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Abstract Purpose Glycolysis and immune metabolism play important roles in acute myocardial infarction (AMI). Therefore, this study aimed to identify and experimentally validate the glycolysis-related hub genes in AMI as diagnostic biomarkers, and further explore the association between hub genes and immune infiltration. Methods Differentially expressed genes (DEGs) from AMI peripheral blood mononuclear cells (PBMCs) were analyzed using R software. Glycolysis-related DEGs (GRDEGs) were identified and analyzed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) for functional enrichment. A protein–protein interaction network was constructed using the STRING database and visualized using Cytoscape software. Immune infiltration analysis between patients with AMI and stable coronary artery disease (SCAD) controls was performed using CIBERSORT, and correlation analysis between GRDEGs and immune cell infiltration was performed. We also plotted nomograms and receiver operating characteristic (ROC) curves to assess the predictive accuracy of GRDEGs for AMI occurrence. Finally, key genes were experimentally validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting using PBMCs. Results A total of 132 GRDEGs and 56 GRDEGs were identified on the first day and 4–6 days after AMI, respectively. Enrichment analysis indicated that these GRDEGs were mainly clustered in the glycolysis/gluconeogenesis and metabolic pathways. Five hub genes (HK2, PFKL, PKM, G6PD, and ALDOA) were selected using the cytoHubba plugin. The link between immune cells and hub genes indicated that HK2, PFKL, PKM, and ALDOA were significantly positively correlated with monocytes and neutrophils, whereas G6PD was significantly positively correlated with neutrophils. The calibration curve, decision curve analysis, and ROC curves indicated that the five hub GRDEGs exhibited high predictive value for AMI. Furthermore, the five hub GRDEGs were validated by RT-qPCR and western blotting. Conclusion We concluded that HK2, PFKL, PKM, G6PD, and ALDOA are hub GRDEGs in AMI and play important roles in AMI progression. This study provides a novel potential immunotherapeutic method for the treatment of AMI.

Abstract Objectives This randomized controlled trial compared the efficacy and tolerability of danzhixiaoyao pills in the accurate treatment of patients with burning mouth syndrome (BMS). Method Collect a total of 78 patients (75 female patients and 3 male patients) from the oral mucosa department who were considered eligible fromOctober 2020 to October 2022.The patients were randomized and divided into trial group and control group.The trail group received danzhixiaoyao pills and mecobalamine tablets while the control group was given mecobalamine tablets.The Visual Analogue Scale (VAS), Beck Anxiety Inventory(BAI), Beck Depression Inventory (BDI), Oral Health Impact Profile (OHIP-14), Traditional Chinese medicine(TCM) syndrome integral and adverse reactions were performed at baseline and after 2, 4, and 6 weeks of treatment. Descriptive statistics, including the Wilcoxon rank-sum test and the Chi-square test for median comparisons between different times, were used. Result 1.After treatment, the VAS, BDI,OHIP-14, and TCM syndrome integral in the trial group had a significant decrease than the control group(P< 0.05).However, there was no statistical difference in the BAI scores between the two groups (P> 0.05). 2.According to the efficacy determination criteria , the total effective rate of the test group was 73.68% , the control group was 52.94% and the recurrence rate was 0. There was a significant difference between the two groups (Z=-2.688, P < 0.05). The results showed that the curative effect of test group was better than that of control group.3. No adverse effects occurred in patients in either group. Conclusion Danzhixiaoyao pills has demonstrated to have a positive effect in relieving BMS symptoms and in improving a patient's overall quality of life with no AEs compared with the control group. The efficacy evaluation systems that can be verified and complementary in this study provide a perfect, effective and referential evaluation system for the use of Chinese patent medicine in the treatment of oral mucosal diseases. Trial Registration Registry name: Chinese Clinical trail Registry Registration number: ChiCTR2000038189 Date of Registration: 2020-09-13 Please visit ( https://www.chictr.org.cn/showproj.html?proj=61462 ) to the protocol.

Abstract Background Early and exclusive breastfeeding may reduce neonatal and post-neonatal mortality in low-resource settings. However, prelacteal feeding (PLF), the practice of giving food or liquid before breastfeeding is established, is still a barrier to optimal breastfeeding practices in many South Asian countries. We used a prospective cohort study to assess the association between feeding non-breastmilk food or liquid in the first three days of life and infant size at 3–5 months of age. Methods The analysis used data from 3,332 mother-infant pairs enrolled in a randomized controlled trial in northwestern rural Bangladesh conducted from 2018 to 2019. Trained interviewers visited women in their households during pregnancy to collect sociodemographic data. Project staff were notified of a birth by telephone and interviewers visited the home within approximately three days and three months post-partum. At each visit, interviewers collected data on breastfeeding practices and anthropometric measures. Infant length and weight measurements were used to produce length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) Z-scores. We used multiple linear regression to assess the association between anthropometric indices and PLF practices, controlling for household wealth, maternal age, weight, education, occupation, and infant age, sex, and neonatal sizes. Results The prevalence of PLF was 23%. Compared to infants who did not receive PLF, infants who received PLF may have a higher LAZ (Mean difference (MD) = 0.02 [95% CI: -0.04, 0.08]) score, a lower WLZ (MD=-0.06 [95% CI: -0.15, 0.03]) score, and a lower WAZ (MD=-0.02 [95% CI: -0.08, 0.05]) score at 3–5 months of age, but none of the differences were statistically significant. In the adjusted model, female sex, larger size during the neonatal period, higher maternal education, and wealthier households were associated with larger infant size. Conclusion PLF was a common practice in this setting. Although no association between PLF and infant growth was identified, we cannot ignore the potential harm posed by PLF. Future studies could assess infant size at an earlier time point, such as 1-month postpartum, or use longitudinal data to assess more subtle differences in growth trajectories with PLF. Trial registration ClinicalTrials.gov: NCT03683667 and NCT02909179.

Abstract Colonization and development of the gut microbiome are crucial for the growth and health of calves. In this review, we summarized the colonization, beneficial nutrition, immune function of gut microbiota, function of the gut barrier, and the evolution of core microbiota in the gut of calves of different ages. Homeostasis of gut microbiome is beneficial for nutritional and immune system development of calves. Disruption of the gut microbiome leads to digestive diseases in calves, such as diarrhea and intestinal inflammation. Microbiota already exists in the gut of calf fetuses, and the colonization of microbiota continues to change dynamically under the influence of various factors, which include probiotics, diet, age, and genotype. Colonization depends on the interaction between the gut microbiota and the immune system of calves. The abundance and diversity of these commensal microbiota stabilize and play a critical role in the health of calves.

Abstract Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications. Graphical Abstract

Abstract Background Dl-3-n-butylphthalide (NBP) is an important medial therapy for acute ischemic stroke in China. Recent studied have revealed that NBP not only rescued the loss of dopaminergic neurons in cellular and animal models of Parkinson's disease (PD), but also could improve motor symptoms in PD patients. However, the protective mechanism is not fully understood. P53 is a multifunctional protein implicated in numerous cellular processes, including apoptosis, DNA repair, mitochondrial functions, redox homeostasis, autophagy and protein aggregations. In PD, p53 integrated with various neurodegeneration-related signals inducing neuronal loss, indicating the suppression of P53 might be a promising target for PD treatment. Therefore, the purpose of the current study was to systemically screen new therapeutic targets of NBP in PD. Method In our study, we constructed mpp + induced N2A cells to investigate the benefit effect of NBP in PD. MTT assay was performed to evaluate the cell viability; TMT-based LC–MS/MS was applied to determine the different expressed proteins (DEPs) of NBP pretreatment; online bioinformatics databases such as DAVID, STRING, and KEGG was used to construe the proteomic data. After further analyzed and visualized the protein–protein interactions (PPI) by Cytoscape, DEPs were verified by western blot. Result A total of 5828 proteins were quantified in the comparative proteomics experiments and 417 proteins were considered as DEPs (fold change > 1.5 and p

Abstract Background This study aims to explore appropriate model for predicting the disease burden of pneumoconiosis in Tianjin by comparing the prediction effects of Autoregressive Integrated Moving Average (ARIMA) model, Deep Neural Networks (DNN) model and multivariate Long Short-Term Memory Neural Network (LSTM) models. Methods Disability adjusted life year (DALY) was used to evaluate the disease burden of occupational pneumoconiosis. ARIMA model, DNN model and multivariate LSTM model were used to establish prediction model. Three performance evaluation metrics including Root Mean Squared Error (RMSE), Mean Absolute Error (MAE) and Mean Absolute Percentage Error (MAPE) were used to compare the prediction effects of the three models. Results From 1990 to 2021, there were 10,694 cases of pneumoconiosis patients in Tianjin, resulting in a total of 112,725.52 person-years of DALY. During this period, the annual DALY showed a fluctuating trend, but it had a strong correlation with the number of pneumoconiosis patients, the average age of onset, the average age of receiving dust and the gross industrial product, and had a significant nonlinear relationship with them. The comparison of prediction results showed that the performance of multivariate LSTM model and DNN model is much better than that of traditional ARIMA model. Compared with the DNN model, the multivariate LSTM model performed better in the training set, showing lower RMES (42.30 vs. 380.96), MAE (29.53 vs. 231.20) and MAPE (1.63% vs. 2.93%), but performed less stable than the DNN on the test set, showing slightly higher RMSE (1309.14 vs. 656.44), MAE (886.98 vs. 594.47) and MAPE (36.86% vs. 22.43%). Conclusion The machine learning techniques of DNN and LSTM are an innovative method to accurately and efficiently predict the burden of pneumoconiosis with the simplest data. It has great application prospects in the monitoring and early warning system of occupational disease burden.

Abstract Background Radiotherapy is the primary therapeutic option for glioblastoma. Some studies proved that radiotherapy increased the release of exosomes from cells. The mechanism by which these exosomes modify the phenotype of microglia in the tumor microenvironment to further determine the fate of irradiated glioblastoma cells remains to be elucidated. Methods We erected the co-culture system of glioblastoma cells and microglia. After radiation, we analyzing the immunophenotype of microglia and the proliferation of radiated glioblastoma cells. By whole transcriptome sequencing, we analyzed of circRNAs in exosomes from glioblastoma cells and microglia. We used some methods, which included RT-PCR, dual-luciferase reporter, et al., to identify how circ_0012381 from radiated glioblastoma cell-derived exosomes regulated the immunophenotype of microglia to further affect the proliferation of radiated glioblastoma cells. Results Radiated glioblastoma cell-derived exosomes markedly induced M2 microglia polarization. These M2-polarized microglia promoted the proliferation of irradiated glioblastoma cells. Circ_0012381 expression was increased in the irradiated glioblastoma cells, and circ_0012381 entered the microglia via exosomes. Circ_0012381 induced M2 microglia polarization by sponging with miR-340-5p to increase ARG1 expression. M2-polarized microglia suppressed phagocytosis and promoted the growth of the irradiated glioblastoma cells by CCL2/CCR2 axis. Compared with the effects of radiotherapy alone, the inhibition of exosomes significantly inhibited the growth of irradiated glioblastoma cells in a zebrafish model. Conclusions Our data suggested that the inhibition of exosome secretion might represent a potential therapeutic strategy to increase the efficacy of radiotherapy in patients with glioblastoma.

Abstract Background Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. Methods Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). Results Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. Conclusion LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

Abstract Background Patients with HIV have a higher prevalence of thrombocytopenia than those without HIV infection, increasing their risk of substantial perioperative blood loss (PBL) during total hip arthroplasty (THA). This study aimed to evaluate PBL risk factors in HIV-infected patients undergoing THA. Methods Eighteen HIV+ patients (21 hip joints) and 33 HIV− patients (36 joints) undergoing THA were enrolled in this study. PBL was calculated using the Gross equation, which comprises total blood loss (TBL), dominant blood loss (DBL), and hidden blood loss (HBL). Risk factors for post-THA PBL in both patient populations was evaluated using multivariable linear regression. Results At baseline, the HIV+ patients were younger, more likely to be male and to have elevated hemoglobin and albumin levels, and lower erythrocyte sedimentation rates than HIV− patients. There were no differences in the T-lymphocyte subsets or coagulation function between the two groups. Age and albumin level were identified as potential HBL risk factors after THA, and albumin level was associated with higher TBL. The unadjusted linear regression analysis showed that the HBL and TBL were significantly higher in HIV+ patients than in HIV− patients. However, after adjusting for other factors, no differences in DBL, HBL, or TBL were observed between HIV− and HIV+ patients. Conclusion PBL was similar in both groups undergoing THA, regardless of their HIV-infection status. THA surgery is a safe and effective procedure in HIV+ patients.

Abstract Background Heart rate (HR) related parameters, such as HR variability, HR turbulence, resting HR, and nighttime mean HR have been recognized as independent predictors of mortality. However, the influence of circadian changes in HR on mortality remains unclear in intensive care units (ICU). The study is designed to evaluate the relationship between the circadian variation in HR and mortality risk among critically ill patients. Methods The present study included 4,760 patients extracted from the Multiparameter Intelligent Monitoring in Intensive Care II database. The nighttime mean HR/daytime mean HR ratio was adopted as the circadian variation in HR. According to the median value of the circadian variation in HR, participants were divided into two groups: group A (≤ 1) and group B (> 1). The outcomes included ICU, hospital, 30-day, and 1-year mortalities. The prognostic value of HR circadian variation was investigated by multivariable logistic regression models and Cox proportional hazards models. Results Patients in group B (n = 2,471) had higher mortality than those in group A (n = 2,289). Multivariable models revealed that the higher circadian variation in HR was associated with ICU mortality (odds ratio [OR], 1.393; 95% confidence interval [CI], 1.112–1.745; P = 0.004), hospital mortality (OR, 1.393; 95% CI, 1.112–1.745; P = 0.004), 30-day mortality (hazard ratio, 1.260; 95% CI, 1.064–1.491; P = 0.007), and 1-year mortality (hazard ratio, 1.207; 95% CI, 1.057–1.378; P = 0.005), especially in patients with higher SOFA scores. Conclusions The circadian variation in HR might aid in the early identification of critically ill patients at high risk of associated with ICU, hospital, 30-day, and 1-year mortalities.

Abstract Background Birth defects pose a major challenge to infant health. Thus far, however, the causes of most birth defects remain cryptic. Over the past few decades, considerable effort has been expended on disclosing the underlying mechanisms related to birth defects, yielding myriad treatises and data. To meet the increasing requirements for data resources, we developed a freely accessible birth defect multi-omics database (BDdb, http://t21omics.cngb.org ) consisting of multi-omics data and potential disease biomarkers. Results In total, omics datasets from 136 Gene Expression Omnibus (GEO) Series records, including 5245 samples, as well as 869 biomarkers of 22 birth defects in six different species, were integrated into the BDdb. The database provides a user-friendly interface for searching, browsing, and downloading data of interest. The BDdb also enables users to explore the correlations among different sequencing methods, such as chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) from different studies, to obtain the information on gene expression patterns from diverse aspects. Conclusion To the best of our knowledge, the BDdb is the first comprehensive database associated with birth defects, which should benefit the diagnosis and prevention of birth defects.

Abstract Objectives To explore the long non-coding RNA (lncRNA) expression pattern of congenital lung malformations on a genome-wide scale and investigate their potential biological function in four subtypes of congenital lung malformations. Methods We obtained both lesions and normal lung control tissues from the patients diagnosed with CPAM-I, CPAM-II, ILS, and ILS-CPAM, and underwent lobectomy (i.e., surgical removal of the whole lobe which contains the localized lesion as well as normal lung tissue). Then, we performed lncRNA transcriptome profiling in these tissues by RNA sequencing (RNA-seq). A comprehensive bioinformatics analysis was conducted to characterize the expression profiles and relevant biological functions and for multiple comparisons of lncRNA expression in the different subtypes of congenital lung malformation tissues. Furthermore, the lncRNA-mRNA co-expression network was constructed, and dysregulated mRNAs were functionally analyzed. Finally, gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of the identified lncRNAs. Results A total of 5921 lncRNA transcripts were identified between congenital lung malformations tissues and normal lung control tissues. Compared with normal lung control, 481of these expressed lncRNAs were upregulated and 142 were downregulated in CPAM-I, 91 were upregulated and 14 were downregulated in CPAM-II, 39 were upregulated and 38 were downregulated in ILS, and 201 were upregulated and 38 were downregulated in ILS-CPAM. Unsupervised clustering and principal component analysis of the expressed lncRNAs visualized the differences between normal lung control and different subtypes of congenital lung malformations samples. We also confirmed significant differences in the composition of differentially expressed genes (DEGs) and the differentially expressed lncRNAs (DE lncRNAs) between CPAM-I and other subtypes of congenital lung malformations, as well as in normal lung control tissues, and observed enrichment of DEGs in the regulation of the immune system, cell projection organization, and inflammatory pathways. Finally, we identified the lncRNA FLJ26850 might be related to congenital lung malformations via ZNF473. Conclusions Significant differences in lncRNAs expression patterns were observed between different subtypes of congenital lung malformations and normal control. The lncRNA FLJ26850 might be related to congenital lung malformations via ZNF473.

Abstract Background Our previous study proved that Salvia miltiorrhiza could enhance fat graft survival by promoting adipogenesis. However, the effect of salvianolic acid B (Sal-B), the most abundant and bioactive water-soluble compound in Salvia miltiorrhiza, on fat graft survival has not yet been investigated. Objective This study aims to investigate whether salvianolic acid B could improve fat graft survival and promote preadipocyte differentiation. The underlying mechanism has also been studied. Methods In vivo, 0.2 ml of Coleman fat was transplanted into nude mice with salvianolic acid B. The grafts were evaluated by HE and IF at 2 and 4 weeks posttransplantation and by micro-CT at 4 weeks posttransplantation. In vitro, the adipogenesis and proliferative activities of salvianolic acid B were analyzed in cultured human adipose-derived stem cells (h-ADSCs) and 3T3-L1 cells to detect the mechanism by which salvianolic acid B affects graft survival. Results In vivo, the weights and volumes of the fat grafts in the Sal-B-treated groups were significantly higher than those of the fat grafts in the control group. In addition, higher fat integrity and more viable adipocytes were observed in the Sal-B-treated groups. In vitro, salvianolic acid B showed the ability to promote 3T3-L1 and h-ADSC proliferation and adipogenesis. Conclusions Our in vitro experiments demonstrated that salvianolic acid B can promote the proliferation of adipose stem cells and enhance the differentiation of adipose stem cells. Simultaneously, in vivo experiments showed that salvianolic acid B can improve the survival rate of fat transplantation. Therefore, our research shed light on the potential therapeutic usage of salvianolic acid B in improving the survival rate of fat transplantation.

Abstract Background Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by detecting low molecular weight degradation products using a spectrophotometric method developed by Japan Bio Science Laboratory Co., Ltd. Subtilisin QK powder can maintain its fibrinolytic activity for more than 24 months when it is stored at room temperature and protected from light. Our previous results showed that subtlisin QK directly degraded cross-linked fibrins in the fibrin plate assay and effectively inhibited thrombosis in the mouse thrombus model. The aim of this study was to determine the acute toxicity, potential subchronic toxicity, and safety pharmacology of subtilisin QK in Sprague–Dawley (SD) rats. Methods In the acute toxicity study, a single oral dose of 100,000 FU/kg was administered to 10 female and 10 male SD rats. In the 28-day subchronic toxicity, 60 female and 60 male SD rats were randomly assigned to four experimental groups (daily oral dose of 0, 2500, 7500 and 25,000 FU/kg). In the safety pharmacology study, 20 female and 20 male SD rats were randomly assigned to four experimental groups (single oral dose of 0, 500, 1500 and 5000 FU/kg). Results No death occurred and no adverse effects were observed in the acute toxicity study at a dose of 100,000 FU/kg. In the 28-day subchronic toxicity study, several hematological and blood biochemical parameters showed increases or decreases; however, due to the lack of a dose–response relationship, these differences were considered unrelated to treatment. In the safety pharmacology study, no adverse effects were observed on the central nervous of SD rats post-administration up to a dose of 5000 FU/kg subtilisin QK. Conclusion The results showed that oral consumption of subtilisin QK is of low toxicological concern. No adverse effects were observed at doses of 2500, 7500, and 25,000 FU/kg in the 28-day subchronic toxicity, and the no-observed-adverse-effect level (NOAEL) of subtilisin QK was 25,000 FU/kg.

Abstract Background Network meta-analysis (NMA) has been widely used in the field of medicine and health, but the research topics and development trends are still unclear. This study aimed to identify the cooperation of countries and institutes and explore the hot topics and future prospects in the field of NMA. Methods Data of publications were downloaded from the Web of Science Core Collection. We used CiteSpace V, HistCite 2.1, and Excel 2016 to analyze literature information, including years, journals, countries, institutes, authors, keywords, and co-cited references. Results NMA research developed gradually before 2010 and rapidly in the following years. 2846 NMA studies were published in 771 journals in six languages. The PLoS One (110, 3.9%) was the most productive journal, and N Engl J Med (5904 co-citations) was the most co-cited journal. The most productive country was the United States (889, 31%) and the most productive institute was the University of Bristol (113, 4.0%). The active collaborations were observed between developed countries and between productive institutes. Of the top 10 authors, four were from the UK, and among the top 10 co-cited authors, six were from the UK. Randomized evidence, oral anti-diabetic drugs, coronary artery bypass, certolizumab pegol, non-valvular atrial fibrillation, and second-line antihyperglycemic therapy were the hot topics in this field. Conclusions NMA studies have significantly increased over the past decade, especially from 2015 to 2017. Compared with developing countries, developed countries have contributed more to these publications and have closer cooperation, indicating that cooperation between developed and developing countries should be further strengthened. The treatment of diabetes, cardiovascular diseases, and immune rheumatism are the main hot topics.

Abstract Ubiquitin-conjugating enzyme E2 M (UBE2M) and ubiquitin-conjugating enzyme E2 F (UBE2F) are the two NEDD8-conjugating enzymes of the neddylation pathway that take part in posttranslational modification and change the activity of target proteins. The activity of E2 enzymes requires both a 26-residue N-terminal docking peptide and a conserved E2 catalytic core domain, which is the basis for the transfer of neural precursor cell-expressed developmentally downregulated 8 (NEDD8). By recruiting E3 ligases and targeting cullin and non-cullin substrates, UBE2M and UBE2F play diverse biological roles. Currently, there are several inhibitors that target the UBE2M-defective in cullin neddylation protein 1 (DCN1) interaction to treat cancer. As described above, this review provides insights into the mechanism of UBE2M and UBE2F and emphasizes these two E2 enzymes as appealing therapeutic targets for the treatment of cancers.

Abstract Background Sjogren’s syndrome (SS) is a chronic autoimmune rheumatic disease with an incidence of 0.03 to 0.3%. In recent years, there are an increasing number of randomized controlled trials of traditional Chinese medicine (TCM) for SS. However, there are generally some problems in these published clinical trials: lack of reporting primary or long-term outcomes and the heterogeneous in different clinical trials’ outcome. Our study aims to determine the priority outcomes and standard TCM syndromes for all stakeholders and reach agreement on the COS and syndromes to be measured and reported in all future TCM trials in patients with SS. Methods and analysis A phase-wise refinement approach will be used, consisting of three phases, yet complementary, sub-work phases, whereby each phase will inform the next coming phases. The following are the three phases: (I-a) identifying of a long initial list of outcomes through systematic literature review and semi-structured qualitative interviews and (I-b) identifying an initial list of TCM syndromes through (1) systematic literature review, (2) referencing ancient Chinese medical books, and (3) retrospective studies of medical records; (II) prioritization of outcomes using Delphi survey with different stakeholders, such as health professionals and patients; and (III) through consensus meetings with patients and professionals to agree on the final COS and TCM syndromes. Discussion We summarized the actions of COS into three points: direct action, indirect action, and final action. After the final COSs is completed, we will publish this research in a journal to promote communication. Trial registration Core Outcome Measures in Effectiveness Trials Initiative (COMET) number 1429 . Registered on 01 December 2019.

Abstract Background The relationship between cancer with overweight and obesity has been extensively reported. However, the association between urinary cancers with these risk factors remains unclear, with existing reports showing conflicting findings. The current review, therefore, sought to clarify the latter association by assessing the methodological and reporting quality of existing systematic reviews on the subject. Methods We first screened PubMed, EMBASE, and Cochrane Library databases for relevant literature and subjected the resulting articles to meta-analysis. We adopted the AMSTAR-2 and PRISMA checklists for assessing methodological and reporting quality, respectively, then performed meta-analyses to determine the relationship between incidence and mortality of three types of urinary cancers with obesity and overweight. Indirect comparisons were also done across subgroups. Results All systematic reviews (SRs) were of critically low methodological quality. Seventeen SRs had minimal reporting flaws, and 11 SRs had minor reporting flaws. We found an association between obesity with an incidence of kidney (RR = 1.68, 95% CI 1.47–1.92), bladder (RR = 1.1, 95% CI 1.07–1.13), and prostate (RR = 1.02, 95% CI 0.91, 1.13) cancers. Similarly, overweight was associated with the incidence of the three types of cancer, recording RR values of 1.37 (95% CI 1.26–1.48), 1.07 (95% CI 1.03–1.1), and 1 (95% CI 0.93, 1.07) for kidney, bladder, and prostate cancers, respectively. With regard to the dose analysis, the RR of BMI (per 5 kg/m2 increase) was associated with kidney (RR = 1.24, 95% CI 1.2–1.28), bladder (RR = 1.03, 95% CI 1.02–1.05), and prostate (RR = 1.02, 95% CI 1.01, 1.03) cancers. Conclusions This comprehensive quantitative analysis provides an affirmation that overweight and obesity are strong risk factors for kidney cancer, owing to a strong association between them. Conversely, a weak association between overweight and obesity with bladder and prostate cancers confirms their status as mild risk factors for the 2 types of cancer. But due to the low quality of included SRs, the results need to be interpreted with caution. Systematic review registration PROSPERO CRD42019119459

Abstract Background Previous studies on the impact of corona virus disease 2019 (COVID-19) on the mental health of the patients has been limited by the lack of relevant data. With the rapid and sustained growth of the publications on COVID-19 research, we will perform a living systematic review (LSR) to provide comprehensive and continuously updated data to explore the prevalence of delirium, depression, anxiety, and post-traumatic stress disorder (PTSD) among COVID-19 patients. Methods We will perform a comprehensive search of the following databases: Cochrane Library, PubMed, Web of Science, EMBASE, and Chinese Biomedicine Literature to identify relevant studies. We will include peer-reviewed cross-sectional studies published in English and Chinese. Two reviewers will independently assess the methodological quality of included studies using the Joanna Briggs Institute Prevalence Critical Appraisal tool and perform data extraction. In the absence of clinical heterogeneity, the prevalence estimates with a 95% confidence interval (CI) of delirium, depression, anxiety, and post-traumatic stress disorder (PTSD) will be calculated by using random-effects model to minimize the effect of between-study heterogeneity separately. The literature searches will be updated every 3 months. We will perform meta-analysis if any new eligible studies or data are obtained. We will resubmit an updated review when there were relevant changes in the results, i.e., when outcomes became statistically significant (or not statistically significant anymore) or when heterogeneity became substantial (or not substantial anymore). Discussion This LSR will provide an in-depth and up-to-date summary of whether the common neuropsychiatric conditions observed in patients hospitalized for severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS) are also prevalent in a different stage of COVID-19 patients. Systematic review registration PROSPERO CRD42020196610

Abstract Background Manure and biochar soil amendments have shown many benefits to soil quality and crop productivity. This study aimed to reveal the effects of biochar and manure applications on soil fertility improvement and crop productivity in yellow cinnamon soil. Results This study based on a 5-year field experiment. Four treatments were designed, included the control (CK), biochar amendment, manure amendment, and both biochar and manure amendment (BM). The results showed that: after five years, both biochar and manure treatment improved soil structure by increasing soil mean weight diameter (MWD), and soil water and nutrient supply was also increased by increasing the contents of water content, available potassium and available phosphorus. The productivity was also enhanced as wheat yield under the biochar, manure, and BM treatments increased by 3.59–11.32% compared with CK. In addition, biochar and manure treatment increased soil microbial biomass carbon (MBC) by > 15%, and soil total nematode abundance was significantly increased. Furthermore, the nematode community structure was significantly affected by biochar and manure treatment, dominant trophic group in CK was herbivores, but bacterivores were dominant in the biochar and manure treatments. The distribution of nematode genera was closely related to soil chemical properties and microbial biomass. Increases in the Shannon's diversity index, and decreases in the dominance index and summed maturity index after the 5-year treatment indicated a sustainable soil ecosystem after the biochar and manure applications. Conclusions These findings indicate that biochar and manure result in better soil quality and increased productivity in yellow cinnamon soil.

Abstract Background Network meta-analyses using individual participant data (IPD-NMAs) have been increasingly used to compare the effects of multiple interventions. Although there have been many studies on statistical methods for IPD-NMAs, it is unclear whether there are statistical defects in published IPD-NMAs and whether the reporting of statistical analyses has improved. This study aimed to investigate statistical methods used and assess the reporting and methodological quality of IPD-NMAs. Methods We searched four bibliographic databases to identify published IPD-NMAs. The methodological quality was assessed using AMSTAR-2 and reporting quality assessed based on PRISMA-IPD and PRISMA-NMA. We performed stratified analyses and correlation analyses to explore the factors that might affect quality. Results We identified 21 IPD-NMAs. Only 23.8% of the included IPD-NMAs reported statistical techniques used for missing participant data, 42.9% assessed the consistency, and none assessed the transitivity. None of the included IPD-NMAs reported sources of funding for trials included, only 9.5% stated pre-registration of protocols, and 28.6% assessed the risk of bias in individual studies. For reporting quality, compliance rates were lower than 50.0% for more than half of the items. Less than 15.0% of the IPD-NMAs reported data integrity, presented the network geometry, or clarified risk of bias across studies. IPD-NMAs with statistical or epidemiological authors often better assessed the inconsistency (P = 0.017). IPD-NMAs with a priori protocol were associated with higher reporting quality in terms of search (P = 0.046), data collection process (P = 0.031), and syntheses of results (P = 0.006). Conclusions The reporting of statistical methods and compliance rates of methodological and reporting items of IPD-NMAs were suboptimal. Authors of future IPD-NMAs should address the identified flaws and strictly adhere to methodological and reporting guidelines.

Abstract Background Stroke is a major cause of death and disability worldwide. Over the years, traditional medicines for stroke treatment have undergone tremendous progress, but few bibliometric studies have been performed. This study explored the trends and issues relating to the application of traditional medicine in stroke research. Methods A bibliometric search was performed in the Web of Science Core Collection database to identify studies that investigated the application of traditional medicine in stroke management. CiteSpace VI and Excel 2016 were used to analyze information from the retrieved studies. Activity index and attractive index were used to explore the worldwide development modes. Results A total of 1083 English articles published between 2004 and 2018 were identified. Over the last 15 years, the developments in research occurred in three geographic clusters. The development modes were investigated and classified into 4 categories. In mainland China, the number and impact of research showed an increasing trend over the study period. The United States played a leading role in this topic. Three clusters of institutes and the majority of authors mainly came from South Korea, Taiwan and mainland China. Reperfusion injury and angiogenesis were identified as the potential topics likely to dominate future research in this field. Conclusion The progress of studies on traditional medicine for stroke could be explained by the global attention to traditional medicine, the geospatial proximity for research collabration, and the increasing resources invested. Based on a large amount of existing research, researchers engaged in this topic should objectively consider the influential studies to identify and solve the common issues worldwide.

Abstract Background Inflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown. Methods Three-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus. Results LPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII+ neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus ShHdac2, which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits. Conclusions Reversing HDAC2 in hippocampal CaMKII+ neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

Abstract Background During human pregnancy, placental trophectoderm cells release extracellular vesicles (EVs) into maternal circulation. Trophoblasts also give rise to cell-free DNA (cfDNA) in maternal blood, and has been used for noninvasive prenatal screening for chromosomal aneuploidy. We intended to prove the existence of DNA in the EVs (evDNA) of maternal blood, and compared evDNA with plasma cfDNA in terms of genome distribution, fragment length, and the possibility of detecting genetic diseases. Methods Maternal blood from 20 euploid pregnancies, 9 T21 pregnancies, 3 T18 pregnancies, 1 T13 pregnancy, and 2 pregnancies with FGFR3 mutations were obtained. EVs were separated from maternal plasma, and confirmed by transmission electronic microscopy (TEM), western blotting, and flow cytometry (FACS). evDNA was extracted and its fetal origin was confirmed by quantitative PCR (qPCR). Pair-end (PE) whole genome sequencing was performed to characterize evDNA, and the results were compared with that of cfDNA. The fetal risk of aneuploidy and monogenic diseases was analyzed using the evDNA sequencing data. Results EVs separated from maternal plasma were confirmed with morphology by TEM, and protein markers of CD9, CD63, CD81 as well as the placental specific protein placental alkaline phosphatase (PLAP) were confirmed by western blotting or flow cytometry. EvDNA could be successfully extracted for qPCR and sequencing from the plasma EVs. Sequencing data showed that evDNA span on all 23 pairs of chromosomes and mitochondria, sharing a similar distribution pattern and higher GC content comparing with cfDNA. EvDNA showed shorter fragments yet lower fetal fraction than cfDNA. EvDNA could be used to correctly determine fetal gender, trisomies, and de novo FGFR3 mutations. Conclusions We proved that fetal DNA could be detected in EVs separated from maternal plasma. EvDNA shared some similar features to plasma cfDNA, and could potentially be used to detect genetic diseases in fetus.

Abstract Background The growth plate is a special region of the cartilage that drives longitudinal growth of long bones. Proliferating chondrocytes in the growth plate, arranged in columns, divide perpendicular to the long axis of the growth plate then intercalate to re-align with parental columns. Which molecular partners maintain growth plate columnar structures and chondrocyte cytokinesis has not been fully revealed. It is reported that kinesin family member 3A (KIF3A), a subunit of kinesin-2, plays an important role in maintaining columnar organization in growth plates via controlling primary cilia formation and cell proliferation. Result Here we identify kinesin family member 5B (KIF5B), the heavy chain of kinesin-1, a ubiquitously expressed motor protein for anterograde intracellular transport along the microtubule network, as a key modulator of cytokinesis in chondrocytes via maintenance of central spindle organization. We show that KIF5B is concentrated in the central spindle during cytokinesis in both primary chondrocytes and chondrogenic ATDC5 cells. Conclusion The failure of cytokinesis in KIF5B null chondrocytes leads to incomplete cell rotation, disrupting proliferation and differentiation, and results in a disorganized growth plate.

Abstract Background Previous studies have found a connection between left coronary artery dominance and worse prognoses in patient with acute coronary syndrome, which remains a predominant cause of morbidity and mortality globally. The aim of this study was to investigate whether coronary dominance is associated with the incidence of acute inferior myocardial infarction (MI). Methods Between January 2011 and November 2014, 265 patients with acute inferior MI and 530 age-matched and sex-matched controls were recruited for a case-control study in the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. All participants underwent coronary angiography. The exclusion criteria included history of coronary artery bypass graft surgery, chronic or systemic diseases (including hepatic failure, kidney failure, hypothyroidism and Grave’s disease), ventricular fibrillation, and known allergy to iodinated contrast agent. Patients with left- or co-dominant anatomies were placed into the LD group and those with right-dominant anatomy were included in the RD group. The association of acute inferior MI and coronary dominant anatomy were assessed using multivariable conditional logistic regression, and to estimate the odds ratio (OR) and 95% confidence interval (95%CI). Results Distributions of right dominance were significantly different between the acute inferior MI group and control group (94.0% vs. 87.9%, P = 0.018). Univariable conditional logistic regression revealed that right dominance may be a risk factor for the incident acute inferior MI (OR: 2.137; 95% CI: 1.210–3.776; P = 0.009). After adjusting for baseline systolic blood pressure, heart rate, smoking status, diabetes mellitus, hypertension, hyperlipidaemia, and family history of coronary artery disease, results of multivariate conditional logistic regression showed that right dominance was associated with the incidence of acute inferior MI (OR: 2.396; 95% CI: 1.328–4.321; P = 0.004). Conclusions Right coronary dominance may play a disadvantageous role in the incidence of acute inferior MI. However, further studies are needed to verify our findings, especially with regard to the underlying mechanisms.

Abstract Background This study aimed to explore the molecular mechanism of estrogen-mediated neuroprotection in the relief of cerebral ischemic injury. The gene expression profiles were downloaded from Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified using limma package in R software. Further, DEGs were subjected to Gene Ontology (GO) cluster analysis using online Gene Ontology Enrichment Analysis Software Toolkit and to GO functional enrichment analysis using DAVID software. Using the Gene Set Analysis Toolkit V2, enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways was performed. In addition, protein-protein interaction (PPI) network was constructed using STRING database, and submodule analysis of PPI network. Lastly, the significant potential target sites of microRNAs (miRNAs) were predicted using Molecular Signatures Database, and the function analysis of targets of predicted miRNA was also performed using DAVID software. Results In total, 321 DEGs were screened in the estrogen-treated sample. The DEGs were mainly associated with intracellular signaling and metabolic pathways, such as calcium channel, calcineurin complex, insulin secretion, low-density lipoprotein reconstruction, and starch or sugar metabolism. In addition, GO enrichment analysis indicated an altered expression of the genes related to starch and sucrose metabolism, retinol metabolism, anti-apoptosis (eg., BDNF and ADAM17) and response to endogenous stimulus. The constructed PPI network comprised of 243 nodes and 590 interaction pairs, and four submodules were obtained from PPI network. Among the module d, four glutamate receptors as Gria4, Gria3, Grin3a and Grik4 were highlighted. Further, 5 novel potential regulatory miRNAs were also predicted. MIR-338 and MIR520D were closely associated with cell cycle, while the targets of MIR-376A and MIR-376B were only involved in cell soma. Conclusions The DEGs in estrogen-treated samples are closely associated with calcium channel, glutamate induced excitotoxicity and anti-apoptotic activity. In addition, some functionally significant DEGs such as BDNF, ADAM17, Gria4, Gria3, Grin3a, Grik4, Gys2 and Ugtla2, and new miRNAs like MIR-338 and MIR-376A were identified, which may serve as potential therapeutic targets for the effective treatment of cerebral ischemic injury.

Abstract Background Neck circumference (NC), representing upper body subcutaneous adipose tissue, may be correlated with increased risk of overweight/obesity, obstructive sleep apnoea, and metabolic and cardiovascular disease. However, the relationship between NC and the incidence of congestive heart failure (CHF) or mortality due to coronary heart disease (CHD) in a community-based population with and without sleep-disordered breathing (SDB) has not yet been clarified. Methods We performed a prospective study using the Sleep Heart Health Study (SHHS) cohort. Cox proportional hazards regression models were used to estimate the association of different levels of NC with CHF incidence or CHD mortality in 2234 individuals with SDB and 2199 without SDB, respectively. Results After adjusting for age, sex, and body mass index (BMI), NC was significantly associated with CHF when comparing the highest NC quartile group with the lowest (hazard ratio, HR, 2.265, 95% confidence interval, CI, 1.074–4.777) in the non-SDB population. This association diminished after further adjustment for other risk factors, but remained statistically significant, with an adjusted HR of 1.082 (95% CI 1.003–1.166) per unit increase in NC. Additionally, after adjustment for age, sex, and BMI, NC was also shown to be remarkably associated with CHD mortality (HR 1.141, 95% CI 1.014–1.282) per unit increase in NC in the non-SDB population but not in the SDB population. After adjustment for all the covariates, there was a significant association between NC and CHD death in those without SDB, with an adjusted HR of 1.134 (95% CI 1.001–1.284) per unit increase in NC. Conclusions NC may correlate with CHF incidence and CHD mortality in population without SDB. NC measurement may help risk stratification for cardiovascular diseases. Trial registration NCT00005275, January 1994.