, Immunofluoresence Staining and Yeast two-hybrid screening. The effect of MKL-1 and STAT5a on the Treg genes expression was analyzed by qPCR and western blotting and Flow cytometry. Results However, the molecular mechanisms mediating STAT5b-dependent Treg genes expression and Treg cell phenotype and function in autoimmune diseases are not well defined. Here, we report that the MKL-1 is a coactivator for the major Treg genes transcription factor STAT5b, which is required for human Treg cell phenotype and function. The N terminus of STAT5b, which contains a basic coiled-coil protein–protein interaction domain, binds the C-terminal activation domain of MKL-1 and enhances MKL-1 mediated transcriptional activation of Treg-specific, CArG containing promoters, including the Treg-specific genes Foxp3. Suppression of endogenous STAT5b expression by specific small interfering RNA attenuates MKL-1 transcriptional activation in cultured human cells. The STAT5b–MKL-1 interaction identifies a role of Treg-specific gene regulation and regulated mouse Treg cell development and function and suggests a possible mechanism for the protective effects of autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP). Conclusions Our studies demonstrate for the first time that MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function. Video abstract

Abstract Background Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. But the exact molecular mechanism of ERα-36 and STAT3 on metastasis is still not fully understood. Methods MCF-7 and MDA-MB-231 human breast cancer cell lines and MCF-10A were overexpressioned or knockdown ERα-36 and STAT3 and tested for migration, invasion and proliferation assays. Direct interaction of STAT3 and ERα-36 were analyzed by coimmunoprecipitation assays. The effect of STAT3 and ERα-36 on MMP2/9 expression was analyzed by qPCR and western blotting. STAT3 phospholyation and acetylation by ERα-36 and p300 were observed and quantified by coimmunoprecipitation assays and western blotting. Results Cross-talk between ERα-36 and STAT3 was demonstrated to mediate through a direct physical association between the two proteins. Furthermore, the interaction between ERα-36 and STAT3 was demonstrated to give rise to functional changes in their signaling events. Both MMP2 and MMP9 expression require the binding of the newly identified protein complex, ERα-36-STAT3, to its promoter, the second phase, which is more robust, depends on ERα-mediated recruitment of p300 onto the complex and the subsequent acetylation of STAT3. In addition, STAT3 is tyrosine-phosphorylated in a biphasic manner, and the late phase requires ERα-36-mediated p300-dependent acetylation. Furthermore, interference with acetylation of STAT3 by overexpression of acetylation null STAT3 mutant led to the loss of MMP2 and MMP9 expression. ChIP analysis and reporter gene assays revealed that ERα-36-STAT3 complex binding to the MMP2 and MMP9 promoter led to an enhanceosome formation and facilitated MMP2 and MMP9 expression. Conclusions Our studies demonstrate for the first time that the function of MMP2 and MMP9 in breast cancer cell migration, which is mediated by interactions between ERα-36 and STAT3.

Abstract Background Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia. Methods A three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia. Results The comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma (P

Abstract Introduction: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans. Methods: We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30–40 mg/kg/m2). Each arm provided 75 grams of either fructose or glucose added to subjects’ individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites. Results: Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention. Conclusions: In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.

Background. To study the effects of z-guggulsterone on gastric cancer cell apoptosis and the mechanism related. Materials and Methods. Human gastric tumor SGC-7901 cells and GES-1 normal epithelial cells were treated with z-guggulsterone (0–75 μM) for 24 h. MTT assay was applied to evaluate cell proliferation. Flow cytometry and Hoechst staining were used to assess cell apoptosis. Western blotting was applied to evaluate FXR, small heterodimer partner (SHP), Bcl-2, and Bax protein expression. ELISA was applied to gain the levels of active caspase-3 and the contents of TNF-α, TGF-β1, and VEGF. Results. The expression levels of FXR and SHP were higher in tumor cells than in normal epithelial cells. Inhibition of FXR signaling with z-guggulsterone dose-dependently inhibited SGC-7901 cell proliferation and promoted SGC-7901 cell apoptosis. Bcl-2 protein expression was significantly decreased, and active caspase-3 and Bax protein expression was increased in SGC-7901 cells incubated with z-guggulsterone. The content of TNF-α was significantly increased, and the contents of VEGF and TGF-β1 were decreased in SGC-7901 cells incubated with z-guggulsterone. Conclusions. Inhibition of FXR signaling with z-guggulsterone induced anticancer effects in SGC-7901 cells by decreasing cell proliferation and promoting apoptosis. Z-guggulsterone induced cell apoptosis through the mitochondria-dependent pathway.

By combining the discrete element method (DEM) with computational fluid dynamics (CFD), this study proposes a three-dimensional CFD-DEM fluid-solid coupling microscopic computational model for analyzing the micromechanisms of instability and failure in a coal-bearing soil slope during rainfall. The CFD-DEM fluid-solid coupling model indicated that the main failure mode of the coal-bearing soil slopes was rainwater washing, and the slope sliding surface was predicted as an approximately linear segment. The adaptability of this numerical method was verified by comparing its results with those of rain-washed slopes in an outdoor model test. Rainfall changed the microscopic parameters such as the force chain, coordination number, and porosity of the slope soil particles. The porosity of the slope's top particles increased from 0.35 in the initial state to 0.80 in the unstable state. This change was directly related to the macroscopic mechanics of the slope soil. By analyzing the changes in the microscopic parameters of the particles, the failure evolution law of the coal-bearing soil slopes during rainfall was explored from a microscopic perspective. This study not only provides a theoretical basis for the protection design and construction of coal-bearing soil slopes in the region but can also analyze macroscopic mechanical laws of discrete media from a micro-macro perspective in geotechnical engineering.

In this paper, we present an efficient algorithm for point cloud registration in presence of low overlap rate and high noise. The proposed registration method mainly includes four parts: the loop voxel filtering, the curvature-based key point selection, the robust geometric descriptor, and the determining and optimization of correspondences based on key point spatial relationship. The loop voxel filtering filters point clouds to a specified resolution. We propose a key point selection algorithm which has a better anti-noise and fast ability. The feature descriptor of key points is highly exclusive which is based on the geometric relationship between the neighborhood points and the center of gravity of the neighborhood. The correspondences in the pair of two point clouds are determined according to the combined features of key points. Finally, the singular value decomposition and ICP algorithm are applied to align two point clouds. The proposed registration method can accurately and quickly register point clouds of different resolutions in noisy situations. We validate our proposal by presenting a quantitative experimental comparison with state-of-the-art methods. Experimental results show that the proposed point cloud registration algorithm has faster calculation speed, higher registration accuracy, and better anti-noise performance.

Objective: Endothelial cells (ECs) are important metabolic and endocrinal organs which play a significant role in regulating vascular function. Vascular ECs, located between the blood and vascular tissues, can not only complete the metabolism of blood and interstitial fluid but also synthesize and secrete a variety of biologically active substances to maintain vascular tension and keep a normal flow of blood and long-term patency. Therefore, this article presents a systematic review of common injuries and healing mechanisms for the vascular endothelium. Data Sources: An extensive search in the PubMed database was undertaken, focusing on research published after 2003 with keywords including endothelium, vascular, wounds and injuries, and wound healing. Study Selection: Several types of articles, including original studies and literature reviews, were identified and reviewed to summarize common injury and repair processes of the endothelial lining. Results: Endothelial injury is closely related to the development of multiple cardiovascular and cerebrovascular diseases. However, the mechanism of vascular endothelial injury is not fully understood. Numerous studies have shown that the mechanisms of EC injury mainly involve inflammatory reactions, physical stimulation, chemical poisons, concurrency of related diseases, and molecular changes. Endothelial progenitor cells play an important role during the process of endothelial repair after such injuries. What's more, a variety of restorative cells, changes in cytokines and molecules, chemical drugs, certain RNAs, regulation of blood pressure, and physical fitness training protect the endothelial lining by reducing the inducing factors, inhibiting inflammation and oxidative stress reactions, and delaying endothelial caducity. Conclusions: ECs are always in the process of being damaged. Several therapeutic targets and drugs were seeked to protect the endothelium and promote repair.

Abstract Recently, the organic functionalization of polyoxometalates (POMs) has drawn increasing interest, and an easy and effective route to achieve organic derivatives is of great importance. Herein, the first reported synthesis of a tosyl ester derivative of the polyoxometalate (Bu4N)2[V6O13{(OCH2)3CCH2SO3C7H4}2]·2.5CH3CN (compound 1) was performed by using DMAP as an activating reagent and triethylamine as an HCl scavenger. The tosyl ester was transformed into an azide or halide group by using sodium azide or sodium bromide, respectively, as the nucleophilic agent. Two derivatives of POMs, (Bu4N)2[V6O13{(OCH2)3CCH2N3}2]·4CH3CN (compound 2) and (Bu4N)2[V6O13{(OCH2)3CCH2Br}2] (compound 3), were easily obtained. All the compounds were structurally and compositionally characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy, NMR spectroscopy, ESI-MS, UV-Vis spectroscopy and TGA. This work provides a new route for the functional group transformation of organic derivatives of polyoxometalates.

Abstract Cognitive impairments in bipolar patients deteriorate as the disorder progresses. Little is known about whether genetic risks impact cognitive recovery during the course from depression to remission. In this six-week open-label trial, we shed light on the impacts of six single nucleotide polymorphisms (SNPs) in the calcium voltage-gated channel subunit alpha1 C (CACNA1C) gene on cognitive recovery in 192 bipolar patients suffering a major depressive episode (MDE). The primary outcome measures were changes in a battery of neuropsychological tests following 6-week treatment. Carriers with rs10466907 GT genotype did not significantly improve their executive function total scores on the Wisconsin Card Sorting Test after six weeks of treatment compared to the TT genotypes (β = −0.944, 95% Confidence Interval (CI) = −1.482–−0.405). Moreover, during a MDE carriers with rs58619945 GG and GA genotypes performed significantly worse than those with AA genotype on the categories completed (p = 0.013 and p = 0.001), total errors (p = 0.039 and p = 0.009), and random errors (p = 0.055 and p = 0.014, respectively). Our data suggest that the tested CACNA1C SNPs may have impacts on cognitive recovery from depression.

Abstract Terrestrial water storage (TWS) variation is crucial for global hydrological cycles and water resources management under climatic changes. In the previous studies, changes in water storage of some part of China have been studied with GRACE data in recent ten years. However, the spatial pattern of changes in water storage over China may be different in a long period. Here, we aimed to present long-term spatial patterns of TWS over China between 1948 to 2015 by unique Global Land Data Assimilation System Version 2 data and identify possible factors to water storage changes. The results revealed that the inner-annual variations in TWS of China exhibited remarkable downward trends with decreased rate of 0.1 cm/yr. Meanwhile, we found that spatial patterns of TWS in China can be divided into three distinct sub-regions of TWS region with increased, TWS region with decreased, TWS region with insignificant variation. The Northeast had decreased trends (−0.05 cm/yr) due to climate change and anthropogenic activities. Urban expansion is a non-ignorable factor to TWS reduction in Jing-Jin-Ji region (r = 0.61); the west had increased from 1948 to 2015 (0.03 cm/yr) due to precipitation increased and recharge by glacier melt; the south had insignificant trends and TWS varied with precipitation (r = 0.78).

Abstract It is recognized that T helper 2 (Th2) polarization plays a critical role in a large number of immune disorders. Yet, the remedies for reconciling the established Th2 polarization are still limited currently. Published data indicate that micro RNA-17-92 cluster is associated with the skewed immune response; 25 vitamin D3 (VD3) can regulate multiple bioactivities in the body. This study tests a hypothesis that VD3 facilitates the effect of specific immunotherapy (SIT) on Th2 response. We observed that treatment with either SIT or VD3 alleviated AR symptoms as well as reduced serum levels of specific IgE and T helper (Th) 2 cytokines, suppressed miR-19a (one of the members of the miR-17-92 cluster) and increased IL-10 in peripheral B cells, which was further improved in those AR patients treated with both SIT and VD3. The expression of miR-19a and IL-10 was significantly negatively correlated with each other in peripheral B cells of AR patients. Metabolites of VD3 formed a complex with retinoid acid receptor to repress the expression of miR-19a in B cells. We conclude that administration with VD3 promotes the effect of SIT on suppression of AR via repressing the expression of miR-19a in peripheral B cells.

Background: Validating the high-risk (HR) and ultra-high-risk (UHR) stages of bipolar disorder (BP) may help enable early intervention strategies. Methods: We followed up with 44 offspring of parents with BP, subdividing into the HR and UHR categories. The offspring were aged 8–28 years and were free of any current DSM-IV diagnoses. Our multilevel, integrative approach encompassed gray matter (GM) volumes, brain network connectivity, neuropsychological performance, and clinical outcomes. Findings: Compared with the healthy controls (HCs) (n = 33), the HR offspring (n = 26) showed GM volume reductions in the right orbitofrontal cortex. Compared with the HR offspring, the UHR offspring (n = 18) exhibited increased GM volumes in four regions. Both the HR and UHR offspring displayed abnormalities in the inferior occipital cortex regarding the measures of degree and centrality, reflecting the connections and roles of the region, respectively. In the UHR versus the HR offspring, the UHR offspring exhibited upwards-shifted small world topologies that reflect high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity, which was suggestive of vulnerability. Finally, processing speed, visual–spatial, and general function were impaired in the UHR offspring but not in the HR offspring. Interpretation: The abnormalities observed in the HR offspring appear to be inherited, whereas those associated with the UHR offspring represent stage-specific changes predisposing them to developing the disorder.

Enteral nutrition (EN) feeding protocol was proposed to have positive impact on critically ill patients. However, current studies showed conflicting results. The present study aimed to investigate whether enteral feeding protocol was able to improve clinical outcomes in critically ill patients.A before (stage 1) and after (stage 2) interventional study was performed in 10 tertiary care hospitals. All patients expected to stay in the intensive care unit (ICU) for over three days were potentially eligible. Clinical outcomes such as 28-day mortality, ICU length of stay, duration of mechanical ventilation (MV), and nosocomial infection were compared between the two stages.A total of 410 patients were enrolled during the study period, including 236 in stage 1 and 174 in stage 2. EN feeding protocol was able to increase the proportion of EN in day 2 (41.8±22.3 vs. 50.0±28.3%; p = 0.006) and day 6 (70.3±25.2 vs. 77.6±25.8%; p = 0.006). EN percentages tended to be higher in stage 1 than that in stage 2 on other days, but statistical significance was not reached. There was no difference in 28-day mortality between stage 1 and 2 (0.14 vs. 0.14; p = 0.984). Implementation of EN feeding protocol marginally reduced ICU length of stay (19.44±18.48 vs. 16.29±16.19 days; p = 0.077). There was no difference in the duration of MV between stage a and stage 2 (14.24±14.49 vs. 14.51±17.55 days; p = 0.877).The study found that the EN feeding protocol was able to increase the proportion of EN feeding, but failed to reduce 28-day mortality, incidence of nosocomial infection or duration of MV.

To evaluate the impact and cost-benefit of clinical pharmacist interventions on inappropriate use of prophylactic acid suppressant in hepatobiliary surgical patients in a Chinese tertiary hospital.A retro-prospective intervention study of patients undergoing elective operations was performed in the Department of Hepatobiliary Surgery of the Affiliated Hospital of Southwest Medical University. Patients admitted from October to December 2015 and from October to December 2016, served as the pre-intervention and the post-intervention group, respectively. Clinical pharmacist interventions in the post-intervention group included real-time monitoring medical records and recommending that surgeons prescribe prophylactic acid suppressants according to the criteria established by the hospital administration. Then, the clinical outcomes of post-intervention group were compared with the pre-intervention group which lacked pharmacist interventions. In addition, cost-benefit analysis was conducted to determine the economic effects of implementing the clinical pharmacist interventions in acid suppressant prophylaxis in perioperative period.Clinical pharmacist interventions significantly decreased the rate of the use of no indications for prophylactic acid suppressant and of the cases of inappropriate drug selection, dose, route, replacement and prolonged duration of prophylaxis (P < 0.05 or P < 0.001), resulting in significant increase by 10.65% in the percentage of cases adhering to all the criteria (P < 0.001). Moreover, significant reductions were found in the average usage quantity (P

The objective of this study was to determine the effects of water regime/soil condition (continuous flooding, saturated, and aerobic), cultivar ('Cocodrie' and 'Rondo'), and soil texture (clay and sandy loam) on rice grain yield, yield components and water productivity using a greenhouse trial. Rice grain yield was significantly affected by soil texture and the interaction between water regime and cultivar. Significantly higher yield was obtained in continuous flooding than in aerobic and saturated soil conditions but the latter treatments were comparable to each other. For Rondo, its grain yield has decreased with soil water regimes in the order of continuous flooding, saturated and aerobic treatments. The rice grain yield in clay soil was 46% higher than in sandy loam soil averaged across cultivar and water regime. Compared to aerobic condition, saturated and continuous flooding treatments had greater panicle numbers. In addition, panicle number in clay soil was 25% higher than in sandy loam soil. The spikelet number of Cocodrie was 29% greater than that of Rondo, indicating that rice cultivar had greater effect on spikelet number than soil type and water management. Water productivity was significantly affected by the interaction of water regime and cultivar. Compared to sandy loam soil, clay soil was 25% higher in water productivity. Our results indicated that cultivar selection and soil texture are important factors in deciding what water management option to practice.

Acute Physiology and Chronic Health Evaluation (APACHE) III score has been widely used for prediction of clinical outcomes in mixed critically ill patients. However, it has not been validated in patients with sepsis-associated acute lung injury (ALI). The aim of the study was to explore the calibration and predictive value of APACHE III in patients with sepsis-associated ALI.The study was a secondary analysis of a prospective randomized controlled trial investigating the efficacy of rosuvastatin in sepsis-associated ALI (Statins for Acutely Injured Lungs from Sepsis, SAILS). The study population was sepsis-related ALI patients. The primary outcome of the current study was the same as in the original trial, 60-day in-hospital mortality, defined as death before hospital discharge, censored 60 days after enrollment. Discrimination of APACHE III was assessed by calculating the area under the receiver operating characteristic (ROC) curve (AUC) with its 95% CI. Hosmer-Lemeshow goodness-of-fit statistic was used to assess the calibration of APACHE III. The Brier score was reported to represent the overall performance of APACHE III in predicting outcome.A total of 745 patients were included in the study, including 540 survivors and 205 non-survivors. Non-survivors were significantly older than survivors (59.71 ± 16.17 vs 52.00 ± 15.92 years, p < 0.001). The primary causes of ALI were also different between survivors and non-survivors (p = 0.017). Survivors were more likely to have the cause of sepsis than non-survivors (21.2% vs. 15.1%). APACHE III score was higher in non-survivors than in survivors (106.72 ± 27.30 vs. 88.42 ± 26.86; p < 0.001). Discrimination of APACHE III to predict mortality in ALI patients was moderate with an AUC of 0.68 (95% confidence interval: 0.64-0.73).this study for the first time validated the discrimination of APACHE III in sepsis associated ALI patients. The result shows that APACHE III score has moderate predictive value for in-hospital mortality among adults with sepsis-associated acute lung injury.

Exposure to electromagnetic field (EMF) emitted by mobile phone and other machineries concerns half the world's population and raises the problem of their impact on human health. The present study aims to explore the effects of electromagnetic field exposures on sleep quality and sleep duration among workers from electric power plant.A cross-sectional study was conducted in an electric power plant of Zhejiang Province, China. A total of 854 participants were included in the final analysis. The detailed information of participants was obtained by trained investigators using a structured questionnaire, which including socio-demographic characteristics, lifestyle variables, sleep variables and electromagnetic exposures. Physical examination and venous blood collection were also carried out for every study subject.After grouping daily occupational electromagnetic exposure into three categories, subjects with long daily exposure time had a significantly higher risk of poor sleep quality in comparison to those with short daily exposure time. The adjusted odds ratios were 1.68 (95%CI: 1.18, 2.39) and 1.57 (95%CI: 1.10, 2.24) across tertiles. Additionally, among the subjects with long-term occupational exposure, the longer daily occupational exposure time apparently increased the risk of poor sleep quality (OR (95%CI): 2.12 (1.23∼3.66) in the second tertile; 1.83 (1.07∼3.15) in the third tertile). There was no significant association of long-term occupational exposure duration, monthly electric fee or years of mobile-phone use with sleep quality or sleep duration.The findings showed that daily occupational EMF exposure was positively associated with poor sleep quality. It implies EMF exposure may damage human sleep quality rather than sleep duration.

For many organisms, the reconstruction of source-sink dynamics is hampered by limited knowledge of the spatial assemblage of either the source or sink components or lack of information on the strength of the linkage for any source-sink pair. In the case of marine species with a pelagic dispersal phase, these problems may be mitigated through the use of particle drift simulations based on an ocean circulation model. However, when simulated particle trajectories do not intersect sampling sites, the corroboration of model drift simulations with field data is hampered. Here, we apply a new statistical approach for reconstructing source-sink dynamics that overcomes the aforementioned problems. Our research is motivated by the need for understanding observed changes in jellyfish distributions in the eastern Bering Sea since 1990. By contrasting the source-sink dynamics reconstructed with data from the pre-1990 period with that from the post-1990 period, it appears that changes in jellyfish distribution resulted from the combined effects of higher jellyfish productivity and longer dispersal of jellyfish resulting from a shift in the ocean circulation starting in 1991. A sensitivity analysis suggests that the source-sink reconstruction is robust to typical systematic and random errors in the ocean circulation model driving the particle drift simulations. The jellyfish analysis illustrates that new insights can be gained by studying structural changes in source-sink dynamics. The proposed approach is applicable for the spatial source-sink reconstruction of other species and even abiotic processes, such as sediment transport.

OBJECTIVE: Though exposure to organochlorine pollutants (OCPs) is considered a risk factor for type 2 diabetes (T2DM), epidemiological evidence for the association remains controversial. A systematic review and meta-analysis was applied to quantitatively evaluate the association between exposure to OCPs and incidence of T2DM and pool the inconsistent evidence. DESIGN AND METHODS: Publications in English were searched in MEDLINE and WEB OF SCIENCE databases and related reference lists up to August 2013. Quantitative estimates and information regarding study characteristics were extracted from 23 original studies. Quality assessments of external validity, bias, exposure measurement and confounding were performed, and subgroup analyses were conducted to examine the heterogeneity sources. RESULTS: We retrieved 23 eligible articles to conduct this meta-analysis. OR (odds ratio) or RR (risk ratio) estimates in each subgroup were discussed, and the strong associations were observed in PCB-153 (OR, 1.52; 95% CI, 1.19-1.94), PCBs (OR, 2.14; 95% CI, 1.53-2.99), and p,p'-DDE (OR, 1.33; 95% CI, 1.15-1.54) based on a random-effects model. CONCLUSIONS: This meta-analysis provides quantitative evidence supporting the conclusion that exposure to organochlorine pollutants is associated with an increased risk of incidence of T2DM.

BackgroundThe purpose of this study is to describe the prevalence of overweight, general obesity, and abdominal obesity and examine their associations with socioeconomic status in a rural Chinese adult population.MethodsThis cross-sectional study was performed on 15,236 participants ≥ 35 years of age (6,313 men [41.4%] and 8,923 women [58.6%]). Each participant's weight, height, waist circumference (WC), and hipline circumference (HC) were measured, and demographic and socioeconomic data were collected using questionnaires.ResultsThe mean body mass index (BMI) values were 23.31 ± 2.96 and 23.89 ± 3.23 kg m(-2) and the mean WC values were 79.13 ± 8.43 and 79.54 ± 8.27 cm for men and women, respectively. The age-standardized prevalence rates of overweight (BMI ≥ 24.0 kg m(-2)), general obesity (BMI ≥ 28.0 kg m(-2)), and abdominal obesity (WC ≥ 85 cm for men and ≥ 80 cm for women) were 32.0%, 6.7%, and 27.0% for men and 35.1%, 9.7%, and 48.3% for women, respectively. All gender differences were statistically significant (p < 0.001). In addition, the age-specific prevalence rates of general and abdominal obesity slowly decreased among men but sharply increased among women as age increased (p < 0.001). In subsequent logistic regression analysis, educational level was negatively associated with both general obesity and abdominal obesity among women but positively associated with abdominal obesity among men. No significant correlation was found between obesity and income.ConclusionsThese results suggest a high prevalence of obesity which might differ by gender and age, and an inverse association among women and a mixed association among men noted between education and obesity in our locality. Preventive and therapeutic programs are warranted to control this serious public health problem. The gender-specific characteristics of populations at high-risk of developing obesity should be taken into consideration when designing interventional programs.

BACKGROUND: In China, the rapid rate of population aging and changes in the prevalence of disability among elderly people could have significant effects on the demand for long-term care. This study aims to describe the urban-rural differences in use and cost of long-term care of the disabled elderly and to explore potential influencing factors. METHODS: This study uses data from a cross-sectional survey and a qualitative investigation conducted in Zhejiang province in 2012. The participants were 826 individuals over 60 years of age, who had been bedridden or suffered from dementia for more than 6 months. A generalized linear model and two-part regression model were applied to estimate costs, with adjustment of covariates. RESULTS: Pensions provide the main source of income for urban elderly, while the principal income source for rural elderly is their family. Urban residents spend more on all services than do rural residents. Those who are married spend less on daily supplies and formal care than the unmarried do. Age, incapacitation time, comorbidity number, level of income, and bedridden status influence spending on medical care (β=-0.0316, -0.0206, 0.1882, 0.3444, and -0.4281, respectively), but the cost does not increase as the elderly grow older. Urban residents, the married, and those with a higher income level tend to spend more on medical equipment. Urban residence and living status are the two significant factors that affect spending on personal hygiene products. CONCLUSIONS: The use of long-term care services varies by living area. Long-term care of the disabled elderly imposes a substantial burden on families. Our study revealed that informal care involves huge opportunity costs to the caregivers. Chinese policy makers need to promote community care and long-term care insurance to relieve the burden of families of disabled elderly, and particular attention should be given to the rural elderly.

OBJECTIVES: To examine the association of living arrangements with functional disability among older persons and explore the mediation of impact factors on the relationship. DESIGN: Cross-sectional analysis using data from Healthy Aging study in Zhejiang Province. PARTICIPANTS: Analyzed sample was drawn from a representative rural population of older persons in Wuyi County, Zhejiang Province, including 1542 participants aged 60 and over in the second wave of the study. MEASUREMENTS: Living arrangements, background, functional disability, self-rated health, number of diseases, along with contemporaneous circumstances including income, social support (physical assistance and emotional support). Instrument was Activities of Daily Living (ADL) scale, including Basic Activities Daily Living (BADL) and Instrumental Activities of Daily Living (IADL). RESULTS: Living arrangements were significantly associated with BADL, IADL and ADL disability. Married persons living with or without children were more advantaged on all three dimensions of functional disability. Unmarried older adults living with children only had the worst functional status, even after controlling for background, social support, income and health status variables (compared with the unmarried living alone, ß for BADL: -1.262, ß for IADL: -2.112, ß for ADL: -3.388; compared with the married living with children only, ß for BADL: -1.166, ß for IADL: -2.723, ß for ADL: -3.902). In addition, older adults without difficulty in receiving emotional support, in excellent health and with advanced age had significantly better BADL, IADL and ADL function. However, a statistically significant association between physical assistance and functional disability was not found. CONCLUSION: Functional disabilities vary by living arrangements with different patterns and other factors. Our results highlight the association of unmarried elders living with children only and functioning decline comparing with other types. Our study implies policy makers should pay closer attention to unmarried elders living with children in community. Community service especially emotional support such as psychological counseling is important social support and should be improved.

BACKGROUND AND AIMS: Current cardiovascular disease (CVD) prevention is based on diagnosis and treatment of specific disease. Little is known for high risk people with CVD at the community level. In rural China, health records of all residents were established after the recent health reforms. This study aims to describe the characters of the rural population with high CVD risk regarding their clinical indicators, disease patterns, drug treatment and adherence. METHODS AND RESULTS: 17042 (87%) of all the 19500 rural residents in the two townships had valid health records in 2009. We employed a validated tool, the Asian Equation, to screen 8182 (48%) resident health records of those aged between 40-75 years in 2010. Those who were identified with a CVD risk of 20% or higher were selected for a face-to-face questionnaire survey regarding their diagnosed disease and drug treatment. 453 individuals were identified as high risk of CVD, with an average age of 53 years, 62% males, 50% smoking rate and average systolic blood pressure of 161 mmHg. 386 (85%) participated in the survey, while 294 (76%) were diagnosed with and 88 (23%) were suspects of CVD, hypertension, diabetes or hyperlipidaemia. 75 (19%) took drug regularly and 125 (32%) either stopped treatment or missed drugs. The most often used drugs were calcium channel blockers (20%). Only 2% used aspirins and 0.8% used statins. The median costs of drugs were 17 RMB (USD2.66) per month. CONCLUSION: The majority of the high risk population in our setting of rural China had already been diagnosed with a CVD related disease, but very few took any drugs, and less still took highly effective drugs to prevent CVD. A holistic strategy focused on population with high risk CVD and based on the current China public health reform is suggested in the context of primary care.

BackgroundWhether the expression of Golgi phosphoprotein 3 (GOLPH3) correlates with esophageal cancer tumorigenesis is currently unclear. The aim of this study was to examine GOLPH3 expression in patients with esophageal squamous cell cancer (ESCC) and explore its clinical significance.MethodsDifferences in the expression of GOLPH3 at the mRNA and protein level were examined via quantitative reverse transcriptase PCR and western blotting, respectively. GOLPH3 expression levels in ESCC tissue were determined through immunohistochemistry, and were compared in accordance with specific clinicopathological features of the patients and tissue specimens. Factors associated with patient survival were also analyzed.ResultsA notably higher level of GOLPH3 expression was found in ESCC cell lines and tissues at both mRNA and protein levels. High expression of GOLPH3 in ESCC patients was positively associated with clinical stage, TNM classification, histological differentiation and vital status (all PConclusionsExperiments demonstrated potential involvement of GOLPH3 in the development, differentiation, and tumorigenesis of ESCC, and concludes the possibility of its use as a diagnostic and prognostic marker in patients with ESCC.

The pathogenic fungus Candida albicans switches from yeast growth to filamentous growth in response to genotoxic stresses, in which phosphoregulation of the checkpoint kinase Rad53 plays a crucial role. Here we report that the Pph3/Psy2 phosphatase complex, known to be involved in Rad53 dephosphorylation, is required for cellular responses to the DNA-damaging agent methyl methanesulfonate (MMS) but not the DNA replication inhibitor hydroxyurea (HU) in C. albicans. Deletion of either PPH3 or PSY2 resulted in enhanced filamentous growth during MMS treatment and continuous filamentous growth even after MMS removal. Moreover, during this growth, Rad53 remained hyperphosphorylated, MBF-regulated genes were downregulated, and hypha-specific genes were upregulated. We have also identified S461 and S545 on Rad53 as potential dephosphorylation sites of Pph3/Psy2 that are specifically involved in cellular responses to MMS. Therefore, our studies have identified a novel molecular mechanism mediating DNA damage response to MMS in C. albicans.