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Background: To investigate the causal link between early-life exposures and long-term health consequences, we established the Tianjin Birth Cohort (TJBC), a large-scale prospective cohort in northern China. Methods: TJBC aims to enroll 10,000 families with follow-ups from pregnancy until children’s six year-old. Pregnant women and their spouses were recruited through a three-tier antenatal healthcare system at early pregnancy, with follow-ups at mid-pregnancy, late pregnancy, delivery, 42 days after delivery, 6 months after delivery, and each year until 6 years old. Antenatal/neonatal examination, biological samples and questionnaires were collected. Results: From August 2017 to January 2019, a total of 3,924 pregnant women have already been enrolled, and 1,697 women have given birth. We observed the prevalence of gestational diabetes mellitus as 18.1%, anemia as 20.4%, and thyroid hypofunction as 2.0%. In singleton live births, 5.6% were preterm birth (PTB), 3.7% were low birth weight, and 7.3% were macrosomia. Based on current data, we also identified maternal/paternal factors which increased the risk of PTB, including paternal age (OR 1.07; 95% CI, 1.01–1.14 for each year increase), vaginal bleeding during pregnancy (OR 2.82; 95% CI, 1.54–5.17) and maternal early-pregnancy BMI (OR 1.08; 95% CI, 1.01–1.15 for each kg/m2 increase). Conclusion: TJBC has the strength of collecting comprehensive maternal, paternal, and childhood information. With a diverse range of biological samples, we are also engaging with emerging new technologies for multi-omics research. The study would provide new insight into the causal link between macro/micro-environmental exposures of early life and short/long-term health consequences.

Background: To assess the association between serum lactate dehydrogenase (LDH) levels and mortality in intensive care unit patients. Materials & methods: A total of 1981 patients in the eICU Collaborative Research Database were divided into four groups according to quartiles of LDH levels. Logistic regressions were performed. Results: Elevated LDH levels were significantly associated with higher mortality (intensive care unit mortality: Q2 vs Q1: 1.046 [0.622–1.758]; Q3 vs Q1: 1.667 [1.029–2.699]; and Q4 vs Q1: 1.760 [1.092–2.839]). Similar results persisted in patients with different acute physiology and chronic health evaluation IV scores, and with or without sepsis. Conclusion: The serum LDH level may aid in the early identification of mortality risk in critically ill patients.

Background Breast cancer is a global health problem that cannot be underestimated. Many studies have shown that breast cancer is related to pathogenic mutations in hereditary predisposition genes. Clinical practice guidelines play a vital role in guiding the selection of breast cancer screening. Little is known about the quality and consistency of guidelines’ recommendations and their changes over these years. Methods We reviewed the existing screening guidelines for genetic susceptibility to breast cancer and assessed the methodological quality, and summarized the recommendations to aid clinicians to make decisions. We conducted a systematic search in PubMed, Embase, Web of Science, and guideline‐specific databases, aiming to find the guidelines of breast cancer due to hereditary predisposition. The necessary information was exacted by Excel. We also summarized different evidence grading systems. The qualities of the guidelines were assessed by the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument. Results A total of 54 recommendations from 13 guidelines were extracted. Generally speaking, the recommendations were consistent, mainly focusing on mammography and MRI. Conclusions The recommendations differ in details. Moreover, different guidelines are based on different grading systems, and some guidelines are not divided for age limits, which may limit the promotion and implementation of the guidelines. It is suggested that improvement can be made in this regard in the future., Systematic and comprehensive search of breast cancer gene mutation screening guidelines, and summarize and analyze the recommendations, to find out the current problems

To determine the impact of initial vancomycin trough concentration (VTC) on mortality in adult patients in the intensive care unit (ICU) undergoing vancomycin therapy. During their first ICU stay, patients with initial VTC records after vancomycin treatment were recruited from the eICU Collaborative Research Database to this multicenter retrospective cohort study, and classified into four groups according to VTC: less than 10, 10–15, 15–20, and greater than 20 mg/L. Multivariable logistic regression and sensitivity analyses were performed to explore the association of VTC, as a continuous and categorical variable, with mortality. This study enrolled 7220 patients from 335 different ICUs at 208 hospitals. Multivariable logistic regression models indicated that VTC was positively correlated with ICU (odds ratio [OR], 1.028, 95% confidence interval [CI], 1.019–1.037) and hospital (OR 1.028, 95% CI, 1.020–1.036) mortalities. Moreover, compared with VTC less than 10 mg/L, VTCs of 10–15, 15–20, and greater than 20 mg/L were associated with a higher risk of ICU mortality (OR, 1.330, 95% CI, 1.070–1.653; OR, 1.596, 95% CI, 1.265–2.015; abd OR, 1.875, 95% CI, 1.491–2.357, respectively), and VTCs of 15–20 and greater than 20 mg/L were also correlated with increased hospital mortality (OR, 1.482, 95% CI, 1.225–1.793; and OR, 1.831, 95% CI, 1.517–2.210, respectively). Similar results persisted in patients with different Acute Physiology and Chronic Health Evaluation Ⅳ scores, creatinine clearance levels, ages, and body mass indexes. Our findings indicated a potential relationship of initial VTC with ICU and hospital mortalities in patients in the ICU. However, due to the retrospective nature of this study, future prospective studies or randomized controlled trials are needed to validate those results.

Background To investigate the value of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) in diagnosing local tumor invasion (T stage), evaluating regional lymph node involvement (N stage), and detecting distant metastasis (M stage) in breast cancer patients. Methods A comprehensive computer search and manual search were performed to select any potentially eligible studies that evaluated the diagnostic efficacy of 18F-FDG PET/MRI in the tumor-node-metastasis (TNM) staging of breast cancer. Data from the included studies were extracted to calculate the pooled sensitivity, specificity, and area under the curve (AUC) to evaluate the value of 18F-FDG PET/MRI in TNM staging. Quality and publication bias were also assessed in this meta-analysis. Results Based on seven studies, the pooled sensitivity, specificity and AUC for the diagnosis of T stage were 91% (95% CI: 84-96%), 91% (95% CI: 81-96%), and 0.96 (95% CI: 0.94-0.98), respectively. For N stage evaluation, four studies were included, with values of 94% (95% CI: 83-98%), 90% (95% CI: 81-95%), and 0.96 (95% CI: 0.94-0.97). For M stage detection, five studies were evaluated, with values of 98% (95% CI: 96-99%), 96% (95% CI: 83-99%), and 0.99 (95% CI: 0.98-1.00). Conclusions 18F-FDG PET/MRI demonstrates higher diagnostic value in the TNM staging of breast cancer and can serve as an effective and promising imaging biomarker for future evaluation of TNM stage in breast cancer patients.

Evidence indicates that glucose variation (GV) plays an important role in mortality of critically ill patients. We aimed to investigate the relationship between the coefficient of variation of 24-h venous blood glucose (24-hVBGCV) and mortality among patients with acute respiratory failure. The records of 1625 patients in the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database were extracted. The 24-hVBGCV was calculated as the ratio of the standard deviation (SD) to the mean venous blood glucose level, expressed as a percentage. The outcomes included ICU mortality and in-hospital mortality. Participants were divided into three subgroups based on tertiles of 24-hVBGCV. Multivariable logistic regression models were used to evaluate the relationship between 24-hVBGCV and mortality. Sensitivity analyses were also performed in groups of patients with and without diabetes mellitus. Taking the lowest tertile as a reference, after adjustment for all the covariates, the highest tertile was significantly associated with ICU mortality [odds ratio (OR), 1.353; 95% confidence interval (CI), 1.018–1.797] and in-hospital mortality (OR, 1.319; 95% CI, 1.003–1.735), especially in the population without diabetes. The 24-hVBGCV may be associated with ICU and in-hospital mortality in patients with acute respiratory failure in the ICU, especially in those without diabetes.

Transcription factor-driven cell fate engineering in pluripotency induction, transdifferentiation, and forward reprogramming requires efficiency, speed, and maturity for widespread adoption and clinical translation. Here, we used Oct4, Sox2, Klf4, and c-Myc driven pluripotency reprogramming to evaluate methods for enhancing and tailoring cell fate transitions, through directed evolution with iterative screening of pooled mutant libraries and phenotypic selection. We identified an artificially evolved and enhanced POU factor (ePOU) that substantially outperforms wild-type Oct4 in terms of reprogramming speed and efficiency. In contrast to Oct4, not only can ePOU induce pluripotency with Sox2 alone, but it can also do so in the absence of Sox2 in a three-factor ePOU/Klf4/c-Myc cocktail. Biochemical assays combined with genome-wide analyses showed that ePOU possesses a new preference to dimerize on palindromic DNA elements. Yet, the moderate capacity of Oct4 to function as a pioneer factor, its preference to bind octamer DNA and its capability to dimerize with Sox2 and Sox17 proteins remain unchanged in ePOU. Compared with Oct4, ePOU is thermodynamically stabilized and persists longer in reprogramming cells. In consequence, ePOU: 1) differentially activates several genes hitherto not implicated in reprogramming, 2) reveals an unappreciated role of thyrotropin-releasing hormone signaling, and 3) binds a distinct class of retrotransposons. Collectively, these features enable ePOU to accelerate the establishment of the pluripotency network. This demonstrates that the phenotypic selection of novel factor variants from mammalian cells with desired properties is key to advancing cell fate conversions with artificially evolved biomolecules.

Desertification land in Gonghe Basin of Tibetan Plateau, China accounts for 91.9% of the total land area. Vegetation restoration and reconstruction with desert shrubs in degraded ecosystem are effective ways to prevent and control desertification. However, the evaluation studies of fine root dynamic characteristics of desert shrubs and their contribution to carbon sequestration of plantation are limited. To gain a better understanding of vegetation restoration, the vertical distribution of fine root biomass, fine root decomposition, fine root turnover was investigated, as well as their coupling effect on carbon sequestration of plantation in three desert vegetation. The results estimated that the total decomposition time of fine roots of Salix cheilophila (S. cheilophila), Salix psammophila (S. psammophila), and Salix microstachya (S. microstachya) are 39.00, 27.99 and 35.95 years. Biomass carbon density for three Salix plantations ranged from 1.42 to 2.39 t/hm2, which showed that three Salix plantations in alpine sandy land are an important carbon pool. In addition, fine root biomass carbon density for the three shrub plantations varied significantly. Fine root biomass carbon density for S. psammophila reached the largest among the three plantations, which was 1.48 t/hm2, accounting for the ratio of 62% of the plantation total biomass carbon density. The results indicated that the root system of S. psammophila, especially the fine roots, was very developed, which was conducive to soil water transportation and carbon sequestration. Therefore, S. psammophila might be a better species for carbon sequestration of plantation in alpine sandy areas. The carbon input from the fine roots of the three shrub plantations through decomposition and turnover into the plantations accounts for 11.5% to 15.5% of total carbon sequestration of plantations. Therefore, the fine roots dynamics must be considered for long‐term carbon pool estimations in three Salix plantations, otherwise the total carbon sequestration of plantations would be underestimated.

Objectives The objective of the study was to assess inconsistencies between individual protocols and associated full-text publications in the development of core outcome sets (COSs). Study Design and Setting Protocols and subsequent full-text publications were retrieved by searching the following electronic databases: PubMed, Embase, Web of Science, and the Core Outcome Measures in Effectiveness Trials database from inception to October 1, 2019. We summarized changes in the general and methodological characteristics by comparing the protocols with the full-text publications and reported change as information frequency and proportion. Results A total of 24 protocols and 32 corresponding full-text publications that encompassed 14 study topics were identified from databases. In the identified initial list of outcomes, five COSs (20.8%) changed the included study type, none of which explained the reasons for these changes. In addition, eight COSs showed inconsistencies between the protocols and full-text publications in the searched databases, of which, only two studies explained the reasons for these changes. Compared with the protocols, three COSs changed the number of Delphi rounds, eight COSs changed the participants (stakeholder groups), and three COSs changed the consensus definition of the Delphi survey. Only two COSs explained the reason for changing the number of Delphi rounds, and none of the studies explained why the participants changed. For the face-to-face consensus meeting, we found that nine COSs changed the participants and none explained the reasons for these changes. Conclusion Our study found many inconsistencies between protocols and the full-text publications concerning COS development. These inconsistencies related to the included study types, databases searched, Delphi surveys, and face-to-face consensus meetings. As it is necessary to publish protocols before developing COSs, transparency regarding any changes to the methods is needed.

Objective The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and paternally derived mutations. Methods A total of 68 pregnancies, including 26 normal pregnancies, 7 cases with fetal aneuploidies, 7 cases with fetal achondroplasia or thanatophoric dysplasia, 18 cases with fetal skeletal abnormalities, and 10 cases with β‐thalassemia high risk were recruited. Plasma cell‐free DNA was amplified by Targeted And Genome‐wide simultaneous sequencing (TAGs‐seq) to generate around 99% of total reads covering the whole‐genome region and around 1% covering the target genes. The reads on the whole‐genome region were analyzed for fetal aneuploidy using a binary hypothesis T‐score and the reads on target genes were analyzed for point mutations by calculating the minor allelic frequency of loci on FGFR3 and HBB. TAGs‐seq results were compared with conventional NIPT and diagnostic results. Results In each sample, TAGs‐seq generated 44.7–54 million sequencing reads covering the whole‐genome region of 0.1–3× and the target genes of >1000×depth. All cases of fetal aneuploidy and de novo mutations of achondroplasia/thanatophoric dysplasia were identified with high sensitivities and specificities except for one false‐negative paternal mutation of β‐thalassemia. Conclusions TAGs‐seq is a novel NIPT method that combines the fetal aneuploidy screening and the detection of de novo FGFR3 mutations and paternal HBB mutations., Key Points What's already known about this topic? Recently, the improvement of noninvasive prenatal testing (NIPT) allowed the expanded detection of chromosomal copy number variants (CNVs) and monogenic diseases in fetus. However, the expanded detection of CNVs and monogenic disease usually requires separate experiment procedures such as quantitative polymerase chain reaction (qPCR), digital PCR or haplotype‐assisted approaches, which could not be integrated with the screening of chromosome aneuploidy and lack of laboratory efficiency What does this study add? We developed a novel NIPT method that could simultaneously detect fetal aneuploidies, autosomal dominant diseases, and the paternally inherited mutations of autosomal recessive diseases without additional experiments. We validated this method using the plasma samples of pregnant women carrying fetal achondroplasia, thanatophoric dysplasia, and β‐thalassemia, which showed promising results

Wound healing is a complex process involved in repairing tissue damage and preventing infection. However, there is a lack of appropriate treatment solutions that can simultaneously promote tissue repair and protect againstbacteria, especially antibiotic-resistant bacteria. In this study, we have developed an injectable hydrogel encapsulating acidic fibroblast growth factor (aFGF) and bacteriophage, termed as ABgel, for combating antibiotic-resistant bacteria and enhancing wound regeneration. ABgel is composed of oxidized sodium alginate (OSA), gelatin and hyaluronic acid (HA), and can rapidly form hydrogel with an elastic modulus of 13 kPa, which mimics the skin tissues. In addition, ABgel can effectively load and stabilize bacteriophage and aFGF, allowing for preventing bacterial infections and improving regeneration of damaged dermal tissues. In vitro studies demonstrate that ABgel exhibits enormous antibacterial activity against antibiotic-resistant E. coli and enhanced angiogenetic activity. Importantly, ABgel can promote skin regeneration and prevent bacterial infections in mice, thereby promoting wound healing process. Therefore, ABgel represents a decent bioactive engineered hydrogel dressing with a broad application potential.

New findings What is the central question of this study? Long non-coding RNAs (lncRNAs) are widely involved in the progression of Hirschsprung's disease (HSCR), but the role of actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), an lncRNA, in HSCR has not been explored before. What is the main finding and its importance? Downregulation of AFAP1-AS1 blocks enteric neural crest stem cell proliferation, differentiation, migration and invasion and promotes the occurrence of HSCR via the miR-195/E2F3 axis, indicating thatAFAP1-AS might be a potential biomarker for HSCR patients. Abstract Long non-coding RNAs (lncRNAs) are involved in several human disorders. Nevertheless, it remains unclear whether they are implicated in the phenotypes of enteric neural crest stem cells (ENCSCs) in Hirschsprung's disease (HSCR). Therefore, we designed this study to explore the pathogenicity of AFAP1-AS1 for HSCR. Microarray analysis and bioinformatic tools were used to screen out the differentially lncRNAs and microRNAs (miRNAs) in patients with HSCR. Small interference RNA transfection was applied to carry out functional experiments in ENCSCs. Cellular activities were detected by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, Transwell assays and flow cytometry. Finally, rescue experiments were performed to examine the cofunction of AFAP1-AS1 and miR-195 and of miR-195 and E2F transcription factor 3 (E2F3). AFAP1-AS1 was reduced in HSCR patients. Meanwhile, knockdown of AFAP1-AS1 reduced the cell migratory and proliferative capacities and facilitated cell apoptosis along with G0/G1 phase arrest. E2F3 was diminished when miR-195 was upregulated, and AFAP1-AS1 inhibition reduced its ability to bind to miR-195. Altogether, AFAP1-AS1 silencing acts as an endogenous RNA by interacting with miR-195 to alter E2F3 expression, thus conferring repressive effects on ENCSC activity and promoting HSCR progression.

Human flap endonuclease 1 (FEN1) is a structure-specific, multifunctional endonuclease essential for DNA replication and repair. Our previous study showed that in response to DNA damage, FEN1 interacts with the PCNA-like Rad9-Rad1-Hus1 complex instead of PCNA to engage in DNA repair activities, such as stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as ultraviolet (UV) irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintaining genome stability.

AIM: To explore the apoptosis of ARPE-19 cells after the treatment with different doses of all-trans-retinoic acid (ATRA). METHODS: ARPE-19 cells were used in the in-vitro experiment. Flow cytometry assay was employed to evaluate the level of reactive oxygen species (ROS) and apoptosis. The effects of ATRA (concentrations from 2.5 to 20 µmol/L) on the expression of endoplasmic reticulum stress (ERS) markers in vitro were evaluated by Western blot and real-time quantitative polymerase chain reaction (qRT-PCR) assays. The contribution of ROS and ERS-induced apoptosis in vitro was determined by using N-acetyl-L-cysteine (NAC) and Salubrinal, an antagonist of NAC and ERS, respectively. RESULTS: Flow cytometry showed that ATRA significantly increased ARPE-19 cell apoptosis and ROS levels in each group (F=86.39, P

Purpose To evaluate the predictive value of blood lymphocyte, monocyte to lymphocyte ratio (MLR), and neutrophil to lymphocyte ratio (NLR) for radiation pneumonia (RP) in patients with thoracic tumors receiving radiotherapy. Patients and Methods The clinical data of 65 patients with thoracic tumor (esophageal cancer, lung cancer) treated by radiotherapy in our hospital were retrospectively analyzed. Patients were divided into the RP group and the non-RP group according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Data on blood cell counts, including lymphocytes, monocytes, and neutrophils, were collected before (0 weeks) and after 1, 2, and 4 weeks of radiotherapy. Results Of the 65 patients enrolled, 27 developed radiation pneumonia and 38 did not. Patients' clinical factors, including age, TNM stage, tumor type, underlying lung disease, and history of smoking, had no correlation with RP. ANOVA of repeated measurement data showed that the changes of MLR in the group with RP during radiotherapy were significantly different from those in the non-RP group (P

Background Cell proliferation of oral squamous cell carcinoma (OSCC) is precisely regulated with a cascade of genes and pathways. Previous studies have identified NR4A1 as an oncogene and plays a crucial role in colorectal cancer development and progression. This study was performed to investigate the potential interaction between lncRNA NR4A1AS and miR-221 and how their interaction is modulated in periodontitis. Patients and methods Research subjects of this study included 62 OSCC patients. Cell transfection and RT-qPCR were applied to detect the expression levels of NR4A1AS and miR-221. Methylation-specific PCR (MSP) was carried out to determine the demethylation of miR-221 by NR4A1AS. CCK-8 assay was used to detect the proliferation of OSCC cells with the overexpression of NR4A1AS or/and overexpression of miR-221. Results In this study, we observed that NR4A1AS was upregulated in tumor tissue samples of OSCC, and its high expression levels were significantly correlated with poor survival in patients with OSCC. In addition, miR-221 was significantly down-regulated in OSCC tumors. NR4A1AS and miR-221 were significantly and positively correlated in OSCC tumors but not in non-dysplastic tissue. In OSCC cells, overexpression of NR4A1AS led to upregulation of miR-221 and decreased the methylation of miR-221 gene. However, overexpression of miR-221 did not affect the expression of NR4A1AS in OSCC cells. In addition, overexpression of NR4A1AS or miR-221 increased the proliferation rate of OSCC cells. Conclusion This study is the first to report that NR4A1AS is upregulated in OSCC. Moreover, we also propose that miR-221 is modulated by NR4A1AS through demethylation and the upregulation of NR4A1AS or miR-221 promotes the proliferation of OSCC cells, which suggests that anti-NR4A1AS might be a perspective approach for the therapy of OSCC.

To present an evidence map for explicating research trends and gaps, we systematically review clinical practice guidelines (CPGs) on diabetic retinopathy (DR) and assess the quality of CPGs and consistency of recommendations. A literature search was performed in PubMed, Embase, Web of Science, CPG databases, and website of diabetes society to include the CPGs. The basic information, methodological quality, and reporting quality of CPGs, recommendations for DR were exacted by the Excel 2013. Methodological and reporting quality of DR CPGs were evaluated by AGREE II instrument and RIGHT checklist. The bubble plot format of evidence map was made by Excel 2013. Nineteen CPGs proved eligible, which included eight DR CPGs and 11 comprehensive diabetic CPGs. The identified CPGs were of mixed quality and they scored poorly in the rigor of development, applicability domains by AGREE II. Field two (background) had the highest reporting rate (86.31%) and field five (review and quality assurance) obtained the lowest reporting rate (31.58%) among the seven domains of RIGHT checklist. According to the recommendations of CPGs, there were three inconsistencies in the screening of DR, and CPGs recommendations for treatment were consistent on the whole. At the same time, recommendations for laser therapy were not accurate. Some recommendations were not specific and clear in some DR CPGs. This evidence map could collect and evaluate the characteristics of published CPGs, add to our knowledge and promote the development of trustworthy CPGs for DR.摘要: 我们对糖尿病视网膜病变 (diabetic retinopathy, DR) 的临床实践指南 (clinical practice guidelines, CPGs) 进行了系统回顾, 并评估了CPGs的质量和建议的一致性, 旨在呈现一份详细阐述研究趋势和差距的证据图。我们对PubMed、Embase、科学网、CPG数据库和糖尿病协会网进行了文献检索。采用2013版Excel对CPGs的基本信息、方法学质量、报告质量以及DR指南推荐进行整理, 采用评价工具AGREE-II和 RIGHT检查表对DR CPGs的方法学和报告质量进行评估, 采用2013版Excel制作证据图的气泡图。结果表明19个CPGs是合格的, 其中包括8个DR CPGs和11个综合性糖尿病CPGs。这些CPGs质量参差不齐, 在AGREE II的严格的开发和其领域的适用性很低。在RIGHT检查表的七项评估内容中, 第二项 (背景) 的报告率最高 (86.31%), 第五项 (综述和质量保证) 的报告率最低 (31.58%) 。根据CPGs推荐, 在DR的筛查上存在三项不一致, CPGs在治疗方面的推荐总体上是一致的。同时, 激光治疗的建议并不精准。在某些DR CPGs中一些推荐并不明确。这份证据图收集了并且针对已发表的CPGs特征进行了评价, 增加了我们对DR的认识, 促进了DR的CPGs的可靠性的不断进步。.

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.

This paper aimed to explore the characteristics of the top-100 cited articles on the biomarkers in the depression field and strive to find the future trend. The top-100 cited articles were selected from the Web of Science Core Collection database. Excel 2016 and VOSviewer 1.6.9 were used to analyze the information. Forty-six journals contributed to these 100 articles, and

Several studies have demonstrated that exosomes have a very broad prospect in the field of cancer therapy. This study aims to identify the general characteristics, cooperation of authors, countries and explore the hot topics of the top 100 cited articles on tumor-related exosomes. We searched the Web of Science Core Collection on June 28, 2019, to collect related publications. Microsoft Excel 2016 and VOSviewer 1.6.9 were applied to analyze the publication year, citations, authors, countries, institutions, journals, and keywords. The top 100 articles were published between 1998 and 2017 with citations ranging from 181 to 2275. Cancer Research (n = 9) had the highest number of publications. Nature Cell Biology, Nature, and Nature Medicine are considered to be the core journals of tumor-related exosomes because they are among top 10 from different analytical perspectives. The USA (n = 49) and Harvard University (n = 9) were the most productive country and institution, respectively. There were active collaborations between countries. Kalluri R (n = 6) contributed the largest number of articles, and Taylor DD was the most co-cited author. Théry C and Al-Nedawi K are probably the two important experts as they are both the top 10 authors and top 10 co-cited authors. Three clusters were obtained after clustering analysis of the keywords. The main hot topics were the proteomic analysis and mechanism of vesicle activation and the role of exosomes in the diagnosis and progression of tumors. Further research should expand and develop new topics such as the role of exosomes in the treatment of cancers.

Aim: Our study aimed to analyze the characteristics of papers published on CAR T-cell in the field of cancer and explore the existing hot topics and prospects. Materials & methods: We explored the global hotspots and future prospects regarding CAR T-cell therapy in cancer research. Papers of CAR T-cell research were retrieved from the Web of Science database. Analysis was performed using VOSviewer, CiteSpace and Excel software. Results: A total number of 1994 papers related to CAR T-cell research of cancer were included. Molecular Therapy published the most papers (n = 85, 4.26%). A total of 9792 authors participated in the publication of all papers. 62 countries and 2065 institutions have participated in the publication of all papers. Conclusion: Research trends are to improve the immunosuppressive microenvironment of cancer, optimize the structure of CAR T-cells and develop ‘super CAR T-cell’ by using gene-editing technology.

Functionalized multi‐walled carbon nanotubes have been extensively gained popularity in pancreatic cancer gene therapy. LyP‐1, a peptide, has been proved to specifically bind pancreatic cancer cells. The potential therapeutic effect of LyP‐1–conjugated functionalized multi‐walled carbon nanotubes in treating pancreatic cancer is still unknown. In this study, LyP‐1–conjugated functionalized multi‐walled carbon nanotubes were successfully synthesized, characterized and showed satisfactory size distribution and zeta potential. Compared with functionalized multi‐walled carbon nanotubes, cellular uptake of LyP‐1–functionalized multi‐walled carbon nanotubes was shown to be increased. Compound of LyP‐1–functionalized multi‐walled carbon nanotubes and MBD1siRNA showed superior gene transfection efficiency. Moreover, LyP‐1‐fMWNTs/MBD1siRNA complex could significantly decrease the viability and proliferation and promoted apoptosis of pancreatic cancer cells in vitro. Further xenograft assays revealed that the tumour burden in the nude mice injected with LyP‐1–functionalized multi‐walled carbon nanotubes/MBD1siRNA was significantly relieved. The study demonstrated that LyP‐1–functionalized multi‐walled carbon nanotubes/MBD1siRNA could be a promising candidate for tumour active targeting therapy in pancreatic cancer.

In plants, the spatiotemporal expression of circadian oscillators provides adaptive advantages in diverse species. However, the molecular basis of circadian clock in soybean is not known. In this study, we used soybean hairy roots expression system to monitor endogenous circadian rhythms and the sensitivity of circadian clock to environmental stimuli. We discovered in experiments with constant light and temperature conditions that the promoters of clock genes GmLCLb2 and GmPRR9b1 drive a self-sustained, robust oscillation of about 24-h in soybean hairy roots. Moreover, we demonstrate that circadian clock is entrainable by ambient light/dark or temperature cycles. Specifically, we show that light and cold temperature pulses can induce phase shifts of circadian rhythm, and we found that the magnitude and direction of phase responses depends on the specific time of these two zeitgeber stimuli. We obtained a quadruple mutant lacking the soybean gene GmLCLa1, LCLa2, LCLb1, and LCLb2 using CRISPR, and found that loss-of-function of these four GmLCL orthologs leads to an extreme short-period circadian rhythm and late-flowering phenotype in transgenic soybean. Our study establishes that the morning-phased GmLCLs genes act constitutively to maintain circadian rhythmicity and demonstrates that their absence delays the transition from vegetative growth to reproductive development.

Purpose Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. Patients and methods This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. Results Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65-6.95), and the median OS was 12.2 months (95% CI, 8.99-15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). Conclusion Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.

Moraxella catarrhalis (M. catarrhalis) is a pathogenic gram-negative bacterium that causes otitis media and sinusitis in children. Three major serotypes A, B and C are identified to account for approximately 95% of the clinical isolates. Understanding the conformational properties of different serotypes of M. catarrhalis provides insights into antigenic determinants. In this work, all-atom molecular dynamics simulations were conducted for M. catarrhalis lipooligosaccharide (LOS) bilayer systems and oligosaccharides (OS) in water solution to investigate the conformational similarities and differences of three serotypes. For up to 10 neutral monosaccharides in the core part, the conformational ensembles described by the pair-wise root mean square deviation distributions are similar among the three serotypes of either the LOS or OS. At the central β-($1\to4$)-linkage, anti-$\psi$ conformation in conjunction with the gauche-gauche (g−) conformation of the central trisubstituted glucosyl residue is observed as the dominant conformation to sustain the structural characteristics of M. catarrhalis three types, which is further supported by calculated transglycosidic ${}^3{J}_{C,H}\Big({\psi}_H\Big)$ of serotype A in comparison to experimental data. Interestingly, the conformational variability of three serotypes is more restricted for the OS in water solution than that in the LOS bilayer systems. The LOS–LOS interactions in the bilayer systems are responsible for the increased conformational diversity despite of tight packing. Solvent-accessible surface area analysis suggests that a trisaccharide attached to the β-($1\to 6$)-linked sugar in all three serotypes of LOS could be the common epitope and have the possibility to interact with antibodies.

Cotton, the leading natural fiber, is cultivated worldwide, but its production is seriously threatened by pathogens. Accordingly, the selection of resistant cultivars has become a key priority of cotton breeding programs. In this study, a spontaneous mutant with red coloration (S156) and a control cultivar (S78) were used as experimental materials for a comparative analysis. Metabolomic analysis revealed the enrichment of flavonoids in S156 leaves compared with S78 leaves, and transcriptomic analysis revealed the upregulated expression of flavonoid biosynthesis genes in S156 leaves relative to S78 leaves. In addition, the red mutant showed a significantly increase in resistance to Verticillium dahliae, a fungal pathogen that poses a major threat to cotton production. The pathogen invasion process was suppressed in the red cotton cultivar. This study reveals the mechanism underlying the red coloration of S156 cotton and indicates the great potential of red cotton in pathogen- and insect-resistant breeding of cotton.

Macrophages (Mφs) can be used as a part of cell-based cancer immunotherapy. However, they may be hampered by a failure to effectively and stably regulate their polarization state to enhance their t...

Objectives: This study aimed to explore the prespecification and conduct of subgroup analyses in cancer individual participant data meta-analyses (IPDMAs). Study Design and Setting: We searched PubMed, Embase.com, Cochrane Library, and Web of Science to identify IPDMAs of randomized controlled trials evaluating intervention effects for cancer. We evaluated how often cancer IPDMAs prespecify subgroup analyses and statistical approaches for examining treatment-subgroup interactions and handling continuous subgroup variables. Results: We included 89 IPDMAs, of which 41 (46.1%) reported a statistically significant treatment-subgroup interaction (P < 0.05) in at least one subgroup analysis. 47 (52.8%) IPDMAs prespecified methods for conducting subgroup analyses and the remaining 42 (47.2%) did not prespecify subgroup analyses. Of the 47 IPDMAs prespecified subgroup analyses, 19 performed the planned subgroup analyses, 21 added subgroup analyses, 7 reduced subgroup analyses. Eighty IPDMAs examined treatment-subgroup interactions, but 72 IPDMAs did not provide enough information to determine whether an appropriate approach that avoided aggregation bias was used. 85 IPDMAs that used continuous variables in subgroup analyses categorized continuous variables and only 1 IPDMA examined non-linear relationships. Conclusion: Many cancer IPDMAs did not prespecify subgroup analyses, nor did they fully perform planned subgroup analyses. Lack of details for the test of treatment-subgroup interactions and examination of non-linear interactions was suboptimal.

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.

Mastitis caused by Escherichia coli (E. coli) remains a threat to dairy animals and impacts animal welfare and causes great economic loss. Furthermore, antibiotic resistance and the lagged development of novel antibacterial drugs greatly challenge the livestock industry. Phage therapy has regained attention. In this study, three lytic phages, termed vB_EcoM_SYGD1 (SYGD1), vB_EcoP_SYGE1 (SYGE1), and vB_EcoM_SYGMH1 (SYGMH1), were isolated from sewage of dairy farm. The three phages showed a broad host range and high bacteriolytic efficiency against E. coli from different sources. Genome sequence and transmission electron microscope analysis revealed that SYGD1 and SYGMH1 belong to the Myoviridae, and SYGE1 belong to the Autographiviridae of the order Caudovirales. All three phages remained stable under a wide range of temperatures or pH and were almost unaffected in chloroform. Specially, a mastitis infected cow model, which challenged by a drug resistant E. coli, was used to evaluate the efficacy of phages. The results showed that the cocktails consists of three phages significantly reduced the number of bacteria, somatic cells, and inflammatory factors, alleviated the symptoms of mastitis in cattle, and achieved the same effect as antibiotic treatment. Overall, our study demonstrated that phage cocktail may be a promising alternative therapy against mastitis caused by drug resistant E. coli.

Alzheimer disease (AD) is the most common cause of dementia in geriatric population. At present, no effective treatments exist to reverse the progress of AD, however, early diagnosis and intervention might delay its progression. The search for biomarkers with good safety, repeatable detection, reliable sensitivity and community application is necessary for AD screening and early diagnosis and timely intervention. Electroencephalogram (EEG) examination is a non-invasive, quantitative, reproducible, and cost-effective technique which is suitable for screening large population for possible AD. The power spectrum, complexity and synchronization characteristics of EEG waveforms in AD patients have distinct deviation from normal elderly, indicating these EEG features can be a promising candidate biomarker of AD. However, current reported deviation results are inconsistent, possibly due to multiple factors such as diagnostic criteria, sample sizes and the use of different computational measures. In this study, we collected two neurological tests scores (MMSE and MoCA) and the resting-state EEG of 30 normal control elderly subjects (NC group) and 30 probable AD patients confirmed by Pittsburgh compound B positron emission tomography (PiB-PET) inspection (AD group). We calculated the power spectrum, spectral entropy and phase synchronization index features of these two groups’ EEG at left/right frontal, temporal, central and occipital brain regions in 4 frequency bands: δ oscillation (1–4 Hz), θ oscillation (4–8 Hz), α oscillation (8–13 Hz), and β oscillation (13–30 Hz). In most brain areas, we found that the AD group had significant differences compared to NC group: (1) decreased α oscillation power and increased θ oscillation power; (2) decreased spectral entropy in α oscillation and elevated spectral entropy in β oscillation; and (3) decrease phase synchronization index in δ, θ, and β oscillation. We also found that α oscillation spectral power and β oscillation phase synchronization index correlated well with the MMSE/MoCA test scores in AD groups. Our study suggests that these two EEG features might be useful metrics for population screening of probable AD patients.

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.

Inflammatory bowel disease (IBD) is a chronic intestinal disorder threatening human health. Di-peptide alanyl-glutamine (Ala-Gln) has various beneficial effects on gut health. However, its role and functional mechanism in treating IBD are still not clear. Therefore, the protective effects of Ala-Gln and glutamine (Gln) on dextran sulfate sodium- (DSS-) induced colitic mice were investigated in this study. The results showed that oral supplementation of Ala-Gln or Gln significantly attenuated the colitis symptoms in mice, including body weight loss, colon length, disease activity index, histological scores, and tissue apoptosis. The concentrations of interleukin- (IL-) 1β, IL-6, tumor necrosis factor-α, and myeloperoxidase were significantly decreased, while the concentrations of immunoglobulins (IgA, IgG, and IgM) and superoxide dismutase were significantly increased by Ala-Gln or Gln supplementation. The expression of occludin and peptide transporter 1 (PepT1) was significantly increased by Ala-Gln or Gln. Interestingly, Ala-Gln had better beneficial effects than Gln in alleviating colitis. In addition, 16S rDNA sequencing showed that the DSS-induced shifts of the microbiome (community diversity, evenness, richness, and composition) in the mouse colon were restored by Gln and Ala-Gln, including Lactobacillus, Bacteroides_acidifaciens, Bacteroidales, Firmicutes, Clostridia, Helicobacter, and Bacteroides. Correspondingly, the functions of the microflora metabolism pathways were also rescued by Ala-Gln, including fatty acid metabolism, membrane transporters, infectious diseases, and immune system. In conclusion, the results revealed that Ala-Gln can prevent colitis through PepT1, enhancing the intestinal barrier and modulating gut microbiota and microflora metabolites.

Ruminants are mostly herbivorous animals that employ rumen fermentation for the digestion of feed materials, including dairy cows. Ruminants consume plant fibre as their regular diet, but lack the machinery for their digestion. For this reason, ruminants maintain a symbiotic relation with microorganisms that are capable of producing enzymes to degrade plant polymers. Various species of microflora including bacteria, protozoa, fungi, archaea, and bacteriophages are hosted at distinct concentrations for accomplishing complete digestion. The ingested feed is digested at a defined stratum. The polysaccharic plant fibrils are degraded by cellulolytic bacteria, and the substrate formed is acted upon by other bacteria. This sequential degradative mechanism forms the base of complete digestion as well as harvesting energy from the ingested feed. The composition of microbiota readily gets tuned to the changes in the feed habits of the dairy cow. The overall energy production as well as digestion is decided by the intactness of the resident communal flora. Disturbances in the homogeneity gastrointestinal microflora has severe effects on the digestive system and various other organs. This disharmony in communal relationship also causes various metabolic disorders. The dominance of methanogens sometimes lead to bloating, and high sugar feed culminates in ruminal acidosis. Likewise, disruptive microfloral constitution also ignites reticuloperitonitis, ulcers, diarrhoea, etc. The role of symbiotic microflora in the occurrence and progress of a few important metabolic diseases are discussed in this review. Future studies in multiomics provides platform to determine the physiological and phenotypical upgradation of dairy cow for milk production.

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.

Centriole duplication is tightly controlled to occur once per cell cycle, and disruption of this synchrony causes centriole amplification, which is frequently observed in many cancers. Our previous work showed that nuclear distribution gene C (NudC)-like protein 2 (NudCL2) localizes to centrosomes; however, little is known about the role of NudCL2 in the regulation of centrosome function. Here, we find that NudCL2 is required for accurate centriole duplication by stabilizing the E3 ligase HECT domain and RCC1-like domain-containing protein 2 (HERC2). Knockout (KO) of NudCL2 using CRISPR/Cas9-based genome editing or depletion of NudCL2 using small interfering RNA causes significant centriole amplification. Overexpression of NudCL2 significantly suppresses hydroxyurea-induced centriole overduplication. Quantitative proteomic analysis reveals that HERC2 is downregulated in NudCL2 KO cells. NudCL2 is shown to interact with and stabilize HERC2. Depletion of HERC2 leads to the similar defects to that in NudCL2-downregulated cells, and ectopic expression of HERC2 effectively rescues the centriole amplification caused by the loss of NudCL2, whereas the defects induced by HERC2 depletion cannot be reversed by exogenous expression of NudCL2. Either loss of NudCL2 or depletion of HERC2 leads to the accumulation of ubiquitin-specific peptidase 33 (USP33), a centrosomal protein that positively regulates centriole duplication. Moreover, knockdown of USP33 reverses centriole amplification in both NudCL2 KO and HERC2-depleted cells. Taken together, our data suggest that NudCL2 plays an important role in maintaining the fidelity of centriole duplication by stabilizing HERC2 to control USP33 protein levels, providing a previously undescribed mechanism restraining centriole amplification.

The cutaneous squamous cell carcinoma (cSCC) originates from epithelial stem cells through the dysregulation of self-renewal and differentiation. Recent studies have identified methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification as key regulator of fate of stem cells. However, little is known about the functional importance of METTL3 in cSCC. Here, Western blot and immunohistochemistry were used to investigate the METTL3 levels in cSCC tissues. Functional experiments including surface marker detection, Brdu incorporation assay, colony forming assay, m6A dot blot and tumor xenograft assay were performed to investigate the properties in cSCC cell lines after METTL3 knock down. The expression of METTL3 was up-regulated in cSCC samples. METTL3 knock down impaired cSCC cell stem-like properties, including colony forming ability in vitro and tumorigenicity in vivo. Furthermore, METTL3 knock down and methylation inhibitor cycloleucine could decrease the m6A levels and the expression of ΔNp63 in cSCC. Exogenous expression of ΔNp63 partially restored the cell proliferation of METTL3-knockdown cSCC cells. Therefore, our data indicated the m6A methyltransferases METTL3 as a critical gene in regulating tumorigeneis of cSCC.

Objectives To identify the cooperation of authors, countries, and institutions and explore the hot topics and future prospects regarding programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) research. Materials and methods Publications on PD-1 and PD-L1 research were retrieved from the Web of Science Core Collection. Bibliometric analyses were performed using VOSviewer 1.6.9, HistCite 2.1, and CiteSpace V software. Network maps were generated to evaluate the collaborations between different authors, countries, and institutions. Results A total of 7359 articles related to PD-1 and PD-L1 research in the field of cancer were identified. We observed rapid growth in the number of publications since 2014. Oncoimmunology (326, 4.43%) had the highest number of publications, while N Engl J Med (18,828 co-citations, 6.30%) was the most co-cited journal. Hodi FS and Wolchok JD were key researchers. There were active collaborations among the top authors. The USA was the leading contributor in this field with 3496 publications. Active cooperations between countries and between institutions were observed. The main hot topics included matters related to the efficacy and prognosis of various tumors after treatment with PD-1 and/or PD-L1 inhibitors, as well as the activation or expression of important immunological factors targeted at tumors. Conclusion PD-1 and PD-L1 studies have significantly increased after 2014. The USA contributed the most publications. There were active cooperations between authors, countries, and institutions. Further research should expand and develop new topics such as those likely to boost therapeutic strategies for cancer.

Obesity and its associated metabolic disorders such as diabetes, hepatic steatosis and chronic heart diseases are affecting billions of individuals. However there is no satisfactory drug to treat such diseases. In this study, we found that alisol A, a major active triterpene isolated from the Chinese traditional medicine Rhizoma Alismatis, could significantly attenuate high‐fat‐diet‐induced obesity. Our biochemical detection demonstrated that alisol A remarkably decreased lipid levels, alleviated glucose metabolism disorders and insulin resistance in high‐fat‐diet‐induced obese mice. We also found that alisol A reduced hepatic steatosis and improved liver function in the obese mice model.In addition, protein expression investigation revealed that alisol A had an active effect on AMPK/ACC/SREBP‐1c pathway. As suggested by the molecular docking study, such bioactivity of alisol A may result from its selective binding to the catalytic region of AMPK.Therefore, we believe that Alisol A could serve as a promising agent for treatment of obesity and its related metabolic diseases.

Adipose‐derived stem cells (ADSCs) are a subset of mesenchymal stem cells (MSCs), which have promised a vast therapeutic potential in tissue regeneration. Recent studies have demonstrated that combining stem cells with mechanical stretch may strengthen the efficacy of regenerative therapies. However, the exact influences of mechanical stretch on MSCs still remain inconclusive. In this study, human ADSCs (hADSCs) were applied cyclic stretch stimulation under an in vitro stretching model for designated duration. We found that mechanical stretch significantly promoted the proliferation, adhesion and migration of hADSCs, suppressing cellular apoptosis and increasing the production of pro‐healing cytokines. For differentiation of hADSCs, mechanical stretch inhibited adipogenesis, but enhanced osteogenesis. Long‐term stretch could promote ageing of hADSCs, but did not alter the cell size and typical immunophenotypic characteristics. Furthermore, we revealed that PI3K/AKT and MAPK pathways might participate in the effects of mechanical stretch on the biological characteristics of hADSCs. Taken together, mechanical stretch is an effective strategy for enhancing stem cell behaviour and regulating stem cell fate. The synergy between hADSCs and mechanical stretch would most likely facilitate tissue regeneration and promote the development of stem cell therapy.

A continuous fibroblast-like cell line, TMF (turbot muscle fibroblasts), was established from juvenile turbot Scophthalmus maximus muscle with the method of trypsin digestion. It has been subcultured more than 60 passages for over 150 days. The TMF cells were cultured in L-15 medium supplemented with HEPES, fetal bovine serum (FBS), GlutaMAX, and basic fibroblast growth factor (bFGF). The optimal temperature for TMF culture was 24 °C. TMF cells were predominantly composed of fibroblastic-like cells, and the transcription factor 4 (TCF-4) was highly expressed in TMF cells. Chromosome analysis revealed that it had a diploid chromosome number of 2n = 44. The transfection efficiency achieved 54.95 ± 6.59%, and the cell mortality rate was about 8.70% when transfected with the nucleofection method. Meanwhile, the TMF cells showed a sensitive response to amino acid levels and activation target of rapamycin (TOR) signaling pathway. These results indicate that TMF was a potential tool to explore the signal transduction of teleost in vitro.

Time-resolved and ultrafast hard X-ray imaging, scattering and spectroscopy are powerful tools for elucidating the temporal and spatial evolution of complexity in materials. However, their temporal resolution has been limited by the storage-ring timing patterns and X-ray pulse width at synchrotron sources. Here we demonstrate that dynamic X-ray optics based on micro-electro-mechanical-system resonators can manipulate hard X-ray pulses on time scales down to 300 ps, comparable to the X-ray pulse width from typical synchrotron sources. This is achieved by timing the resonators with the storage ring to diffract X-ray pulses through the narrow Bragg peak of the single-crystalline material. Angular velocities exceeding 107 degrees s−1 are reached while maintaining the maximum linear velocity well below the sonic speed and material breakdown limit. As the time scale of the devices shortens, the devices promise to spatially disperse the temporal width of X-rays, thus generating a temporal resolution below the pulse-width limit., It is desirable to improve spatiotemporal control of light generated by synchrotron user facilities or table-top X-ray sources. Here the authors demonstrate manipulation of hard X-rays using microelectro mechanical systems (MEMS) oscillators on timescales of 300 ps, approaching the synchrotron pulse width.

Skin fibrosis is mainly characterized by excessive collagen deposition. Studies have recently identified a number of flavonoids with variable structures that have the potency of inhibiting collagen synthesis and thus attenuating organ fibrosis. In this study, we found that flavones with 5, 7, 3′, 4′ hydroxy substitution reduced collagen expression most efficiently. Among those flavones, luteolin, quercetin, and myricetin were selected for follow-up. In vivo, the three compounds ameliorated skin fibrosis and reduced collagen deposition. Further analysis showed the compounds had significant inhibition on the proliferation, activation and contractile ability of dermal fibroblasts in vitro and in vivo. More importantly, we revealed that luteolin, quercetin, and myricetin selectively downregulated the phosphorylation of Smad2/3 in TGF-β/Smads signaling via binding to activin receptor-like kinase 5 (ALK5) and impairing its catalytic activity. We also found flavones with 5, 7, 3′, 4′ hydroxy substitution showed stronger affinity with ALK5 compared with other flavonoids. Herein, we identified at least in part the underlying molecular basis as well as the critical structures that contribute to the antifibrotic bioactivity of flavones, which might benefit drug design and modification.

Neuroblastoma is a heterogeneous cancer frequently occurring in childhood. Germline mutations of PARP1 oncogene are implicated in several types of cancer. However, whether common single nucleotide polymorphisms (SNPs) in PARP1 gene are associated with neuroblastoma risk has received relatively few attentions. In this multi-center study, we aimed to elucidate the contributing role of PARP1 SNPs in neuroblastoma risk. We successfully genotyped three potentially functional PARP1 SNPs (rs1136410 A>G, rs2666428 T>C, rs8679 A>G) in 469 neuroblastoma cases and 998 controls. We did not detect any significant association between the analyzed SNPs and neuroblastoma risk in single SNP analysis. However, stratified analysis revealed that rs1136410 AG/GG carriers were more likely to develop tumors arising from mediastinum (AG/GG vs. AA: adjusted OR=1.65, 95% CI=1.06-2.56, P=0.028). Moreover, rs2666428 TC/CC carriers were at significantly lower risk to develop tumors from “other sites” (TC/CC vs. TT: adjusted OR=0.44, 95% CI=0.20-0.96, P=0.040). Our findings failed to provide evidence of the conferring role of the PARP1 gene polymorphisms in the risk of neuroblastoma. Further investigations of the association between PARP1 gene SNPs and neuroblastoma risk are warranted.

Objective: Using the traditional Chinese medicine theory of “Bi-zheng'' caused by kidney deficiency, combined with modern medical science and technology, this study assessed the relationships among organ weight, cytokines, pathological manifestations, and traditional Chinese medicine kidney deficiency syndrome in rats with rheumatoid arthritis. Methods: Sixty Sprague–Dawley rats were randomly divided into normal, collagen-induced arthritis (CIA) model, and kidney deficiency arthralgia model groups. Rats in the kidney deficiency arthritis group underwent removal of the testis or ovary and administration of an inflammatory agent. Rats in the control group solely received an inflammatory agent. Type II collagen-induced arthritis was induced within 1 week of the winter solstice or summer solstice, in order to sample organs and observe the mental state, posture, fur color, activity level, excrement, body weight, and organ weight of the rats. Results: Compared with the normal and CIA model groups, the kidney deficiency arthralgia model group showed fast and acute onset, prominent symptoms, most obvious potential joint swelling, worst general state, and least amount of weight gain. Compared with the normal group, the proportion of thymus, spleen, and adrenal glands of model rats were larger in winter, with varying degrees of hyperplasia and hypertrophy; these differences were statistically significant (P

The lactic acid bacterial diversity of wheat sourdoughs collected in Ya'an city, Sichuan province was investigated by culture-dependent methods combined with 16S rRNA gene sequencing, and the exopolysaccharide (EPS) production characteristics of ropy lactic acid bacteria (LAB) strains from these sourdoughs were evaluated. Two hundred nineteen LAB strains were isolated, and genotypic characterization indicated that the isolated LAB strains included Lactobacillus plantarum (L. plantarum), L. pantheris, Leuconostoc citreum (Leu. citreum), Weissella viridescens, Leu. pseudomesenteroides, Lactococcus lactis (L. lactis), L. raffinolactis, and Leu. mesenteroides. All the isolates were found to harbor genes coding for EPS, and the yield of EPS produced by “ropy” LAB strains ranged between 2.3 and 229.5 mg/g wet cell weight. The present study enhances our knowledge about LAB diversity in Ya'an sourdoughs and provides information about the EPS-producing LAB strains in sourdough samples, which might be favorable for the application of specific LAB strains in sourdough technology.

Background: It remains unclear whether the mean vancomycin trough concentration (VTC) derived from the entire course of therapy is of potential benefit for critically ill patients. This study was conducted to explore the association between mean serum VTC and mortality in intensive care units (ICUs).Methods: 3,603 adult patients with two or more VTC records after receiving vancomycin treatment in the eICU Collaborative Research Database were included in this multicenter retrospective cohort study. Mean VTC was estimated using all measured VTCs and investigated as a continuous and categorical variable. Patients were categorised into four groups according to mean VTC: 20 mg/L. Multivariable logistic regression and subgroup analyses were performed to investigate the relationship of mean VTC with mortality.Results: After adjusting for a series of covariates, logistic regression analyses indicated that mean VTC, as a continuous variable, was positively correlated with ICU (odds ratio, 1.038, 95% confidence interval, [1.014–1.063]) and hospital (1.025 [1.005–1.046]) mortalities. As a categorical variable, mean VTC of 10–15 mg/L was not associated with reduced ICU (1.705 [0.975–2.981]) and hospital (1.235 [0.829–1.841]) mortalities. Mean VTC of 15–20 mg/L was not correlated with a lower risk of hospital mortality (1.370 [0.924–2.029]). Moreover, mean VTCs of 15–20 and >20 mg/L were significantly associated with higher ICU mortality (1.924 [1.111–3.332]; 2.428 [1.385–4.258]), and mean VTC of >20 mg/L with higher hospital mortality (1.585 [1.053–2.387]) than mean VTC of Conclusion: Mean VTC was not associated with reduced ICU/hospital related mortality. Our results suggested that VTC monitoring might not guarantee vancomycin efficacy for ICU patients.

Although previous reports have shown that Curcumin inhibits many viruses, including some important members of different genera of Flaviviridae family (Japanese encephalitis virus, dengue virus and hepatitis C virus), the antiviral activity of curcumin against Classical swine fever virus (CSFV), which belongs to Pestivirus genus, is still unclear. In this study, we found that curcumin inhibited CSFV replication in a dose-dependent manner, but had no effect on virus adsorption and entry. Furthermore, the results showed that curcumin inhibited the expression of FASN, one of the key enzymes of fatty acid synthesis pathway, thereby, causing the reduction of the production of LDs upon infection. To this end, we detected transcription factor 6 (ATF6), the key factor of regulating lipid metabolism along with other related molecules (CHOP and GPR78) and found that curcumin significantly impaired the gene synthesis of ATF6, while CSFV infection promoted ATF6 expression. Therefore, it is confirmed that curcumin inhibited CSFV replication by interfere lipid metabolism. In addition, our subsequent studies found that curcumin played an antiviral role by promoting the innate immune independent of NF-κB signaling pathway. Taken together, our finding highlights that curcumin is a potential candidate drug against CSFV for controlling CSF.

Coronavirus disease 2019 (COVID-19) has become a global pandemic. Previous studies showed that comorbidities in patients with COVID-19 are risk factors for adverse outcomes. This study aimed to clarify the association between nervous system diseases and severity or mortality in patients with COVID-19. We performed a systematic literature search of four electronic databases and included studies reporting the prevalence of nervous system diseases in COVID-19 patients with severe and non-severe disease or among survivors and non-survivors. The included studies were pooled into a meta-analysis to calculate the odds ratio (OR) with 95% confidence intervals (95%CI). We included 69 studies involving 17 879 patients. The nervous system diseases were associated with COVID-19 severity (OR = 3.19, 95%CI: 2.37 to 4.30, P < 0.001) and mortality (OR = 3.75, 95%CI: 2.68 to 5.25, P < 0.001). Specifically, compared with the patients without cerebrovascular disease, patients with cerebrovascular disease infected with COVID-19 had a higher risk of severity (OR = 3.10, 95%CI: 2.21 to 4.36, P < 0.001) and mortality (OR = 3.45, 95% CI: 2.46 to 4.84, P < 0.001). Stroke was associated with severe COVID-19 disease (OR = 1.95, 95%CI: 1.11 to 3.42, P = 0.020). No significant differences were found for the prevalence of epilepsy (OR = 1.00, 95%CI: 0.42 to 2.35, P = 0.994) and dementia (OR = 2.39, 95%CI: 0.55 to 10.48, P = 0.247) between non-severe and severe COVID-19 patients. There was no significant association between stroke (OR = 1.79, 95%CI: 0.76 to 4.23, P = 0.185), epilepsy (OR = 2.08, 95%CI: 0.08 to 50.91, P = 0.654) and COVID-19 mortality. In conclusion, nervous system diseases and cerebrovascular disease were associated with severity and mortality of patients with COVID-19. There might be confounding factors that influence the relationship between nervous system diseases and COVID-19 severity as well as mortality.

Streptococcus suis (S. suis) serotype 2 (SS2) is the causative agent of swine streptococcosis and can cause severe diseases in both pigs and humans. Although the traditional inactive vaccine can protect pigs from SS2 infection, novel vaccine candidates are needed to overcome its shortcomings. Three infection-associated proteins in S. suis—muramidase-released protein (MRP), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and DLD, a novel putative dihydrolipoamide dehydrogenase—have been previously identified by immunoproteomic assays. In this study, the effective immune protection of the recombinant trivalent protein GAPDH-MRP-DLD (JointS) against SS2, SS7, and SS9 was determined in zebrafish. To improve the immune efficacy of JointS, monophosphoryl lipid A (MPLA) as a TLR4 agonist adjuvant, which induces a strong innate immune response in the immune cells of mice and pigs, was combined with JointS to immunize the mice. The results showed that immunized mice could induce the production of a high titer of anti-S. suis antibodies, as a result, 100% of mice survived after SS2 infection. Furthermore, JointS provides good protection against virulent SS2 strain infections in piglets. Given the above, there is potential to develop JointS as a novel subunit vaccine for piglets to prevent infection by SS2 and other S. suis serotypes.