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Abstract Background Education is an important part of the work of most doctors. Clinical preceptors act as role models and supervisors. Preceptors’ quality of supervision strongly influences the learning quality of clinical interns (Bartlett et al. BMC Med Educ 20:165, 2020). To ensure a consistent approach to every preceptorship experience, the competency of clinical preceptors should be assessed to ensure that the desired outcomes are achieved. This study aims to evaluate clinical preceptors’ competency in learner-centered teaching, to provide constructive feedback to develop the preceptors’ competency and improve supervisory skills and internship quality at Kunming Medical University (KMU) in Kunming of China. Methods This is a cross-sectional study with a quantitative self-administered online questionnaire. The convenience sampling technique was employed. In the undergraduate internship stage of KMU, clinical preceptors (N = 340) and interns (N = 487) were invited to use the augmented Stanford Faculty Development Program questionnaire (SFDPQ) (Stalmeijer et al. Med Teach 30:e272–e277, 2008), to (self-) assess the preceptor’s competency of learner-centered teaching on a five-point scale (1 = strongly disagree, 5 = strongly agree). Results Two hundred twenty-eight preceptors and two hundred thirty-six interns completed the questionnaire correctly. Overall, the assessment was positive, but the preceptors’ self-assessment significantly higher than the interns’ (p

Abstract NAD-dependent deacetylase Sirt2 is involved in mammalian metabolic activities, matching energy demand with energy production and expenditure, and is relevant to a variety of metabolic diseases. Here, we constructed Sirt2 knockout and adeno-associated virus overexpression mice and found that deletion of hepatic Sirt2 accelerated primary obesity and insulin resistance in mice with concomitant hepatic metabolic dysfunction. However, the key targets of Sirt2 are unknown. We identified the M2 isoform of pyruvate kinase (PKM2) as a key Sirt2 target involved in glycolysis in metabolic stress. Through yeast two-hybrid and mass spectrometry combined with multi-omics analysis, we identified candidate acetylation modification targets of Sirt2 on PKM2 lysine 135 (K135). The Sirt2-mediated deacetylation-ubiquitination switch of PKM2 regulated the development of glycolysis. Here, we found that Sirt2 deficiency led to impaired glucose tolerance and insulin resistance and induced primary obesity. Sirt2 severely disrupted liver function in mice under metabolic stress, exacerbated the metabolic burden on the liver, and affected glucose metabolism. Sirt2 underwent acetylation modification of lysine 135 of PKM2 through a histidine 187 enzyme active site-dependent effect and reduced ubiquitination of the K48 ubiquitin chain of PKM2. Our findings reveal that the hepatic glucose metabolism links nutrient state to whole-body energetics through the rhythmic regulation of Sirt2.

Abstract NOTCH receptor 3 (NOTCH3) is known to regulate the transcription of oncogenes or tumor suppressor genes, thereby playing a crucial role in tumor development, invasion, maintenance, and chemotherapy resistance. However, the specific mechanism of how NOTCH3 drives immune infiltration in gastrointestinal cancer remains uncertain. The expression of NOTCH3 was analyzed through Western blot, PCR, Oncomine database, and the Tumor Immune Estimation Resource (TIMER) site. Kaplan–Meier plotter, PrognoScan database, and gene expression profile interactive analysis (GEPIA) were used to assess the impact of NOTCH3 on clinical prognosis. The correlation between NOTCH3 expression and immune infiltration gene markers was investigated using TIMER and GEPIA. NOTCH3 was found to be commonly overexpressed in various types of gastrointestinal tumors and was significantly associated with poor prognosis. Furthermore, the expression level of NOTCH3 showed a significant correlation with the tumor purity of gastrointestinal tumors and the extent of immune infiltration by different immune cells. Our findings suggest that NOTCH3 may act as a crucial regulator of tumor immune cell infiltration and can serve as a valuable prognostic biomarker in gastrointestinal cancers.

Abstract Background Circular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC. Methods The expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance. Results CircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype. Conclusion CircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.

Abstract Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Abstract Based on existing researches, field drillings and numerical simulations are carried out in this paper to analyze the problems of subsidence control in the goaf of multi-layer inclined coal seam. Midas/GTS NX is used to build a three-dimensional calculation model of the goaf. A new method of using borehole data to check simulation parameters is proposed. The whole process of goaf excavation, construction of roadbed (pile foundation) and grouting treatment is analyzed. Analysis theory of different subgrade construction schemes and grouting treatment process on goaf is established. Response characteristics of displacement and equivalent stress and strain of goaf in multilayer inclined coal seam are obtained. A new method for analyzing the characteristics of the stress and deformation of the rock strata before and after grouting in the goaf under the conditions of different foundation schemes on the surface is provided in this research.

ObjectiveThe aim of this study was to investigate the association between sleep duration and muscle quality index (MQI) in middle-aged and older age groups, as limited evidence exists on this topic.MethodsIn order to assess the relationship between sleep duration and MQI, a cross-sectional study was undertaken, utilizing data from the National Health and Nutrition Examination Survey (NHANES) acquired during the period from 2011 to 2014. The study comprised a total of 4598 participants aged 20 years and above. To examine the association between sleep duration and MQI, sophisticated weighted multivariate linear regression models were employed. Additionally, smooth curve fitting techniques were applied to examine the possibility of any non-linear relationship between the two variables.ResultsThe average age of the adults who were enrolled in the study was 38.48±11.69 years, and 46.75% of them were female. The results of the multivariable linear regression models showed that sleep duration had a positive correlation with MQI. However, when subgroup analysis was conducted, it was found that this positive correlation only existed among women (β = 0.09, 95% CI: 0.014 to 0.167). To further confirm the differences between sexes in the relationship between sleep duration and MQI, a weighted generalized additive model (GAM) was used.ConclusionsThis research study provides evidence that there is a positive correlation between the duration of sleep and MQI specifically in females, while no such association was observed in males. These findings shed light on the existence of gender disparities in the connection between sleep duration and MQI.

Background Sepsis is often accompanied by the formation of disseminated intravascular coagulation (DIC). Microparticles can exert their procoagulant and proinflammatory properties in a variety of ways. The purpose of this study was to investigate the relationship between microparticle-associated tissue factor activity (TF+-MP activity) and the inflammatory response. Methods Data from a total of 31 DIC patients with sepsis and 31 non-DIC patients with sepsis admitted to the ICU of the First Affiliated Hospital of Harbin Medical University from December 2017 to March 2019 were collected. Blood samples were collected and DIC scores were calculated on the day of enrollment. The hospital’s clinical laboratory completed routine blood, procalcitonin, and C-reactive protein tests. TF+-MP activity was measured using a tissue factor-dependent FXa generation assay. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels were determined using ELISA kits. Results Compared with the non-DIC group, the DIC group had higher levels of leukocytes, neutrophils, procalcitonin, C-reactive protein, IL-1β, and TNF-α, and more severe inflammatory reactions. TF+-MP activity in the DIC group was higher than that in the non-DIC group. In sepsis patients, TF+-MP activity was strongly correlated with inflammatory response indices and DIC scores. Conclusion TF+-MP activity may play a major role in promoting inflammatory response in septic DIC.

Abstract Prospective inter-relationships among biomarkers were unexplored, which may provide mechanistic insights into diseases. We investigated the longitudinal associations of BMI change with trajectories of biomarkers related to cardiometabolic or breast cancer risk. A longitudinal study was conducted among 444 healthy women between 2019 to 2021. Cross‑lagged path analysis was used to examine the temporal relationships among BMI, cardiometabolic risk score (CRS), and obesity‑related proteins score (OPS) of breast cancer. Linear mixed-effect models were applied to investigate associations of time-varying BMI with biomarker-based risk score trajectories. Baseline BMI was associated with subsequent change of breast cancer predictors (P = 0.03), and baseline CRS were positively associated with OPS change (P

Abstract Background The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). Methods This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. Results The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. Conclusions The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. Trial registration Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.

BACKGROUND Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.FUNDING Fundación Alfonso Martín Escudero, NIH R01 DE027738, US Department of Defense CA210784, The Geoffrey Beene Cancer Research Center, The MSKCC Population Science Research Program, the Jayme Flowers Fund, the Sebastian Nativo Fund, and the NIH/NCI Cancer Center Support Grant P30 CA008748.

Abstract Magnolia sinostellata is one of the endangered species in China and largely suffers light deficiency stress in the understory of forest. However, the weak light response molecular mechanism remains unclear. More importantly, hub genes in the molecular network have not been pinpointed. To explore potential regulators in the mechanism, weighted gene co-expression network analysis (WGCNA) was performed to analysis the trancriptome data of M. sinostellata leaves subjected to weak light with different time points. Gene co-expression analysis illustrated that module 1, 2 and 3 were closely associated with light deficiency treatment, which. Gene ontology and KEGG analyses showed that genes in module 1 mainly participated in amino and nucleotide metabolism, module 2 mostly involved in carbon fixation and module 3 mostly regulated photosynthesis related pathways, among which 6, 7 and 8 hub genes were identified, respectively. Hub genes isoform_107196 in module 1 and isoform_55976 in module 2 were unique to M. sinostellata. This study found that light deficiency inhibited photosynthesis and stress tolerance, while improved carbon metabolism and flowering related pathways in M. sinostellata, which can impact its accumulation reserves of growth and reproduction in the next season. In addition, key shade response regulators identified in this study have laid a firm foundation for further investigation of shade response molecular mechanism and protection of other shade sensitive plants.

Objectives This investigation sought to elucidate promising treatment modalities for rotator cuff tears (RCTs) by delving into the molecular machinations instigating the affliction. The focus was on differentially expressed genes (DEGs) linked to RCTs, and the exploration of their roles and operative pathways. Methods DEGs were discerned from GEO datasets, followed by the establishment of a protein-protein interaction (PPI) network. Subsequently, the network’s core genes were determined employing a Venn diagram. Enrichment analysis facilitated the unveiling of the biological roles and signal transduction pathways of these pivotal genes, thus shedding light on molecular strategies for RCT-targeted treatment. The Discovery Studio 2019 software was employed to sift through FDA-sanctioned drugs targeting these essential proteins. Moreover, the efficaciousness of these FDA-endorsed drugs vis-à-vis RCTs was corroborated by the construction of an in vivo animal model of the injury and the in vitro cultivation of tendon-derived stem cells. Results Bioinformatics outcomes revealed a significant overexpression of S100A1 and RASSF8 in RCT patients. The FDA drug repository indicated that Butanediamide has a selective affinity for S100A1 and RASSF8. Subsequent in vivo and in vitro experimentation demonstrated that Butanediamide could suppress S100A1 expression and bolster TDSC proliferation, thereby facilitating RCT healing. Conclusions S100A1 and RASSF8 are pivotal genes implicated in RCTs, and their roles have been elucidated. The FDA-approved compound, Butanediamide, may represent a prospective therapeutic agent for RCTs by targeting S100A1 and RASSF8, respectively.

Summary: Background: Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis. Methods: Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs. Findings: We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44–82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem. Interpretation: This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss. Funding: National Science Foundation, and National Institutes of Health.

Abstract The present study aimed to explore whether chromosomal polymorphisms (CPs) have negative effects on reproductive outcomes of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET)/frozen-thawing embryo transfer (FET)? We conducted a retrospective study consisting of 21,867 assisted reproductive technology treatment cycles, among which, fresh embryo transfer cycles accounted for 10,400, and the rest were FET cycles. According to karyotype of CPs, the former was grouped as: group 1 (male carrier, n = 425), group 2 (female carrier, n = 262), and group 3 (couple without CPs, n = 9713). Accordingly, FET cycles were divided into 3 groups: group 4 (male carrier, n = 298), group 5 (female carrier, n = 311), and group 6 (couple without CPs, n = 10,858). The embryo implantation rate (IR), clinical pregnancy rate (CPR), live birth rate (LBR), and early miscarriage rate (EMR) were compared among the groups. In fresh embryo transfer cycles after IVF/ICSI, there were no significant differences in the infertility duration, BMI, basal FSH, no. of oocyte, no. of 2PN, endometrial thickness on trigger day, serum E2, P, and LH level on trigger day (P > 0.05). The female age, no. of 2PN embryo cleavage, top-quality embryo, and no. of embryo transferred were significantly different among groups (P 0.05), but the female age, BMI, no. of embryo transferred were significantly different among groups (P > 0.05). The IR was 24.3%, 23.6% and 22.3% in group 4, 5, and 6, receptivity. The CPR was 31.8%, 30.9%, and 30.0%, the LBR was 23.8%,26.3%, and 23.8%, while the EMR was 12.6%, 13.1%, 14.4%, respectively. The IR, CPR, EMR, and LBR showed no significant differences among groups (P > 0.05). Binary logistic regression analysis indicated that female age, infertility duration, and no. of embryo transferred were independently factors affecting CPR and LBR after FET. The CPs were not associated with CPR and LBR after FET. The results suggested that uniparental carrying of CPs have no effects on the reproductive outcomes after IVF/ICSI-ET/FET. However, it is not clear whether both parents carrying CPs would affect pregnancy outcome.

Smart services are expected to solve the dilemma of development and emission reduction, but there is still no conclusive evidence on whether and how they work. This article aims to explore the relationship between smart services and sustainable green transformation and the effect mechanism. To achieve this goal, a text mining analysis is performed to assess 970 Chinese listed manufacturing enterprises' smart services development; a regression analysis is then conducted. The results show that smart services have a significant positive impact on the quality and quantity of green innovation, especially for heavily polluting enterprises. The substitution of technology and labor for capital, as well as the upgrading of human resource quality, are effective mechanisms. Smart services can assist as a management strategic tool to balance environmental protection and development, but such an effect fails to work in areas not covered by new infrastructure and is weaker for private enterprises.

Abstract Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.

Accumulating data show that N6-methyladenosine (m 6 A) methyltransferase METTL3 and long noncoding RNA MALAT1 act pivotal roles in multiple malignancies including prostate cancer (PCa). However, the role and molecular mechanism underlying METTL3-mediated m 6 A modification of MALAT1 in PCa remain undocumented. The association of METTL3 and MALAT1 expression with clinicopathological characteristics and prognosis in patients with PCa was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and public The Cancer Genome Atlas (TCGA) dataset. The in vitro and in vivo experiments were executed to investigate the role of METTL3 in PCa. m 6 A dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated m 6 A modification of MALAT1. The effects of METTL3 on MALAT1-mediated PI3K/AKT pathway were assessed by Western blot analysis. As a result, we found that METTL3 was significantly upregulated in PCa tissues and high expression of METTL3 was associated with Gleason score and tumor recurrence in patients with PCa. Knockdown of METTL3 markedly repressed growth and invasion of PCa cells in vitro and in vivo , whereas ectopic expression of METTL3 showed the opposite effects. Moreover, knockdown of METTL3 decreased the total m 6 A levels of PCa cells as well as the MALAT1 m 6 A levels, leading to reduced MALAT1 expression. Overexpression of MALAT1 reversed METTL3 knockdown-induced antitumor effects and PI3K/AKT signaling inactivation. MALAT1 harbored a positive correlation with METTL3 expression and tumor recurrence in PCa. In conclusion, our findings demonstrate that METTL3-mediated m 6 A modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.

Summary: Background: As a rare subtype of lung adenocarcinoma, the diagnosis of pulmonary enteric adenocarcinoma (PEAC) remains challenging due to overlapping morphologic spectrum with lung metastatic colorectal cancer (lmCRC). However, the molecular features of PEAC as a separate lung cancer entity are poorly understood. Methods: We performed whole-exome sequencing and targeted bisulfite sequencing of 32 PEAC and 30 lmCRC to improve differential molecular characterization of the two diseases. We used machine learning methods to select key markers and developed a diagnostic classifier. In addition, we validated the classifier in the internal test cohort and an independently recruited external validation cohort with 17 PEAC and 7 lmCRC. Findings: Our results showed that EGFR was the key driver mutation in PEAC but at a lower prevalence compared to typical lung adenocarcinomas, whereas ERBB2 and KRAS were more frequently observed in PEAC. By contrast, we observed significant enrichment of KRAS and APC mutations in lmCRC compared with PEAC. At the chromosome arm level, copy number variations in 13q, 14q, and 18p were the major chromosomal differences observed between PEAC and lmCRC. Furthermore, by comparing differentially methylated regions (DMRs), we established a neat DNA methylation-based classifier consisting of eight DMRs. This classifier correctly classified all samples in the training cohort and 95% of the samples in the internal test cohort. An external validation cohort of 24 cases recruited from multiple centers in China also reliably agreed with pathological diagnosis. Interpretation: These results provide solid evidence of PEAC-specific genomic characteristics and demonstrate the potential utility of DNA methylation markers for auxiliary diagnosis of PEAC and lmCRC. Funding: This work was supported by National key research and development project 2019YFC1315700, CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035), and Beijing Natural Science Foundation (7222144).

Abstract There is strong evidence to suggest that obesity-related proteins play a key role in pathways that are related to breast cancer. In this study, we aimed to establish a robust obesity-related protein score (ORPS) that could be used to assess breast cancer risk. Based on evidence from high-quality systematic reviews and population studies, we selected nine such proteins that are stable in vitro, and measured their circulating concentrations by ELISA in a case–control study conducted in Chengdu, Sichuan, China, with 279 breast cancer cases and 260 healthy controls. Two obesity-related protein scores (ORPS) were calculated using a three-step method, with linear-weighted summation, and the one with a larger area under the curve was chosen for further evaluation. As a result, ORPS (PS5pre or PS4post) was positively correlated with breast cancer risk (premenopausal: OR≤63 VS >63 3.696, 95% CI 2.025–6.747; postmenopausal: OR≤38 VS >38 7.100, 95% CI 3.134–16.084), and represented a better risk predictor among obese women compared to non-obese in pre- and postmenopausal women. Among different molecular subtypes, ORPS was positively correlated with Luminal breast cancer, with additionally positive association with triple-negative breast cancer in premenopausal women. The ORPS might be a potential marker of breast cancer risk among Chinese women.

Abstract Transdifferentiation of human non-muscle cells directly into myogenic cells by forced expression of MyoD represents one route to obtain highly desirable human myogenic cells. However, functional properties of the tissue constructs derived from these transdifferentiated cells have been rarely studied. Here, we report that three-dimensional (3D) tissue constructs engineered with iMyoD-hTERT-NHDFs, normal human dermal fibroblasts transduced with genes encoding human telomerase reverse transcriptase and doxycycline-inducible MyoD, generate detectable contractile forces in response to electrical stimuli upon MyoD expression. Withdrawal of doxycycline in the middle of 3D culture results in 3.05 and 2.28 times increases in twitch and tetanic forces, respectively, suggesting that temporally-controlled MyoD expression benefits functional myogenic differentiation of transdifferentiated myoblast-like cells. Treatment with CHIR99021, a Wnt activator, and DAPT, a Notch inhibitor, leads to further enhanced contractile forces. The ability of these abundant and potentially patient-specific and disease-specific cells to develop into functional skeletal muscle constructs makes them highly valuable for many applications, such as disease modeling.

Tau aggregation associates with multiple neurodegenerative diseases including Alzheimer’s disease and rare tauopathies such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. The molecular and structural basis of tau aggregation and related diverse misfolded tau strains are not fully understood. To further understand tau-protein aggregation mechanisms, we performed systematic truncation mutagenesis and mapped key segments of tau proteins that contribute to tau aggregation, where it was determined that microtubule binding domains R2 and R3 play critical roles. We validated that R2- or R3-related hexameric PHF6 and PHF6* peptide sequences are necessary sequences that render tau amyloidogenicity. We also determined that the consensus VQI peptide sequence is not sufficient for amyloidogenicity. We further proposed single- and dual-nucleation core-based strain classifications based on recent cryo-EM structures. We analyzed the structural environment of the hexameric peptide sequences in diverse tau strains in tauopathies that, in part, explains why the VQI consensus core sequence is not sufficient to induce tau aggregation. Our experimental work and complementary structural analysis highlighted the indispensible roles of the hexameric core sequences, and shed light on how the interaction environment of these core sequences contributes to diverse pathogenic tau-strains formation in various tauopathy brains.

This study explores the relationship between the proportion of basic research investment in R&D expenditure and regional economic growth efficiency and its influence path. A panel of data from 31 China’s provincial was analysed by the fixed-effects model over 2009 to 2019. Empirical results highlight that: (1) the increase in the proportion of basic research investment has a significant promoting effect on regional economic growth efficiency, but it presents an "inverted U-shaped" impact path. Meanwhile, the threshold effect model test results reveal that basic research investment plays a more significant role in promotion when the per capita income level exceeds a certain threshold. (2) The test results of the mediating effect model indicate that the improvement of the level of human capital is the intermediate channel through which the investment in basic research affects regional economic growth efficiency, while the mediating effect of the increase of knowledge storage on the process of the investment in basic research affecting regional economic growth efficiency is not supported by data. Potential policy measures are discussed.

During January 26–February 10, 2020, an outbreak of 2019 novel coronavirus disease in an air-conditioned restaurant in Guangzhou, China, involved 3 family clusters. The airflow direction was consistent with droplet transmission. To prevent the spread of the virus in restaurants, we recommend increasing the distance between tables and improving ventilation.

Abstract Background Coronavirus disease 2019 (COVID-19) has infected more than 4 million people within 4 months. There is an urgent need to properly identify high-risk cases that are more likely to deteriorate even if they present mild diseases on admission. Methods A multicenter nested case-control study was conducted in four designated hospitals in China enrolling confirmed COVID-19 patients who were mild on admission. Baseline clinical characteristics were compared between patients with stable mild illness (stable mild group) and those who deteriorated from mild to severe illness (progression group). Results From Jan 17, 2020, to Feb 1, 2020, 85 confirmed COVID-19 patients were enrolled, including 16 in the progression group and 69 in the stable mild group. Compared to stable mild group (n = 69), patients in the progression group (n = 16) were more likely to be older, male, presented with dyspnea, with hypertension, and with higher levels of lactase dehydrogenase and c-reactive protein. In multivariate logistic regression analysis, advanced age (odds ratio [OR], 1.012; 95% confidence interval [CI], 1.020–1.166; P = 0.011) and the higher level of lactase dehydrogenase (OR, 1.012; 95% CI, 1.001–1.024; P = 0.038) were independently associated with exacerbation in mild COVID-19 patients. Conclusion Advanced age and high LDH level are independent risk factors for exacerbation in mild COVID-19 patients. Among the mild patients, clinicians should pay more attention to the elderly patients or those with high LDH levels.

Abstract The newly synthesized LN-type ZnTiO3 (J. Am. Chem. Soc. 2014, 136, 2748) contains cations with the electronic configurations nd10 (Zn2+: 3d10) along with second-order Jahn-Teller (SOJT) nd0 (Ti4+: 3d0) cations. This is different from traditional ferroelectrics with the electric configurations of d0 transition metal ions or/and lone pair electrons of ns2. Using a first-principles approach based on density functional theory, we investigate the electronic structure, zone-center phonon modes, piezoelectric and nonlinear optical properties of the LiNbO3-type ZnTiO3. The electronic structure indicates that this compound is a wide direct-band-gap insulator. The results reveal that this compound is a good ferroelectric material with a large spontaneous polarization of 90.43μC/cm2. The Raman scattering peaks of A1 and E modes are assigned to their zone-center optical modes. Additionally, the large piezoelectric and nonlinear optical susceptibilities reveal that LiNbO3-type ZnTiO3 is a high-performance lead-free piezoelectric and nonlinear optical crystal.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

Cells possess a multiplicity of non-membrane-bound compartments, which form via liquid-liquid phase separation. These condensates assemble and dissolve as needed to enable central cellular functions. One important class of condensates is those composed of two associating polymer species that form one-to-one specific bonds. What are the physical principles that underlie phase separation in such systems? To address this question, we employed coarse-grained molecular dynamics simulations to examine how the phase boundaries depend on polymer valence, stoichiometry, and binding strength. We discovered a striking phenomenon – for sufficiently strong binding, phase separation is suppressed at rational polymer stoichiometries, which we termed the magic-ratio effect. We further developed an analytical dimer-gel theory that confirmed the magic-ratio effect and disentangled the individual roles of polymer properties in shaping the phase diagram. Our work provides new insights into the factors controlling the phase diagrams of biomolecular condensates, with implications for natural and synthetic systems.

Objective: Transarterial and transvenous embolization methods are considered effective and safe approaches for the treatment of cavernous sinus dural arteriovenous fistula (CSDAVF). Here., we report the angioarchitectural features and clinical outcomes of CSDAVF in patients treated with either the inferior arterial approach (IAA) or the inferior petrosal sinus approach (IPSA). Methods: The clinical data of 32 patients with CSDAVF treated at our institution from May 2008 to May 2014 were retrospectively analyzed. All patients underwent routine diagnostic digital subtraction angiography (DSA) before surgery. Embolization was performed using the IPSA through the internal jugular vein or IAA, based on angioarchitectural features. Results: Of the 32 patients with CSDAVF, 24 underwent embolization treatment through the internal jugular vein-IPSA and 8 patients underwent treatment through IAA. Nineteen patients in the IPSA group experienced mild headache, which improved after specific treatment. The immediate postembolization angiographic results revealed complete occlusion in 26 cases (18 IPSA and 8 IAA) and almost complete occlusion in 6 cases (IPSA). Complications that occurred during the procedure included abducens nerve palsy (n = 1, IPSA) and prosopoplegia (n = 1, IAA). One patient developed tinnitus, which was diagnosed as anterior cranial fossa new-onset dural arteriovenous fistula on DSA, whereas the symptoms of other patients all improved with no recurrence. Conclusions: On the basis of the angioarchitectural features of CSDAVF, IAA can be considered the primary treatment when the blood-supplying artery and fistula are relatively singular, and when the microcatheter can easily reach the fistula through the artery. The venous approach should be selected as the primary approach when the fistula is indistinguishable and blood is supplied by multiple arteries through small plexiform vessels. Choosing the optimal surgical approach may increase the success rate of intravascular CSDAVF surgery and may help avoid complications. Keywords: Cavernous sinus, Dural arteriovenous fistula, Embolization, Intravascular treatment

Objective: The objective of this study was to evaluate the feasibility and outcomes of transvenous endovascular embolization (TVE) for superficial intracranial arteriovenous malformations (AVMs). Methods: After collecting clinical and imaging data, a prospective series of 11 patients presenting with superficial AVMs were treated by endovascular embolization using a transvenous approach between November 2016 and October 2018. Results: Ten patients (90.9%) had ruptured AVMs before TVE. The mean nidus size was 3.27 ± 1.47 cm, and the median Spetzler-Martin grade was II. The rate of immediate angiographic occlusion of the AVMs was 90.9% (10/11). One patient was treated with transarterial embolization since TVE was not achieved due to an unsuccessful positioning of the microcatheter. Two patients (cases 8 and 11) suffered a intracranial hemorrhage and a cerebral infarction with encephaledema, respectively, but no procedure-related mortalities were observed. Eight patients (72.7%) were independent with a modified Rankin Score (mRS) ≤ 2 at discharge and the mRSs of all patients, which were collected 30 days postintervention, were not more than 2. The mean follow-up period was 17 months. There were no nidus recurrences during the follow-up period. Conclusions: The curative transvenous embolization of superficial AVMs seems feasible and effective while carefully monitoring for embolization-related complications.

With the rapid development of Unmanned Aerial Vehicles, vehicle detection in aerial images plays an important role in different applications. Comparing with general object detection problems, vehicle detection in aerial images is still a challenging research topic since it is plagued by various unique factors, e.g. different camera angle, small vehicle size and complex background. In this paper, a Feature Fusion Deep-Projection Convolution Neural Network is proposed to enhance the ability to detect small vehicles in aerial images. The backbone of the proposed framework utilizes a novel residual block named stepwise res-block to explore high-level semantic features as well as conserve low-level detail features at the same time. A specially designed feature fusion module is adopted in the proposed framework to further balance the features obtained from different levels of the backbone. A deep-projection deconvolution module is used to minimize the impact of the information contamination introduced by down-sampling/up-sampling processes. The proposed framework has been evaluated by UCAS-AOD, VEDAI, and DOTA datasets. According to the evaluation results, the proposed framework outperforms other state-of-the-art vehicle detection algorithms for aerial images.

Our previously study shown that Lysophosphatidylcholine Acyltransferase1 (LPCAT1) is overexpressed in castration resistant prostate cancer (CRPC) relative to primary prostate cancer (PCa), and androgen controls its expression via the Wnt signaling pathway. While highly expressed in CRPC, the role of LPCAT1 remains unclear. In vitro cell experiments referred to cell transfection, mutagenesis, proliferation, migration, invasion, cell cycle progression and apoptosis, Western blotting, Pulse-chase RNA labeling. BALB/c nude mice were used for in vivo experiments. We found that LPCAT1 overexpression enhanced the proliferation, migration, and invasion of CRPC cells both in vitro and in vivo. Silencing of LPCAT1 reduced the proliferation and the invasive capabilities of CRPC cells. Providing exogenous PAF to LPCAT1 knockdown cells increased their invasive capabilities; however platelet activating factor acetylhydrolase (PAF-AH) and the PAFR antagonist ABT-491 both reversed this phenotype; proliferation of CRPC cells was not affected in either model. LPCAT1 was found to mediate CRPC growth via nuclear re-localization and Histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates. We also found that LPCAT1 overexpression led to CRPC cell resistance to treatment with paclitaxel. LPCAT1 overexpression in CRPC cells drives tumor progression via increased mRNA synthesis and PAF production. Our results highlight LPCAT1 as a viable therapeutic target in the context of CRPC.

Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.

We report human endophthalmitis caused by pseudorabies virus infection after exposure to sewage on a hog farm in China. High-throughput sequencing and real-time PCR of vitreous humor showed pseudorabies virus sequences. This case showed that pseudorabies virus might infect humans after direct contact with contaminants.

Background: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). Materials and Methods: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT-upregulated PD-L1 expression using human glioma cell lines U87 and U251. Results: Our data demonstrated that the PD-L1 expression was significantly correlated with EGFR expression in glioma specimens (χ2 = 5.00, P = 0.025). The expressions of PD-L1 at the protein and mRNA levels were both significantly up-regulated by RT (P 0.05). The combination of RT with EGFR inhibitor exhibited the same effect on antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). Conclusions: RT could up-regulate the PD-L1 expression through the pathways downstream of EGFR in glioma.

Abstract Interleukin-6 acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. IL-6/IL-6R signaling pathway, in particular, has been proposed to be a pivotal cytokine promoting ovarian cancer progression. This study aimed to elucidate potential clinical and biological function of IL-6R mRNA expression in ovarian cancer. We used the keywords “ovarian cancer” and searched through GEO database and finally a total of 7 studies together with TCGA database were incorporated in this analysis. We used Cutoff Finder to determine a cutoff point and stratified patients into two groups and found that high-expression of IL-6R mRNA in tumor tissues was a positive prognostic factor for overall survival. Simultaneously, high expression level of IL-6R mRNA correlates with better survival of patients who had additional chemotherapy treatment. These analyses suggested a possible role of tumoral expression of IL-6R in ovarian cancer. In conclusion, our results showed that mRNA levels of IL-6R in ovarian cancer was positively associated with better prognosis and sensitivity to chemotherapy and can potentially be used as a prognostic marker for this cancer.

Abstract Overexposure to manganese (Mn) could disrupt neurotransmitter release via influencing the formation of SNARE complex, but the underlying mechanisms are still unclear. A previous study demonstrated that SNAP-25 is one of substrate of calpains. The current study investigated whether calpains were involved in Mn-induced disorder of SNARE complex. After mice were treated with Mn for 24 days, Mn deposition increased significantly in basal nuclei in Mn-treated and calpeptin pre-treated groups. Behaviorally, less time spent in the center of the area and decreased average velocity significantly in an open field test after 24 days of Mn exposure. With the increase in MnCl2 dosage, intracellular Ca2+ increased significantly, but pretreatment with calpeptin caused a dose-dependent decrease in calpains activity. There were fragments of N-terminal of SNAP-25 protein appearance in Mn-treated groups, but it is decreased with pretreatment of calpeptin. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in increasing first and then decreasing, which was consistent with Glu release and the 80 kDa protein levels of SNARE complexes. In summary, Mn induced the disorder of neurotransmitter release through influencing the formation of SNARE complex via cleaving SNAP-25 by overactivation of calpains in vivo.

Abstract NAC proteins comprise of a plant-specific transcription factor (TF) family and play important roles in plant development and stress responses. Switchgrass (Panicum virgatum) is the prime candidate and model bioenergy grass across the world. Excavating agronomically valuable genes is important for switchgrass molecular breeding. In this study, a total of 251 switchgrass NAC (PvNACs) family genes clustered into 19 subgroups were analyzed, and those potentially involved in stress response or tissue-specific expression patterns were pinpointed. Specifically, 27 PvNACs were considered as abiotic stress-related including four membrane-associated ones. Among 40 tissue-specific PvNACs expression patterns eight factors were identified that might be relevant for lignin biosynthesis and/or secondary cell wall formation. Conserved functional domains and motifs were also identified among the PvNACs and potential association between these motifs and their predicted functions were proposed, that might encourage experimental studies to use PvNACs as possible targets to improve biomass production and abiotic stress tolerance.

Abstract Since rural reforms in the 1980s, both the state and local governments of China have devoted great efforts to combating desertification through a number of eco-environmental restoration campaigns, resulting in burgeoning contention at all levels of government and sparking public concern. Monitoring and accurately assessing the statuses and trends of grassland desertification are important for developing effective restoration strategies. The Horqin Sandy Land (HSL), a very typical desertified grassland (DG) with better hydrothermal conditions among sandy lands in north China, was recently selected (1985–2013) to assess the spatiotemporal dynamic performances of grassland desertification before and after implementing restoration projects. Landsat images (TM/ETM+/OLI), field investigations and expert review were integrated to form a classification scheme for the HSL. Then, spectral mixture analysis and the decision-tree method were used to extract bare-sand ratios and vegetation cover fraction dynamics. A favourable phenomenon of DG was seen to be reversed in an accelerated pace during 2001–2013, despite challenge from both climatic and anthropogenic factors. However, overexploitation of grassland (especially for farming) and ground water for irrigation has led to remarkable decreases in the ground water level in recent decades, which should be highly concerning regarding the formulation of restoration campaigns in the sandy land.

Abstract Anterior cervical discectomy and fusion (ACDF) and total cervical disc replacement (TDR) are considered effective treatments for patients with cervical degenerative disc disease (CDDD). An indirect meta-analysis including 19 randomized controlled trials (5343 patients) was conducted to compare the clinical outcomes of ACDF with TDR. Primary outcomes including functional indicators (NDI [neck disability index] score, neurological success and patient satisfaction), secondary outcomes including surgical outcomes (operation time, blood loss and length of stay) and secondary surgical procedures (secondary surgery at an adjacent level, secondary surgery at the index level, secondary surgery at both levels, removal, reoperation, revision and supplemental fixation) were included in the study. TDR using the Bryan disc was associated with a greater improvement in NDI score than ACDF (MD = −5.574, 95% CrIs [credible intervals] −11.73–−0.219). For neurological success, the Bryan (odds ratio [OR] = 0.559, 95% CrIs 0.323–0.955) and Prestige (OR = 0.474, 95% CrIs 0.319–0.700) discs were superior to ACDF. However, no differences in the patient satisfaction rate were shown between TDR and ACDF. For patients with CDDD, ACDF using allograft and a plate is most effective for determining the surgical parameters. Moreover, TDR using the ProDisc-C, Mobi-C, Prestige and Bryan discs are good choices for improving functional outcomes and reducing secondary surgeries.

Background: Nontraumatic spontaneous subarachnoid hemorrhage (SAH) is associated with a high mortality. This study was conducted to investigate the epidemiological features of nontraumatic spontaneous SAH in China. Methods: From January 2006 to December 2008, the clinical data of patients with nontraumatic SAH from 32 major neurosurgical centers of China were evaluated. Emergent digital subtraction angiography (DSA) was performed for the diagnosis of SAH sources in the acute stage of SAH (≤3 days). The results and complications of emergent DSA were analyzed. Repeated DSA or computed tomography angiography (CTA) was suggested 2 weeks later if initial angiographic result was negative. Results: A total of 2562 patients were enrolled, including 81.4% of aneurysmal SAH and 18.6% of nonaneurysmal SAH. The total complication rate of emergent DSA was 3.9% without any mortality. Among the patients with aneurysmal SAH, 321 cases (15.4%) had multiple aneurysms, and a total of 2435 aneurysms were detected. The aneurysms mostly originated from the anterior communicating artery (30.1%), posterior communicating artery (28.7%), and middle cerebral artery (15.9%). Among the nonaneurysmal SAH cases, 76.5% (n = 365) had negative initial DSA, including 62 cases with peri-mesencephalic nonaneurysmal SAH (PNSAH). Repeated DSA or CTA was performed in 252 patients with negative initial DSA, including 45 PNSAH cases. Among them, the repeated angiographic results remained negative in 45 PNSAH cases, but 28 (13.5%) intracranial aneurysms were detected in the remaining 207 cases. In addition, brain arteriovenous malformation (AVM, 7.5%), Moyamoya disease (7.3%), stenosis or sclerosis of the cerebral artery (2.7%), and dural arteriovenous fistula or carotid cavernous fistula (2.3%) were the major causes of nonaneurysmal SAH. Conclusions: DSA can be performed safely for pathological diagnosis in the acute stage of SAH. Ruptured intracranial aneurysms, AVM, and Moyamoya disease are the major causes of SAH detected by emergent DSA in China.

The association between obesity and sarcopenia remains controversial. The present study was conducted to explore the associations among body mass index (BMI), visceral fat area (VFA), and sarcopenia in older people and analyze their potential mechanisms. This cross-sectional study included 861 community-dwelling older Chinese people from three regions of China. BMI, VFA, muscle mass, muscle strength, physical performance, body composition, and metabolic markers were measured. Muscle mass and muscle strength were positively correlated with BMI, but were negatively correlated with VFA. Simple overweight/obesity was negatively associated with sarcopenia (OR = 0.07, 95% CI = 0.03~0.18), and the OR value was lower than combined obesity (OR = 0.16, 95% CI = 0.09~0.28). Fat free mass and total body protein were positively associated with high BMI but negatively associated with high VFA. Furthermore, high VFA was adversely associated with some metabolic risk factors of sarcopenia. Combination of BMI and VFA increased diagnostic efficiency of low muscle mass and sarcopenia. In conclusion, high BMI was negatively associated with sarcopenia, while high VFA attenuated the negative association between high BMI and sarcopenia. The opposite association may partially be attributed to their different associations with body composition and metabolic risk factors of sarcopenia. Therefore, bedsides BMI, VFA and its interaction with BMI should be considered in sarcopenia prevention.

Lung cancer is one of the deadliest malignancies. The immune checkpoint-blockade (ICB) tumor therapy has led to striking improvement of long-term survival for some lung cancer patients. However, the response rate of immunotherapy is still low for lung cancer. Studying the tumor microenvironment (TME) should shed light on improvement of immunotherapy of lung cancer. Interleukin-33 (IL-33), an "alarmin" cytokine, has been implicated in tumor associated immune responses and inflammatory diseases of the lung. The role of IL-33 in lung cancer progression, however, remains elusive. This study is designed to characterize IL-33 expression in lung tumor tissues and establish the clinical significance of IL-33 in non-small cell lung cancer lung cancer (NSCLC).Tumor tissue specimens from patients suffering from NSCLC were analyzed for expression of IL-33 protein by immunohistochemistry and expression of IL-33 and ST2 mRNA by RT-quantitative PCR (RT-QPCR). The expression data were analyzed for their association with clinical and pathological parameters of NSCLC. In addition, the association between expression levels of IL-33 mRNA and patient survival was determined using 5 independent expression profiling datasets of human lung cancer.The expression levels of IL-33 and ST2 were significantly down-regulated in both adenocarcinoma and squamous cell carcinoma of the lung when compared to adjacent normal lung tissues. In addition, the level of IL-33 protein was inversely correlated with tumor grade and size. Moreover, analysis of TCGA and GEO lung cancer expression datasets revealed that higher expression levels of IL-33 mRNA were correlated with longer overall survival of patients suffering from adenocarcinoma of the lung. These data indicate that the expression levels of IL-33 are inversely associated with lung cancer progression, consistent with the hypothesis that IL-33 is involved in immune surveillance of NSCLC.

BACKGROUND:Although pemetrexed plus cis/carboplatin has become the most effective chemotherapy regimen for patients with advanced lung adenocarcinoma, predictive biomarkers are not yet available, and new tools to identify chemosensitive patients who would likely benefit from this treatment are desperately needed. In this study, we constructed and validated predictive peptide models using the serum peptidome profiles of two datasets. METHODS:One hundred eighty-three patients treated with first-line platinum-based pemetrexed treatment for advanced lung adenocarcinoma were retrospectively enrolled and randomized into the training (n = 92) or validation (n = 91) set, and pre-treatment serum samples were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Serum peptidome profiles from the training set were used to identify potential predictive peptide biomarkers and construct a predictive peptide model for accurate group discrimination; which was then used to classify validation samples into "good" and "poor" outcome groups. The clinical outcomes of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed based on the classification result. RESULTS:Eight potential peptide biomarkers were identified. A predictive peptide model based on four distinct m/z features (2,142.12, 3,316.19, 4,281.94, and 6,624.02 Da) was developed based on the clinical outcomes of training set patients after first-line pemetrexed plus platinum treatment. In the validation set, the good group had significantly higher ORR (49.1% vs. 8.3%, P

The polyphagous mirid bug Apolygus lucorum (Heteroptera: Miridae) has more than 200 species of host plants and is an insect pest of important agricultural crops, including cotton (Gossypium hirsutum) and mungbean (Vigna radiata). Previous field trials have shown that A. lucorum adults prefer mungbean to cotton plants, indicating the considerable potential of mungbean as a trap crop in cotton fields. However, direct evidence supporting the migration of A. lucorum adults from cotton to mungbean is lacking. We developed a DNA-based polymerase chain reaction (PCR) approach to reveal the movement of A. lucorum between neighboring mungbean and cotton fields. Two pairs of PCR primers specific to cotton or mungbean were designed to target the trnL-trnF region of chloroplast DNA. Significant differences in the detectability half-life (DS50) were observed between these two host plants, and the mean for cotton (8.26 h) was approximately two times longer than that of mungbean (4.38 h), requiring weighted mean calculations to compare the detectability of plant DNA in the guts of field-collected bugs. In field trials, cotton DNA was detected in the guts of the adult A. lucorum individuals collected in mungbean plots, and the cotton DNA detection rate decreased successively from 5 to 15 m away from the mungbean-cotton midline. In addition to the specific detection of cotton- and mungbean-fed bugs, both cotton and mungbean DNA were simultaneously detected within the guts of single individuals caught from mungbean fields. This study successfully established a tool for molecular gut-content analyses and clearly demonstrated the movement of A. lucorum adults from cotton to neighboring mungbean fields, providing new insights into understanding the feeding characteristics and landscape-level ecology of A. lucorum under natural conditions.

Resource allocation could be influenced by various dynamic elements, such as the skills of engineers and the growth of skills, which requires managers to find an effective and efficient tool to support their staffing decision-making processes. Rescheduling happens commonly and frequently during the project execution. Control options have to be made when new resources are added or tasks are changed. In this paper we propose a software project staffing model considering dynamic elements of staff productivity with a Genetic Algorithm (GA) and Hill Climbing (HC) based optimizer. Since a newly generated reschedule dramatically different from the initial schedule could cause an obvious shifting cost increase, our rescheduling strategies consider both efficiency and stability. The results of real world case studies and extensive simulation experiments show that our proposed method is effective and could achieve comparable performance to other heuristic algorithms in most cases.

To comprehensively evaluate the association between rs7517847 and rs2201841 polymorphisms in the Interleukin-23 (IL-23) receptor gene and ankylosing spondylitis (AS), a meta-analysis was performed. The Pubmed, Embase, MEDLINE, Cochrane, China National Knowledge Infrastructure (CNKI), VIP, Wanfang and China Biology Medicine disc (CBMdisc) databases were searched to identify eligible studies on rs7517847 and rs2201841 polymorphisms in the IL-23 receptor gene and AS that were published through September 2014. Data of interest were extracted from each study, and the meta-analysis was performed using STATA 12.0. Four studies were eligible for the meta-analysis and included a total patient population of 2,465. With regards to rs7517847, the current study showed that the genotype GG and allele G might play a protective role during AS (OR = 0.76, 95% CI [0.59–0.99]; OR = 0.88, 95% CI [0.78–0.99] for homozygote and allelic models, respectively). However, according to the meta-analysis, there was no statistical association between the genotype or allele of rs2201841 and an individual’s susceptibility to AS in all genetic models. In conclusion, it was the IL-23 rs7517847 polymorphism rather than the rs2201841 polymorphism that had a statistical association with AS. Nevertheless, more evidence is needed to confirm this result. Consequently, it is necessary to carry out more high-quality studies to confirm the associations between these two single nucleotide polymorphisms and AS.

Delayed healing or non-union of skeletal fractures are common clinical complications. Ibandronate is a highly potent anti-catabolic reagent used for treatment of osteopenia and fracture prevention. We hypothesized that local application of ibandronate after fracture fixation may improve and sustain callus formation and therefore prevent delayed healing or non-union. This study tested the effect of local application of an ibandronate/gelatin sponge composite on osteotomy healing. A right-side distal-femoral osteotomy was created surgically, with fixation using a k-wire, in forty adult male rabbits. The animals were divided into four groups of ten animals and treated by: (i) intravenous injection of normal saline (Control); (ii) local implantation of absorbable gelatin sponge (GS); (iii) local implantation of absorbable GS containing ibandronate (IB+GS), and (iv) intravenous injection of ibandronate (IB i.v.). At two and four weeks the affected femora were harvested for X-ray photography, computed tomography (CT), biomechanical testing and histopathology. At both time-points the results showed that the calluses in both the ibandronate-treated groups, but especially in the IB+GS group, were significantly larger than in the control and GS groups. At four weeks the cross sectional area (CSA) and mechanical test results of ultimate load and energy in the IB+GS group were significantly higher than in other groups. Histological procedures showed a significant reduction in osteoclast numbers in the IB+GS and IB i.v. groups at day 14. The results indicate that local application of an ibandronate/gelatin sponge biomaterial improved early osteotomy healing after surgical fixation and suggest that such treatment may be a valuable local therapy to enhance fracture repair and potentially prevent delayed or non-union.

BackgroundLung cancer is one of the most common human malignant diseases and the leading cause of cancer death worldwide. The rs931794, a SNP located in 15q25.1, has been suggested to be associated with lung cancer risk. Nevertheless, several genetic association studies yielded controversial results.Methods and findingsA hospital-based case-control study involving 611 cases and 1062 controls revealed the variant of rs931794 was related to increased lung cancer risk. Stratified analyses revealed the G allele was significantly associated with lung cancer risk among smokers. Following meta-analysis including 6616 cases and 7697 controls confirmed the relevance of rs931794 variant with increased lung cancer risk once again. Heterogeneity should be taken into account when interpreting the consequences. Stratified analysis found ethnicity, histological type and genotyping method were not the sources of between-study heterogeneity. Further sensitivity analysis revealed that the study "Hsiung et al (2010)" might be the major contributor to heterogeneity. Cumulative meta-analysis showed the trend was increasingly obvious with adding studies, confirming the significant association.ConclusionsResults from our current case-control study and meta-analysis offered insight of association between rs931794 and lung cancer risk, suggesting the variant of rs931794 might be related with increased lung cancer risk.