National Natural Science Fund Research Articles

Study of Flow Pressure Characteristics of Improved Rotary Valve

This work was supported in part by The National Natural Science Fund of China, Scientific research fund of Nanjing Institute of Technology, Open fund project of Anhui University of Technology, Practical innovation project of graduate students in Jiangsu Province. Support Fund Nos. 51505211, 11302097, CKJB201901, HVC202004, SJCX20_0700.

Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis.

BackgroundThe survival time of amyotrophic lateral sclerosis (ALS) is greatly variable and protective or risk effects of the potential survival predictors are controversial. Thus, we aim to undertake a comprehensive meta-analysis of studies investigating non-genetic prognostic and survival factors in patients with ALS.MethodsA search of relevant literature from PubMed, Embase, Cochrane library and other citations from 1st January 1966 to 1st December 020 was conducted. Random-effects models were conducted to pool the multivariable or adjusted hazard ratios (HR) by Stata MP 16.0. PROSPERO registration number: CRD42021256923.FindingsA total of 5717 reports were identified, with 115 studies meeting pre-designed inclusion criteria involving 55,169 ALS patients. Five dimensions, including demographic, environmental or lifestyle, clinical manifestations, biochemical index, therapeutic factors or comorbidities were investigated. Twenty-five prediction factors, including twenty non-intervenable and five intervenable factors, were associated with ALS survival. Among them, NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10) and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), diagnostic delay (HR:0.97) were superior predictors for a good prognosis. Our results did not support the involvement of gender, education level, diabetes, hypertension, NIV, gastrostomy, and statins in ALS survival.InterpretationOur study provided a comprehensive and quantitative index for assessing the prognosis for ALS patients, and the identified non-intervenable or intervenable factors will facilitate the development of treatment strategies for ALS.FundingThis study was supported by the National Natural Science Fund of China (Grant No. 81971188), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. 2019HXFH046), and the Science and Technology Bureau Fund of Sichuan Province (No. 2019YFS0216).

Disparities in stage at diagnosis for five common cancers in China: a multicentre, hospital-based, observational study

Stage information is crucial for cancer care and essential to improve polices for cancer control. However, the distribution of stage at diagnosis for common cancers in China is not well known. We aimed to identify the distribution and factors associated with stage at diagnosis for five major cancers in China. In this multicentre, hospital-based, observational study, we included 23 hospitals in 12 provinces from China. We focused on cancers of the lung, stomach, oesophagus, colorectum, and female breast, and using electronic medical records at the individual level from the local hospitals, and cancer registration records from population-based cancer registries, identified diagnoses made between Jan 1, 2016, and Dec 31, 2017. We collected information on sociodemographic characteristics, lifestyle factors, insurance types, and stage at diagnosis. We analysed the prevalence of late-stage (stages III-IV) cancer cases overall, by sex, and by geographical region. We used logistic regression to identify the factors that were associated with late stage at diagnosis. We further compared these estimates with data from the USA using the Surveillance, Epidemiology, and End Results database. We included 52 103 eligible patients. Among 41 671 patients with known stage at diagnosis, 22 009 (52·8%) were diagnosed with late-stage cancer. The proportion of late-stage cases was higher in men and boys than in women and girls (14 084 [64·1%] of 21 973 vs 7925 [40·2%] of 19 698 patients; diagnosed at stages III-IV; adjusted odds ratio [OR] 1·3, 95% CI 1·2-1·5). There is a persistent diagnostic disparity between rural and urban areas (adjusted OR 1·2, 1·1-1·4). Patients with the new rural cooperative medical scheme insurance had a significantly higher risk of late-stage diagnosis compared with patients with urban insurance (adjusted OR 1·4, 1·1-1·9). By specific cancer type, sex and rural-urban disparities were the largest in lung cancer. Compared with the USA, our study patients had a higher percentage of stage II-IV breast cancer (72·4% in China vs 48·8% in the USA), lung cancer (82·7% in China vs 74·7% in the USA), and colorectal cancer (84·8% in China vs 75·9% in the USA). The disparities of cancer diagnosis within China, and between China and the USA, indicate an urgent need for early detection of cancer in China. National Key R&D Programme of China, Major State Basic Innovation Programme of the Chinese Academy of Medical Sciences, and National Natural Science Fund.

Thrombosis and major bleeding risk after primary percutaneous coronary intervention among patients with multi-vessels coronary artery disease

Abstract Background and aims The present study aimed to develop and validate separate risk prediction models for thrombosis events (TEs) and major bleeding (MB) in patients with multi-vessel coronary artery lesions who had undergone primary percutaneous coronary intervention (PCI). Methods and results TEs were defined as the composite of myocardial infarction recurrence or ischemic cerebrovascular events, whereas MB was defined as the occurrence of bleeding academic research consortium (BARC) 3 or 5 bleeding. The derivation and validation cohorts comprised 2976 patients who underwent primary PCI between January 2010 and June 2017. At a median follow-up of 3.07 years (1122 days), TEs and MB occurred in 167 and 98 patients, respectively. Independent predictors of TEs were older age, prior PCI, non-ST elevated MI (NSTEMI), and stent thrombosis (ST). Independent predictors of MB were triple therapy at discharge, coronary artery bifurcation lesions, lesion restenosis, target lesion of the left main coronary artery, and PTCA. In the derivation and validation cohorts, the areas under the curve were 0.817 and 0.820 for thrombosis and 0.886 and 0.976 for bleeding, respectively. In the derivation cohort, high thrombotic risk (n=755) was associated with a higher 3-year incidence of TEs, major adverse cardiovascular events (MACEs), and all-cause death, compared to low risk (n=1275) (p=0.0022, 0.019, 0.012, respectively). High bleeding risk (n=1675) was associated with a higher incidence of bleeding, MACEs, cardiac death, compared to low risk (n=355) (p<0.0001). Conclusion Simple risk scores can be useful in predicting the risks of ischemic and bleeding events after primary PCI, thereby stratifying thrombotic or MB risks and facilitating clinical decisions. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This study was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1–009), National Natural Science Funds (number: 81970308) and the Fund of “Sanming” Project of Medicine in Shenzhen (number: SZSM201911017). Figure 2Figure 3

The changing pattern of enteric pathogen infections in China during the COVID-19 pandemic: a nation-wide observational study.

BackgroundNon pharmaceutical interventions (NPI) including hand washing directives were implemented in China and worldwide to combat the COVID-19 pandemic, which are likely to have had impacted a broad spectrum of enteric pathogen infections.MethodsEtiologically diagnostic data from 45 937 and 67 395 patients with acute diarrhea between 2012 and 2020, who were tested for seven viral pathogens and 13 bacteria respectively, were analyzed to assess the changes of enteric pathogen infections in China during the first COVID-19 pandemic year compared to pre-pandemic years.FindingsTest positive rates of all enteric viruses decreased during 2020, compared to the average levels during 2012−2019, with a relative decrease of 71•75% for adenovirus, 58•76% for norovirus, 53•50% for rotavirus A, and 72•07% for the combination of other four uncommon viruses. In general, a larger reduction of positive rate in viruses was seen among adults than pediatric patients. A rebound of rotavirus A was seen after September 2020 in North China rather than South China. Test positive rates of bacteria decreased during 2020, compared to the average levels during 2012−2019, excepting for nontyphoidal Salmonella and Campylobacter coli with 66•53% and 90•48% increase respectively. This increase was larger for pediatric patients than for adult patients.InterpretationThe activity of enteric pathogens changed profoundly alongside the NPIs implemented during the COVID-19 pandemic in China. Greater reductions of the test positive rates were found for almost all enteric viruses than for bacteria among acute diarrhea patients, with further large differences by age and geography. Lifting of NPIs will lead to resurgence of enteric pathogen infections, particularly in children whose immunity may not have been developed and/or waned.FundingChina Mega-Project on Infectious Disease Prevention; National Natural Science Funds.

Temporal trends in semen concentration and count among 327 373 Chinese healthy men from 1981 to 2019: a systematic review.

Are there temporal trends of sperm concentration (SC) and total sperm count (TSC) in Chinese healthy males from 1981 to 2019? Our result indicated a temporal decrease in SC and TSC among 327 373 healthy Chinese men in the recent four decades. A review of 61 papers reported a temporal decline in SC and TSC from 1938 to 1990. This trend was later confirmed by a systematic review of 185 published papers from 1981 to 2013. However, the majority of the included individuals were from western countries. In China, whether SC and TSC have declined remains controversial. This systematic review of published articles used data extracted from Pubmed, Science Direct, Embase, China-National-Knowledge-Infrastructure (CNKI) and Wanfang Data to assess changes in SC and TSC in China from 1981 to 2019. A total of 111 studies including 327 373 individuals who provided semen samples from 1981 to 2019 were extracted for the present analysis. Study selection and data extraction were performed by two independent researchers. The trends in SC and TSC were analysed using liner-regression and meta-regression before and after adjusting for potential covariates. Moreover, subgroups, categorised based on geographic region, fertility status or recruitment source, were also analysed. SC declined significantly (slope liner-regression = -0.748 million/ml/year; P = 0.005; slope meta-regression = -0.824 million/ml/year; P < 0.001) between 1981 and 2019 in China. Trends for TSC was similar to that for SC (slope liner-regression = -2.073 million/year; P = 0.032; slope meta-regression = -2.188 million/year; P = 0.003). In subgroup meta-regression analyses, males with definite fertility had continuous declines in SC (slope northern group=-2.268, P = 0.009; slope southern group=-1.014, P = 0.009) and TSC (slope northern group=-9.675, P = 0.010; slope southern group=-3.215, P = 0.042). However, in the unselected group, where fertility status was unknown, the obvious downward trend in SC was only seen in males from Northern regions (slope = -0.836, P = 0.003). Another subgroup analysis demonstrated that obvious decreases in SC (slope = -1.432, P < 0.001) and TSC (slope=-4.315, P = 0.001) were only seen in volunteer groups but not in pre-pregnancy examination groups and other recruitment groups. The results changed minimally in multiple sensitivity analyses. The validity of the meta-analysis results was limited mainly by the quality of the included studies. Additionally, our study spanned many decades and the recommended criteria for some semen parameter assessments have significantly changed, which may bring about some unavoidable bias. Moreover, the data remain insufficient especially in some provinces of China. The present study is the first study to report significant decreases in SC and TSC in 327 373 healthy Chinese men between 1981 and 2019, indicating a serious reproductive health warning. Further studies on the causes of the declines are urgently needed. D.Z. is supported by the National Natural Science Funding of China, Natural Science Funding of Shaanxi Province, Science Funding of Health Department, Shaanxi Province, Fundamental Research Funds for the Central University and the Project of Independent Innovative Experiment for Postgraduates in Medicine in Xi'an Jiaotong University. The authors have no conflicts of interests to declare. N/A.

LiCoO2 Epitaxial Film Enabling Precise Analysis of Interfacial DegradationsSupported by the National Natural Science Fund for Innovative Research Groups (China) (Grant No. 51621003), the National Key Research and Development Program of China (Grant No. 2016Yu7FB0700700), the Beijing Municipal Fund for Scientific Innovation (Grant No. PXM2019 014204 500031) and the Beijing Municipal High Level Innovative Team Building Program (Grant No. IDHT20190503).

Interfacial structure evolution and degradation are critical to the electrochemical performance of LiCoO2 (LCO), the most widely studied and used cathode material in lithium ion batteries. To understand such processes requires precise and quantitative measurements. Herein, we use well-defined epitaxial LCO thin films to reveal the interfacial degradation mechanisms. Through our systematical investigations, we find that surface corrosion is significant after forming the surface phase transition layer, and the cathode electrolyte interphase (CEI) has a double layer structure, an inorganic inner layer containing CoO, LiF, LiOH/Li2O and Li x PF y O z , and an outmost layer containing Li2CO3 and organic carbonaceous components. Furthermore, surface cracks are found to be pronounced due to mechanical failures and chemical etching. This work demonstrates a model material to realize the precise measurements of LCO interfacial degradations, which deepens our understanding on the interfacial degradation mechanisms.

Changes in Notifiable Infectious Diseases in China During the COVID-19 Pandemic: A National Surveillance Study

Background: Nationwide nonpharmaceutical interventions (NPI) were used to combat the novel coronavirus disease (COVID-19) during 2020 in the mainland of China. These NPIs have proven effective on mitigating the spread of COVID-19, but their broad impact on other diseases remains under-investigated. In this study, we aim to assess whether such broad impact exists on notifiable diseases in China.Methods: Weekly incidence and mortality data for 31 major notifiable infectious diseases at the province level were extracted from the China Information System for Disease Control and Prevention from 2014 to 2020. We assessed the impact of NPIs by contrasting the incidences of each infectious disease in predefined COVID-19 phases during 2020 to the average incidences in the corresponding time intervals during 2014-2019.Findings: We observed decreased incidences of most diseases during the phases after the lockdown of Wuhan. In general, respiratory diseases and gastrointestinal or enteroviral diseases were more affected than sexually transmitted or bloodborne diseases and vector-borne or zoonotic diseases. Seasonal flu and rubella were the most sensitive to the NPIs, with reductions of 67-99% in incidence rates throughout the NPI-implemented phases in China (Jan 27-Dec 31, 2020). Among gastrointestinal or enteroviral diseases, the hand, foot and mouth disease (HFMD) was subject to the largest declines during Jan 27-Aug 31, 2020, with >90% reduction in incidence rate. Phases with more stringent NPIs were associated with more reductions. Non-respiratory diseases, particularly HFMD, gonorrhea and brucellosis, rebounded towards the end of the year as the NPIs were relaxed.Interpretation: NPIs are broadly effective in containing infectious diseases. Less disruptive NPIs such as wearing face masks are still effective in mitigating respiratory diseases but are not adequate for containing non-respiratory diseases.Funding Statement: This work was supported by grants from the National Natural Science Funds [91846302, 81825019], the China Mega-Project on Infectious Disease Prevention [2018ZX10713001, 2018ZX10713002, 2018ZX10201001 and 2017ZX10103004], and the US National Institutes of Health [R56 AI148284].Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: Missing.

Multivariable Clinical-Genetic Model for Predicting Dyskinesia in Early-Onset Parkinson's Disease

Background: Levodopa-induced dyskinesias (LIDs) is one of important motor complications, which negatively affect the quality of life of patients with Parkinson disease (PD).Objects: This study aims to establish clinical-genetic models of LIDs prediction and explore clinical and genetic predictors of LIDs in early-onset PD (EOPD). Methods: A prospective cohort design including 279 EOPD patients were followed-up about 9.2 years. Clinical and genetic data were investigated. LIDs prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curve. A multivariable logistic regression model was conducted to discriminate the independent predictive factors of LIDs incident. An independent cohort including 144 EOPD was used as the validation group to confirm the developed prediction models. Results: The incidence of LIDs in EOPD at the first 5 years of duration and at the first 5 years after receiving dopamine replacement therapy (DRT) were 15.4% and 29.7%, respectively. In two clinical-genetic models, adding genotypes from 11 candidate variants significantly increased LIDs predictability compared to prediction based on clinical variables only (p<0.005), which were confirmed in the validation group. Importantly, the AUCs of clinical or clinical-genetic model for predicting LIDs incident were not significantly different when patients carrying seven PD causative genes were excluded or not. In addition, LEDD, DRD3 rs6280, SLC6A3 rs460000 and COMT rs4680 , were the strongest independent predictive factors. Conclusion: LIDs incident was common in the early stage of EOPD, established clinical-genetic models and identified independent predictive factors have good application prospects to LIDs prediction and DRT management. Funding: This study was supported the National Key Research and Development Program of China (grant no. 2016YFC0901504 and 2018YFC1312001), the National Natural Science Fund of China (Grant No. 81571247) and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYJC18038, Grant No. ZYJC18003 and Grant No. 2019HXFH046). Declaration of Interest: None to declare Ethical Approval: This study was approved by the ethics committee of West China Hospital, Sichuan University.

Discipline layout and application guide for earth sciences from leading international science foundations and agencies

According to the principle of being “derived from the logical structure of the knowledge system and promoted through the integration and application of knowledge”, advancement in interdisciplinary research is one of the three core tasks of the deepening reform of the National Natural Science Fund in the new era. This article takes an international vision by first investigating the disciplinary layout and application guide for the field of earth sciences offered by leading international science foundations and agencies including the National Science Foundation, United States (NSF); National Research Foundation of Korea (NRF); Japan Society for the Promotion of Science; Agence Nationale De Le Recherche; Deutsche Forschungsgemeinschaft (DFG); European Research Council; Australian Research Council; Ministry of Business, Innovation &amp; Employment; and National Natural Science Foundation of China (NSFC). These application guides include categories of guidelines, extensive application codes, and subdivided application codes. Compared with the existing hierarchical structure for application codes in the field of earth sciences at NSFC, the feasibility and necessity of promoting the optimization of the disciplinary layout and reform of application codes are discussed. Then, it is proposed that the disciplinary layout should be based on the current conditions as well as the future developmental needs of China and that the optimization of application codes should consider the needs of both application guidance rationality and management applicability. Moreover, the setting of application codes should include self-consistent disciplines; exhibit stable inheritance; and support services, emerging intersections, and national needs. To optimize the disciplinary layout, improve the basic research capabilities, and account for the scale of basic research teams and human management resources, the application codes need to be optimized on the basis of three key factors: Extensive application codes, subdivided application codes, and intelligent assistance. Only in this way can the core mission of science foundation management reforms be fulfilled and the goal of building a science foundation management system with advanced concepts, standardized systems, fairness, and efficiency be achieved. In the future, NSFC should focus on the differences between basic scientific research conducted by large and small countries, pay more attention to balanced development in the discipline layout, develop basic general research, and comprehensively promote the growth of the earth science fund. During the past two years, under the guidance of clear, overall strategic planning and top-level design, NSFC’s Department of Earth Sciences has deployed multiple major projects by guidelines, such as those for the major basic science projects of the Sichuan-Tibet railway and frontier projects of basic polar science as well as special projects related to 2019-nCoV research, ecological protection and sustainable development of the Yellow River Basin, and deep-time earth science knowledge graphing and knowledge evolution. These established projects have played key roles in enabling NSFC to meet the major national needs and push forward international scientific frontiers. In the future, NSFC should continue to pay significant attention to strategic research and the top-level design of funding deployment. Moreover, the foundation should strengthen the overall consideration of the top-level strategic results of earth sciences and the layout of the science fund. In practice, the focus should be on the promotion of basic scientific research rather than servicing the other needs of different disciplines. By further improving the condensed mechanism and management methods of the major projects of earth sciences, the important role of guidelines in funding effectiveness will be strengthened. This article can provide the necessary international vision and strategic support for the reform of the application codes of NSFC.

Application Management of National Natural Science Fund from Perspective of Scientific Research Secretary

Application Management of National Natural Science Fund from Perspective of Scientific Research Secretary

A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis.

BackgroundFibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo. To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments .MethodsUtilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists.FindingsTwo Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo. One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone.InterpretationThis novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH.FundingHEC Pharm R&D Co., Ltd, National natural science fund of China.

Prognostic Value of Diverse TP53 Mutations in Metastatic Cancers: An Analysis of the Cbioportal Database

Background: Functional heterogeneity among TP53 mutations necessitates a need to dissect the prognostic potential of TP53 mutations at different sites or against different molecular background. Methods: The information of TP53 mutations and overall survival time among 7572 patients with metastatic cancers in the MSK-IMPACT clinical sequencing cohort were collected. The effects of TP53 mutations on survival were conducted using the Kaplan-Meier approach, log-rank test and Cox regression model in pan-cancer, and in major subtypes of lung, breast, and colon cancers. Findings: Mutations in exons 4, 5, 6, 7, 8, and 10, p.R342*, p.Y220C, and p.G245S were identified as potential pan-cancer poor prognosticators (p < 0.05 for all). R213* was identified as a significant poor prognosticator only in metastatic lung adenocarcinoma (p = 0.01). The negative prognostic effect of mutated TP53 was statistically significant in lung adenocarcinoma patients harboring EGFR p.L858R (p = 0.002), but not in those with exon 19 deletion (p = 0.173). Compared with wild-type TP53, higher risk of death correlated with TP53 mutational status located in exon 4, 5, 6, 7, or 8 among patients with metastatic breast invasive ductal carcinoma. In addition, p.R282W substitution was significantly associated with poor prognosis in metastatic colon adenocarcinoma (mCOAD), while TP53 mutation was also significantly negative associated with poor survival in COAD patients carrying driving mutations (KRAS or RAS/RAF). Interpretation: The prognostic values of TP53 mutation depended on cancer type and concurrent genomic abnormality. Our results may facilitate prognosis, patient identification for further investigation, and development of TP53 -targeted anti-cancer therapy. Funding: This work was supported by the Logistics Support Department of PLA [grant number 19BJZ03, 2019], Military Medicine Fund of Changzheng Hospital [grant number 2019CZJS208-1, 2019], Science and Technology Commission of Shanghai Municipality [grant number17511103403, 2017], Medical Innovation Research Project of Shanghai Science and Technology Commission (grant number 20Y11914400, 2020), Chinese National Natural Science Funding [grant number 82002522, 2020]and State Key Program for Chronic non- communicable Disease Prevention and Control of the Ministry of Science and Technology, China (grant number 2017YFC1309202, 2017). Declaration of Interest: All authors declare no conflicts of interest.

METTL14 Regulates Autophagy and Osteogenic Differentiation of BMSCs Targeting Beclin-1 via an M &lt;sup&gt;6&lt;/sup&gt; A-IGF2BPs-Dependent Mechanism

Background: The development of osteoporosis is often accompanied by autophagy disturbance, which also caused new osteoblasts defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. We aimed to explore the biological functions of autophagy mediated by METTL14 in osteoporosis and the possibility of METTL14 as an effective target for the treatment of osteoporosis. Methods: Calcein staining and microcomputed tomography (μ-CT) were used to analyze the bone formation. immunohistochemical (IHC) staining was used to detect the expression of METTL14 and beclin-1 in bone tissues. The quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Alizarin red staining (ARS) and alkaline phosphatase (ALP) staining were used to explore the osteogenic differentiation of BMSCs. The production of autophagy was determined by transmission electron microscopy (TEM) and mRFP-GFP-LC3 adenoviral. Moreover, RNA binding protein immunoprecipitation (RIP)-qPCR was used to investigate the m6A modification of beclin-1 and the binding capability of beclin-1 and IGF2BPs. Findings: Herein, we demonstrate that the expression of METTL14 is downregulated during the development of osteoporosis both in human and mice. In vivo, METTL14+/- knockdown mice exhibits elevated bone loss and impaired autophagy similar to the ovariectomized (OVX) mice, while injecting METTL14 overexpressing adenovirus delays the process of osteoporosis.In vitro, forced expression of METTL14 significantly facilitates the osteogenic differentiation ability of BMSCs through regulating the activation of autophagy by enhancing the expression of beclin-1 dependent on the m6 A modification; the opposite is true under METTL14 silencing condition. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A methylated beclin-1 mRNA and promotes its translation via mediating RNA stabilization. Interpretation: Our study reveals the METTL14-IGF2BPs-beclin-1 signaling axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14 mediated m 6 A modification in osteoporosis. Funding: This work was supported by grants from the National Natural Science Fund of China (81972117), Natural Science Foundation of Heilongjiang Province of China for excellent youth (JJ2020JQ0004), The First Affiliated Hospital of Harbin Medical University Excellent Young Talents Funding (HYD2020JQ0013), Special fund for clinical research of Wu Jieping Medical Foundation (320.6750.2020-04-50), and CAMS Innovation Fund for Medical Sciences (CIFMS, 2020-I2M-5-003). Declaration of Interest: The authors declare that they have no competing interests. Date Availability Ethical Approval: The experiments were performed under the guidance of the Experimental Animal Ethic Committee of the Harbin Medical University.

Probing the universality of acceleration scale in modified Newtonian dynamics with SPARC galaxies * *Supported by the National Natural Science Fund of China (11603005, 11775038, 11947406), Fundamental Research Funds for the Central Universities (2020CQJQY-Z003)

We probe the universality of acceleration scale in Milgrom's modified Newtonian dynamics (MOND) using the recently released rotation curve data from SPARC galaxies. We divide the SPARC data into different subsamples according to the morphological types of galaxies, and fit the rotation curve data of each subsample with the theoretical prediction of MOND. MOND involves an arbitrary interpolation function which connects the Newtonian region and the MOND region. Here we consider five different interpolation functions that are widely discussed in the literature. It is shown that the best-fitting significantly depends on the interpolation functions. For a specific interpolation function, also depends on the morphological types of galaxies, implying that may be not a universal constant. Introducing a dipole correction to can significantly improve the fits. The dipole directions for four of the five interpolation functions point towards an approximately consistent direction, but still varies for different interpolation functions.

Interleukin-2 Inducible T-Cell Kinase: A Potential Prognostic Biomarker and Tumor Microenvironment Remodeling Indicator for Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the dominant type of primary liver cancer, which leads to the fourth-ranked common cause of cancer-related death worldwide. The highly heterogeneous tumor microenvironment (TME) contributes to poor prognosis, particularly tumor recurrence of HCC. There is still a great challenge to illuminate the complicated modulation of TME during HCC progression. Methods: In the current study, RNA expression data and clinical-pathological data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The immune and stromal scores of the samples were calculated using ESTIMATE algorithm and DEGs were obtained by comparison of low- and high-score groups. Intersection of hubgenes in protein-protein interaction (PPI) network and factors correlated with survival from univariate COX regression analysis were applied to screen out the key DEGs. The proportion of tumor-infiltrating immune cells (TICs) and stromal components were evaluated using CIBERSORT algorithm. Further Gene Set Enrichment Analysis (GSEA) and correlation analysis were carried out to elucidate the relation between ITK and TIC composition. Findings: The Immune score and Estimate score were proved to be significantly correlated with long-term recurrence-free survival (RFS) of HCC patients. 197 DEGs were carried out based on the Immune and Stromal scores. Two factors including interleukin-2 inducible T-cell kinase (ITK) and HLA Class II histocompatibility antigen DRB5 (HLA-DRB5) were identified as key DEGs. Further analysis proved that ITK was the most powerful DEG to evaluate the clinical-pathological characteristics and outcomes of HCC patients.The results of GSEA revealed that genes in the high ITK subgroup were enriched in inflammatory-immunological terms. CIBERSORT analysis for the proportion of TICs indicated that activated CD4+ memory T cells, CD8+ T cells, and M1 Macrophages were positively correlated with ITK expression, while plasma cells, resting natural killer (NK) cells, activated dendritic cells, activated NK cells, naive CD4+ T cells and resting mast cells were negatively correlated with ITK expression. Interpretation: Our work identified ITK as a novel indicator for tumor recurrence and microenvironment remodeling in HCC, and provide a potential therapeutic target for HCC treatment. Funding Statement: National ST National Natural Science Funds for Distinguished Young Scholar of China (No. 81625003); Key Program, National Natural Science Foundation of China (No. 81930016); Key Research & Development Plan of Zhejiang Province (No. 2019C03050); Youth Program of National Natural Science Foundation of China (No.81702858); Medical and health science and technology program of Zhejiang Province (No.2018256286) Declaration of Interests: None.

Strongly lensed gravitational waves as probes to test the cosmic distance duality relation * *Supported by the National Natural Science Fund of China (11603005, 11775038, 11947406)

The cosmic distance relation (DDR) associates the angular diameters distance ( ) and luminosity distance ( ) by a simple formula, i.e., . The strongly lensed gravitational waves (GWs) provide a unique way to measure and simultaneously to the GW source, hence they can be used as probes to test DDR. In this study, we investigated the use of strongly lensed GW events from the future Einstein Telescope to test DDR. We assumed the possible deviation of DDR as , and considered two different parametrizations of , namely, and . Numerical simulations showed that, with about 100 strongly lensed GW events observed by ET, the parameter was constrained at 1.3% and 3% levels for the first and second parametrizations, respectively.

Temporal Trends in Semen Quality Among 271,545 Chinese Healthy Men From 1981 to 2019

Background: Recent studies reported a decrease of sperm count around the world, however, little data from China was included. In China, declines in sperm quality remain controversial. Therefore, this study attempted to explore the temporal trends in sperm quality of Chinese healthy males from 1981 to 2019. Methods: Based on the protocol provided by Levine et al, data extracted from Pubmed, Science Director, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang Data were collected to assess changes of sperm concentration (SC) and total sperm count (TSC) in recent decades using simple liner regression and meta-regression before and after adjusting for potential covariates including fertility group, region group, mean age, abstinence time, sperm collection and counting methods and whether individual provides more than one sample selection of population. Moreover, subgroups, categorizing based on geographic region or fertility status, were also conducted. Findings: A total of 102 studies with 271,545 individuals who provided semen samples from 1981 to 2019 were finally extracted for the present meta-regression analysis. SC declined significantly, on average, 0.43% per year with an overall decline of 16.3% between 1981 and 2019 (slope in unadjusted simple regression models -0.848 million/ml/year; 95% CI: -1.392 to -0.304; P = 0.002; slope in adjusted meta-regression models = -0.854; −1.452 to -0.630; P < 0.001). Trends for TSC was similar to that for SC with 0.89% per year and 33.08% overall decline from 1981 to 2019 (slope in unadjusted simple regression models = -2.063 million/year; 95% CI: -3.840 to -0.287, P = 0.023; slope in adjusted meta-regression models = -2.536; -4.052 to -1.022; P = 0.001). In subgroup meta-regression analysis, the slopes in model could be modified by fertility and region group (PSC for interaction = 0.031 and PTSC for interaction = 0.006). Fertility males in northern China had continuous declines in both SC (slope= -2.393; -3.964 to -0.822; P = 0.006) and TSC (slope= -9.675; -16.295 to -3.054; P = 0.010). Similarity, unselected group (unknown fertility males) in northern China also showed significant decreases in both SC (slope= -0.866; -1.403 to -0.329; P = 0.002) and TSC (slope= -1.806; -3.744 to -0.131; P = 0.047). Meanwhile, in southern China, only SC had significant down trends in fertility individuals (slope= -0.997; -1.736 to -0.258; P = 0.008). No changes in SC or TSC were seen in other groups separately. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. Interpretation: The present study was the first study to assess semen quality among 271,545 Chinese general healthy men in the recent 4 decades and our result indicated a serious reproductive health warning that sperm quality in general healthy Chinese men decreases between 1981 and 2019. Further studies on causes of the decreases are urgently needed. Funding Statement: This research was financially supported by National Natural Science Funding of China (to DZ) and Natural Science Funding of Shaanxi Province (to DZ). Declaration of Interests: All authors declare no conflict of interest.

Genetic polymorphisms and cardiovascular outcomes in Chinese patients undergoing PCI and treated with clopidogrel and aspirin

Abstract Background Genetic polymorphisms of key proteins involved in clopidogrel absorption, metabolism, and action may contribute to variability in platelet inhibition in patients undergoing percutaneous coronary intervention (PCI), but their impacts on cardiovascular outcomes remain unclear. Purpose To examine the associations between genetic polymorphisms and cardiovascular outcomes in Chinese patients undergoing PCI and treated with clopidogrel and aspirin. Methods This prospective cohort study consecutively enrolled 2,453 post-PCI patients treated with clopidogrel and aspirin. Adenosine diphosphate-induced platelet aggregation was measured by light transmission aggregometry. A total of 40 single nucleotide polymorphisms (SNPs) of 18 genes selected according to published studies were investigated using an improved multiplex ligation detection reaction technique. The primary outcome was major adverse cardiovascular event (MACE), the composite of cardiovascular death, non-fatal myocardial infarction (MI), and ischemic stroke within one year after PCI. Results We restricted the analyses to the first 1,452 patients who had finished one-year follow-up and complete data on genotyping and platelet aggregation. 44 (3.03%) patients suffered MACE. Among the 40 SNPs, only the A-allele carriers of CYP2C19*2 had a significant higher risk of MACE (adjusted HR 2.05; 95% CI, 1.01–4.19; p=0.048) and platelet aggregation than non-A-carriers after adjusting age, sex, MI presentation, and left ventricular ejection fraction. CYP2C19*3, CYP2B6 rs3745274, and PEAR1 rs12041331 variants were also significantly associated with platelet aggregation (all p&amp;lt;0.05) but not with MACE at 1 year. Conclusion About 54.2% of Chinese patients with PCI were A-allele carriers of CYP2C19*2, who face a two-fold higher risk of MACE than non-A-allele carriers in Chinese patients after PCI. It would help identify low clopidogrel responders and optimize antiplatelet therapy before drug administration. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Funding of China

Development and usability test of an intelligent cardiovascular risk elimination application for patients with coronary heart disease

Abstract Background The mortality of coronary heart disease (CHD) can be largely reduced by improving CHD risk factors through facilitating adherence to unhealthy lifestyle modification (UhLM) and secondary preventive medications (SPMs). Current interventions, however, have been unsatisfactory worldwide. Purpose To develop an Individualized, Intelligent and Integrated Cardiovascular Application for Risk Elimination system (iCARE) for facilitating adherence to UhLM and SPMs, and test its usability and feasibility for implementation. Methods Based on a set of individualized interventions formulated in our preliminary work, we developed iCARE using mHealth techniques and a user-centred approach, which included 3 phases: (1) identifying patient preferences regarding formats for providing interventions; (2) designing the functions, architecture, and user interface (UI); (3) developing the iCARE using prototyping techniques. Usability test was conducted in patients with acute coronary syndromes and/or underwent percutaneous coronary intervention from January to March 2019 in two University affiliated hospitals in our city. The iCARE was implemented in 4 cardiac units of the same hospitals thereafter. Results The iCARE architecture and UI are displayed in Fig 1. Different from most current available mHealth CHD management system, the iCARE has a set of interventions and IF-THEN algorithms triggering interventions to ensure that patients receive individualized recommendations for UhLM and SPMs adherence. To improve effectiveness of iCARE interventions, visualization was used to augment patients' perceptions of risks of non-adherence to UhLM and SPMs, and effectiveness of adopting healthy lifestyles etc. Interventions are triggered by results of initial assessment and health data from daily monitoring. The initial assessment is conducted before patients are discharged, and a health report as well as individualized goals for risk reduction are formulated automatically. Daily diet, physical activities, smoking, medication adherence, blood pressure, blood sugar, and symptoms are monitored either through wearable devices or manual entry. Instant and individualized feedbacks as well as recommended actions are sent to patients automatically. A build-in artificial intelligent Q-A function was also included in iCARE. For the usability test, 88 patients with 71.3% male and mean age of 60 (SD 9.9) were recruited, 87.5% were satisfied with iCARE; 89.5% and 81.4% reported that iCARE was useful and easy to use, respectively. Currently, a total of 201 patients with 83.1% male and mean age of 54 (SD 10.2) were recruited from June 2019 to January 2020, and 46 of them have been followed up for 3 months. Conclusions The iCARE has achieved its functions of serving as an individualized and intelligent CHD management tool to improve adherence to UhLM and SPMs. The usability is satisfactory and it is feasible to implement in clinical settings. Figure 1. The iCARE system. iCARE, Individualized, Intelligent and Integrated Cardiovascular Applicaton for Risk Elimination (iCARE) system, CHD, coronary heart disease. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Funding of China