The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis.

Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes is still needed. Rosuvastatin, a typical ß-hydroxy ß-methylglutaryl-CoA reductase inhibitor licensed for reducing the levels of low-density lipoprotein cholesterol in patients with hyperlipidemia, has displayed anti-inflammatory capacity in different types of organs and tissues. However, its effects on the development of sepsis are less reported. Here, we found that the administration of Rosuvastatin reduced the mortality of sepsis mice and prevented body temperature loss. Additionally, it inhibited the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and migration inhibitory factor (MIF) in peritoneal lavage supernatants of animals. The increased number of mononuclear cells in the peritoneum of sepsis mice was reduced by Rosuvastatin. Interestingly, it ameliorated lung inflammation and improved the hepatic and renal function in the sepsis animals. Further in vitro experiments show that Rosuvastatin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory cytokines in RAW 264.7 macrophages by preventing the activation of nuclear factor kappa-B (NF-κB). Our findings demonstrate that the administration of Rosuvastatin hampered organ dysfunction and mitigated inflammation in a relevant model of sepsis.

Dual-trait genomic analysis in highly stratified Arabidopsis thaliana populations using genome-wide association summary statistics.

Genome-wide association study (GWAS) is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset of Arabidopsis thaliana. We demonstrate the efficiency of dual-phenotype analysis to uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, a common allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate gene AT1G11560 that potentially causes this association. Further analysis indicates that this locus is co-selected with flowering-time-related genes. The discovered pleiotropic genotype-phenotype map provides new insights into understanding the genetic correlation of complex traits.

Occurrence and ecological risk assessment of 16 phthalates in surface water of the mainstream of the Yangtze River, China.

Phthalic acid esters (PAEs), a class of typical endocrine disruptors, have received considerable attention due to their widespread applications and adverse effects on biological health. In this study, 30 water samples, along the mainstream of the Yangtze River (YR), were collected from Chongqing (upper stream) to Shanghai (estuary) from May to June in 2019. The total concentrations of 16 targeted PAEs ranged from 0.437 to 20.5 µg/L, with an average of 1.93 µg/L, where dibutyl phthalate (DBP, 0.222-20.2 µg/L), bis (2-ethylhexyl) phthalate (DEHP, 0.254-7.03 µg/L), and diisobutyl phthalate (DIBP, 0.0645-0.621 µg/L) were the most abundant PAEs. According to the pollution level in the YR to assess the ecological risk posed by PAEs, the results showed medium risk level of PAEs in the YR, among which DBP and DEHP posed a high ecological risk to aquatic organisms. The optimal solution for DBP and DEHP is found in ten fitting curves. The PNECSSD of them is 2.50 µg/L and 0.34 µg/L, respectively.

The Role and Positioning of Clinical Trial Ethics Review under Pharmaceutical Innovation Strategy / 中国医学伦理学

Ethical review runs through the whole process of drug clinical trials, and is a critical step to ensure the rights and interests of subjects. This paper analyzed and discussed the role and positioning of ethical review in new drug clinical trials, cleared the principles of ethical review, identified the responsibilities of ethical review, and clarified the authority of ethical review approval documents. The ethical review should primarily focus on the ethics of the clinical trials, not replace other professional institutions to review the clinical trials’ legality and scientific nature. Ethical approval is only one of the necessary conditions for conducting clinical trials, not the only factor. It is recommended to strengthen the publicity and popularization of scientific and technological ethics awareness, improve the clinical trial approval mechanism, and optimize the phrasing of ethical review approval documents. It is warranted to further optimize the quality of ethical review, improve the construction of ethical review system, ultimately achieve the unity of promoting innovation and preventing risks, so as to effectively realize the benign interaction between high-quality development of scientific and technological innovation and high-level safety.

Integration of Distinct Analysis Strategies Improves Tissue-Trait Association Identification.

Integrating genome-wide association studies (GWAS) with transcriptomic data, human complex traits and diseases have been linked to relevant tissues and cell types using different methods. However, different results from these methods generated confusion while no gold standard is currently accepted, making it difficult to evaluate the discoveries. Here, applying three methods on the same data source, we estimated the sensitivity and specificity of these methods in the absence of a gold standard. We established a more specific tissue-trait association atlas by combining the information captured by different methods. Our triangulation strategy improves the performance of existing methods in establishing tissue-trait associations. The results provide better etiological and functional insights for the tissues underlying different human complex traits and diseases.

Genetic Landscape of the ACE2 Coronavirus Receptor.

BACKGROUND: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. METHODS: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. RESULTS: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. CONCLUSIONS: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.

Genetic and phenotypic links between obesity and extracellular vesicles.

Obesity has a highly complex genetic architecture, making it difficult to understand the genetic mechanisms, despite the large number of discovered loci via genome-wide association studies (GWAS). Omics techniques have provided a better resolution to view this problem. As a proxy of cell-level biology, extracellular vesicles (EVs) are useful for studying cellular regulation of complex phenotypes such as obesity. Here, in a well-established Scottish cohort, we utilized a novel technology to detect surface proteins across millions of single EVs in each individual's plasma sample. Integrating the results with established obesity GWAS, we inferred 78 types of EVs carrying one or two of 12 surface proteins to be associated with adiposity-related traits such as waist circumference. We then verified that particular EVs' abundance is negatively correlated with body adiposity, while no association with lean body mass. We also revealed that genetic variants associated with protein-specific EVs capture 2-4-fold heritability enrichment for blood cholesterol levels. Our findings provide evidence that EVs with specific surface proteins have phenotypic and genetic links to obesity and blood lipids, respectively, guiding future EV biomarker research.

Projected changes in terrestrial water storage and associated flood potential across the Yangtze River basin.

Terrestrial water storage is a crucial component in water cycle and plays an important role in flood formations process, particularly in a changing environment. In this study, we aim to examine the future variation of terrestrial water storage anomaly (TWSA) and associated flood potential in one of the most flood-prone regions, the Yangtze River basin in China. Using the Gravity Recovery and Climate Experiment (GRACE) data, we perform bias correction for seven general circulation models (GCMs) from the Coupled Model Intercomparison Project Phase 6 under three Shared Socio-economic Pathway (SSP) scenarios: SSP126, SSP245, and SSP585. The spatiotemporal characteristics of changes in future Flood Potential Index are projected and compared between the near (2031-2060) and far (2071-2100) future with reference to the historical period (1985-2014). The results show that GCMs-simulated TWSA generally agrees well with the GRACE results after downscaling and bias correction with the average correlation coefficient of 0.86, Nash-Sutcliffe efficiency of 0.73 and the root mean square error of 21.68 mm. We found that the total variance of projected TWSA is mainly sourced from the internal variability and model uncertainties, while the uncertainties in scenarios contribute relatively less. Moreover, the flood potential is projected to decline during the near future under various scenarios and even lower during the far future under SSP585 scenario. Our findings provide implications for flood control and management under climate change over high flood risk regions worldwide.

Bibliometric analysis of the MOOC application in higher medical education in China / 中华医学教育探索杂志

Objective:To explore the application status and development trend of massive open online course (MOOC) in the field of higher medical education in China, so as to provide the reference for future research in this field.Methods:The related literatures collected from China National Knowledge Infrastructure (CNKI), Wanfang Data service platform, VIP database and China Biology Medicine disc were searched from their inception to March 1st, 2020, and the statistical analysis was carried out on the annual volume, journal distribution, fund support, author distribution, cited frequency, literature type and high-frequency keywords by using the bibliometrics method. The extracted data was set up in Excel 2010, and descriptive statistics was made by frequency analysis.Results:The study collected 754 articles, which were included in 262 journals, mainly medical education journals. The funding rate reached 50%. Huang Ping, Zhang Xin, Li Xinhui and seven others were core authors. Basic medical curriculum application research represented by human anatomy was the most. MOOC application research focused on theoretical curriculum. The curriculum evaluation included such five aspects as terminal evaluation, formative evaluation, platform assessment, comprehensive ability and autonomous learning ability. The research focus was the mixed teaching mode based on MOOC and its application in nursing education, traditional Chinese medicine education and continuing medical education.Conclusion:In the past five years, MOOC has developed rapidly in China's higher medical education, and the core authors have formed, but there is a lack of in-depth cooperation. In the future, we should increase the applied research of experimental (training) courses, and further improve the design of experimental research and curriculum evaluation system.

Analysis and Discussion on the Ethical Pre-review Model of Clinical Trials under the Pharmaceutical Innovation Strategy / 中国医学伦理学

With the implementation of the national biomedical innovation strategy, new requirements for ethical review of clinical trials have been put forward, and more attention has been paid to the ethical pre-review. Based on the current situation of clinical trials and ethical review of new drugs in China, this paper discussed the concept, advantages and necessity of ethical pre-review, sorted out the problems and challenges in the implementation of ethical pre-review at this stage, and put forward the following suggestions on how to better implement ethical pre-review in clinical trials under the pharmaceutical innovation strategy: the complete definition of "ethical pre-review" should be made clearly; ethical review should be carried out on the basis of necessary reference; the scope of application of ethical pre-review should be clarified; after the ethical pre-review, the statement of the approval document should be standardized and accurate.

Study on the university students' satisfaction of the wisdom tree massive open online course platform based on parameter optimization intelligent algorithm.

INTRODUCTION: Curriculum learning through the wisdom tree massive open online course platform not only gets rid of the limitations of specialty, school and region, eliminates the limitations of time and space in traditional teaching, but also effectively solves the problem of educational equity. OBJECTIVES: This paper proposes an intelligent algorithm combining decision tree, support vector machine, and simulated annealing to obtain the best classification accuracy and decision rules for university students' satisfaction with the wisdom tree massive open online course platform. METHODS: This study takes the university students in Fuzhou city information management department as the survey object, and adopts the electronic questionnaire survey method. A total of 1136 formal questionnaires were responded, and 1028 valid questionnaires were obtained after data cleaning and deleting invalid questionnaires (the effective rate was 90.49%). In this paper, the reliability and validity of the questionnaire were tested by IBM SPSS-20.0 software, and six explanatory variables including function, achievement, exercise, quality, richness, and interaction were obtained by principal component analysis. Then, the questionnaire data is converted to CSV (comma separated values) format for analysis. This paper proposes an intelligent algorithm combining decision tree, support vector machine, and simulated annealing to obtain the best classification accuracy and decision rules for university students' satisfaction with the wisdom tree massive open online course platform. In this paper, the proposed algorithm is compared with decision tree, random forest, k-nearest neighbor, and support vector machine to verify its performance. RESULTS: The experimental results show that training set classification accuracy of decision tree, random forest, k-nearest neighbor, only support vector machine and the proposed algorithm (simulated annealing + support vector machine) are 92.21%, 96.10%, 95.67%, 97.29%, and 99.58%, respectively. CONCLUSION: The proposed algorithm simulated annealing + support vector machine does increase the classification accuracy. At the same time, the 11 decision rules generated by simulated annealing + decision tree can provide useful information for decision makers.

Improved Estimation of Phenotypic Correlations Using Summary Association Statistics.

Estimating the phenotypic correlations between complex traits and diseases based on their genome-wide association summary statistics has been a useful technique in genetic epidemiology and statistical genetics inference. Two state-of-the-art strategies, Z-score correlation across null-effect single nucleotide polymorphisms (SNPs) and LD score regression intercept, were widely applied to estimate phenotypic correlations. Here, we propose an improved Z-score correlation strategy based on SNPs with low minor allele frequencies (MAFs), and show how this simple strategy can correct the bias generated by the current methods. The low MAF estimator improves phenotypic correlation estimation, thus it is beneficial for methods and applications using phenotypic correlations inferred from summary association statistics.

Total genetic contribution assessment across the human genome.

Quantifying the overall magnitude of every single locus' genetic effect on the widely measured human phenome is of great challenge. We introduce a unified modelling technique that can consistently provide a total genetic contribution assessment (TGCA) of a gene or genetic variant without thresholding genetic association signals. Genome-wide TGCA in five UK Biobank phenotype domains highlights loci such as the HLA locus for medical conditions, the bone mineral density locus WNT16 for physical measures, and the skin tanning locus MC1R and smoking behaviour locus CHRNA3 for lifestyle. Tissue-specificity investigation reveals several tissues associated with total genetic contributions, including the brain tissues for mental health. Such associations are driven by tissue-specific gene expressions, which share genetic basis with the total genetic contributions. TGCA can provide a genome-wide atlas for the overall genetic contributions in each particular domain of human complex traits.

Exploring the genotoxicity triggers in the MP UV/H2O2-chloramination treatment of bisphenol A through bioassay coupled with non-targeted analysis.

Bisphenol A (BPA) is a well-known xenoestrogen, and UV/H2O2 advanced oxidation process (AOP) is one of the most effective technologies to remove BPA from water. Using BPA spiked tap water, a batch-scale photochemical experiment was conducted to investigate whether BPA can pose a genotoxicity concern during the medium pressure (MP) UV/H2O2 treatment and the post-chloramination. Samples at different UV exposure and post-chloramination durations were collected and analyzed by CALUX® gene reporter assays regarding estrogen receptor α (ERα) and p53 transcriptional activity. MP UV/H2O2 process did not cause extra estrogenic effects from the degradation of BPA, whereas genotoxicity occurred when the treated water was exposed with monochloramine. Seven frequently reported nitrogenous disinfection byproducts (N-DBPs) were detected, but none of them were responsible for the observed genotoxicity. Employed with gas chromatography-quadrupole time-of-flight mass spectrometry (GC-QTOF-MS), four compounds possibly contributed to the genotoxicity were tentatively identified and two of them with aminooxy- or cyano- group were considered as "new" N-DBPs. This study demonstrated that by-products differ from their parent compounds in toxicity can be formed in the UV oxidation with post-disinfection process, which should become a cause for concern.

Nontrivial Replication of Loci Detected by Multi-Trait Methods.

The ever-growing genome-wide association studies (GWAS) have revealed widespread pleiotropy. To exploit this, various methods that jointly consider associations of a genetic variant with multiple traits have been developed. Most efforts have been made concerning improving GWAS discovery power. However, how to replicate these discovered pleiotropic loci has yet to be discussed thoroughly. Unlike a single-trait scenario, multi-trait replication is not trivial considering the underlying genotype-multi-phenotype map of the associations. Here, we evaluate four methods for replicating multi-trait associations, corresponding to four levels of replication strength. Weak replication cannot justify pleiotropic genetic effects, whereas strong replication using our developed correlation methods can inform consistent pleiotropic genetic effects across the discovery and replication samples. We provide a protocol for replicating multi-trait genetic associations in practice. The described methods are implemented in the free and open-source R package MultiABEL.

Slopes and intercepts from log-log correlations of gas/particle quotient and octanol-air partition coefficient (vapor-pressure) for semi-volatile organic compounds: II. Theoretical predictions vs. monitoring.

The logarithm of gas/particle (G/P) partition quotient (logKP) has been found to have a linear relationship with logKOA (octanol-air partition coefficient) with slope mo and intercept bo and logPL (subcooled liquid vapor pressure) with slope mp and intercept bp. In the sister paper of the present work, analytical equations to predict the slope mo and intercept bo based on logKOA and predict the slope mp and intercept bp based on logPL are developed using steady state theory. In this work, the equations are evaluated using world-wide monitoring data (262 pairs for mo and bo values and 292 pairs for mp and bp values produced from more than 10,000 monitiring data worldwide) for selected seven groups of semi-volatile organic compounds (SVOCs), including polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzo-p-dioxins and polychorinated dibenzofurans (PCDD/Fs), polyclorinated biphenyl (PCBs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated naphthalenes (PCNs), organochlorinated pesticides (OCPs), novel brominated flame retardants (NBFRs), and other selected halogenated flame retardants. The slopes and intercepts predicted by the steady state equations reproduce the trends observed in monitoring regression results for the seven SVOC groups, with 44.4% of the variation of monitoring mo values accounted for by logKOA and 48.2% of the variation of monitoring mp values accounted for by logPL. Theoretically, the values of mo can be any value between 0 and 1 dependent on the values of KOA, and are not constrained to 1 as in equilibrium theory. Likewise, the values of mp can be any value between 0 and -1 dependent on the values of PL, and not constrained to -1 predicted by the equilibrium theory. The influence of sampling artifacts on the G/P partitioning of SVOCs has most likely been overemphasized by the equilibrium theory. Thus, the equilibrium approach should be abandoned in favor of the steady state approach for calculating the G/P partition quotients for SVOCs with high KOA values (>1011.38) or low PL values (<10-4.92).

Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, increased by Astragalus polysaccharides to attenuate nonalcoholic fatty liver disease in mice / 中国药理学与毒理学杂志

OBJECTIVE Although the underlying mechanism is largely unknown, gut dysbiosis has emerged as a central initiator of obesity-related diseases including nonalcoholic fatty liver disease (NAFLD), type 2 diabetes and meta?bolic syndrome. The emerging evidence support the use of prebiotics like herb-derived polysaccharides for treating NAFLD by modulating gut microbiome. So, our study focused on the microbiota-dependent anti-NAFLD effect and the exact mechanisms of Astragalus polysaccharides (APS) extracted from Astragalus mongholicus Bunge in high-fat diet (HFD) fed mice. METHODS Co-housing experiment was used to assess the microbiota dependent anti-NAFLD effect of APS. Then, targeted metabolomics and metagenomics were adopted for determining short-chain fatty acids (SCFAs) and bacteria that were specifically enriched by APS. Further in vitro experiment was carried out to test the capacity of SCFAs-producing of identified bacterium. Finally, the anti-NAFLD efficacy of identified bacterium was tested in HFD fed mice. RESULTS Our results first demonstrated the anti-NAFLD effect of APS in HFD fed mice and the contribution of gut microbiota. Moreover, our results indicated that SCFAs, predominantly acetic acid were elevated in APS-supplemented mice and ex vivo experiment. Metagenomics revealed that D. vulgaris from Desulfovibrio genus was not only enriched by APS, but also a potent generator of acetic acid, which showed significant anti-NAFLD effects in HFD fed mice. In addition, D. vulgaris modulated the hepatic gene expression pattern of lipids metabolism, particularly suppressed hepatic fatty acid synthase (FASN) and CD36 protein expression. CONCLUSION APS enriched D. vulgaris is effective on attenuating hepatic steatosis possibly through producing acetic acid, and modulation on hepatic lipids metabolism in mice. Further studies are warranted to explore the long-term impacts of D. vulgaris on host metabolism and the underly?ing mechanism.

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration.

Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.

Persistence of antibiotic resistance genes from river water to tap water in the Yangtze River Delta.

Antibiotic resistance genes (ARGs) raise public concern as emerging contaminants. The abundance and variation of 11 ARGs, intI1 and 16S rRNA gene were deciphered using quantitative PCR (qPCR) in two drinking water treatment systems that include river, wetland, drinking water treatment plants (DWTPs) and tap water from the Yangtze River Delta. The influencing factors for ARG abundance in river water were also explored. All investigated genes were detected in river water and there was no significant difference between the two systems, with sulfonamide ARGs occupying the highest abundance. Temperature had a significant effect on the ARG distribution based on permutational multivariate analysis of variance (PERMANOVA). Further Spearman analysis demonstrated that temperature was strongly correlated with the abundance of sul1, sul2, tetA and tetC, and these genes were significantly correlated with environmental factors (including temperature, total organic carbon (TOC) and dissolved oxygen (DO)). Considering the frequency and abundance of ARGs, as well as their correlation with other genes, sul1, sul2, tetA and tetC could be used as indicators of ARGs in river water. No significant reduction was noted for the absolute abundance of ARGs from river water to wetland water. Principle coordinates analysis (PCoA) combined with PERMANOVA revealed that drinking water treatment was responsible for reducing 16S rRNA gene and ARG abundance resulting in 3-log reductions. However, it should be noted that after transportation of distribution pipeline, both 16S rRNA gene and ARGs still detected in tap water, which indicated persistence of ARGs and will require further research.