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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.

Background: The outbreak of a new coronavirus (2019-nCoV) induced pneumonia (NCP) in the central city of Wuhan in China poses a threat to the public health Thi

Background: Immunotherapy is among the most promising advances in oncology. Limited information exists regarding the interrelationship between CD47 expression and the tumour-associated macrophage-related immune microenvironment in patients with non-small cell lung cancer (NSCLC). These factors may predict novel immunotherapy efficacy. Methods: CD47 and PD-L1 expression was retrospectively studied in 191 resected NSCLC specimens using immunohistochemistry. Additionally, 46 cases with pulmonary infectious diseases were enrolled as a control group. The infiltration of macrophages (M2 and M1) and CD8+ T-lymphocytes was evaluated using dual-immunofluorescence staining. Targeted DNA sequencing was performed on all 191 specimens. Finally, the pattern of immune infiltrates was determined and their prognostic role was assessed. Findings: The prevalence of positive CD47 (CD47pos) expression in NSCLC was 33.0% (63/191), significantly higher than that in pulmonary infectious diseases. CD47pos expression was significantly higher in female, non-smoking, and adenocarcinoma patients (p=0·020, p

We formulate the problem of designing a personalized recommendation system for an online business-to-business (B2B) marketplace, propose a method to solve it, and evaluate results using a controlled pilot test. Our research is conducted in collaboration with IndiaMart, the dominant online B2B platform in India serving approximately 60 million buyer fi rms and 5 million seller fi rms in more than 50 million products and services. In this problem, buyers place requests for quotation (RFQs) to the platform, and the objective of the platform is to match the RFQs with suitable sellers with the highest likelihood of acceptance. Our problem entails two major challenges: (1) high-dimensional and sparse data regarding product category and spatial engagement, and (2) class imbalance because the volume of "accepted" records in historical clickstream data is significantly larger than that of "declined" records. We propose new variables motivated by the choice estimation literature to address high-dimensionality, and evaluate alternative approaches including the Synthetic Minority Over-sampling Technique (SMOTE) and a new resampling approach, which we call Panel Data Augmentation Technique (PDATE), to counter class imbalance. Our method yields a significant improvement in out-of-sample predictive accuracy. A controlled pilot test conducted at IndiaMart shows that our method provides a consistent and significant improvement in the quality of recommendations sustained over time.

Glaucoma is the leading cause of irreversible blindness worldwide. The proteome characterization of glaucoma is not clearly understood. A total of 175 subjects, including 57 primary acute angle-closure glaucoma (PAACG), 50 Primary chronic angle-closure glaucoma (PCACG), 35 neovascular glaucoma (NVG) and 33 cataract patients, were enrolled and comparison proteomic analysis was provided. Above samples were randomly divided into discovery group or validation group, whose AH proteome were analyzed by data-independent acquisition method or by parallel reaction monitor method. The common proteome features of three types of glaucoma were immune response, lipid metabolism and cell death. Three proteins, VTN, SERPIND1 and CD14, showed significantly up-regulated in glaucoma, and could discriminate glaucoma from cataract. Mutual differential proteomic analysis of PAACG, PCACG and NVG showed different proteome characterization of the three types of glaucoma. NVG was characterized with activated angiogenesis. PAACG was characterized with activation of inflammation response. SERPIND1 was discovered to play vital role in glaucoma occurrences, which is associated with eye transparency decrease and glucose metabolism. This study would provide insights in understanding proteome characterization of glaucoma and benefit the clinical application of AH proteome. Funding Statement: This work was supported by the National Key Research and Development Program of China (No. 2016 YFC 1306300, 2018YFC0910202), National Natural Science Foundation of China (No. 30970650, 31200614, 31400669, 81371515, 81170665, 81560121, 81572082), Beijing Natural Science Foundation (No. 7173264, 7172076), Peking Union Medical College Hospital (No.2016-2.27), and Biologic Medicine Information Center of China, National Scientific Data Sharing Platform for Population and Health. Declaration of Interests: All authors have no conflict of interest. Ethics Approval Statement: The study was approved by the Institutional Review Board of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. Informed consent was obtained from each participant before enrolment.

Long intergenic noncoding RNAs (lincRNAs) are critical regulators involved in diverse biological processes. However, the roles and related mechanisms of lincRNAs in axon development are largely unknown. Here, we report a previously unappreciated axon-enriched lincRNA regulating axon elongation, thus referred to as ALAE. Profiling of highly expressed lincRNAs detected abundant and enriched ALAE in the axon of dorsal root ganglion (DRG) neurons, where it locally promoted axon elongation. Mechanically, ALAE directly interacted with the KH3-4 domains of KH-type splicing regulatory protein (KHSRP) and impeded its association with growth-associated protein 43 (Gap43) mRNA. Knockdown of ALAE reduced the protein, but not the mRNA, level of GAP43 in the axon of DRG neurons. Furthermore, local disruption of the interaction between ALAE and KHSRP in the axon significantly inhibited Gap43 mRNA translation, thereby impairing axon elongation. Together, this study implicates crucial roles of axon-enriched lincRNAs in spatiotemporally regulating local translation during axon development.

Background: The COVID-19 pandemic seriously threatens general public health services globally. This study aimed to evaluate the impact of the COVID-19 pandemic on HIV care continuum in Jiangsu province, China. Methods: Data for analysis was retrieved from the web-based Comprehensive Response Information Management System (CRIMS) for HIV/AIDS in China. Expert modeler in SPSS time series model was used in the forecast model and Chi-square or fisher’s exact tests were performed to assess subgroup differences. Findings: Overall, a 34.2% (898,936) decrease in testing rates was observed when real data was compared with the estimated number of recorded tests from the first quarter of 2020. Although an estimated 1610 confirmatory tests were expected to be recorded in 2020, only 749 (46.5%) of confirmed HIV/AIDS cases in Jiangsu were recorded by CRIMS. Of 982 clients that received confirmatory tests, only 696 (70.9%) were reportedly linked to care. Only 34.2% (238) out of the expected 523 (53.4%) estimated number of clients received CD4 cell count test services. Meanwhile 208 (29.9%) had initiated antiretroviral therapy (ART) which is comparatively lower than the 315 (32.2%) reported in the previous year. PLWHIV who were migrants, infected through homosexual transmission, and tested via key population surveillance were more likely to be influenced by the COVID-19 policies. Interpretation: The COVID-19 pandemic had a negative impact on the HIV healthcare systems in Jiangsu, China. There is a need to scale up HIV testing systems by encouraging HIV self-testing or community-based testing and providing flexible policies to facilitate ART initiation. Funding Statement: National Key Research and Development Program of China (2017YFE0103800); NIMH (R34MH119963), National Science and Technology Major Project (2018ZX10101-001-001-003); National Nature Science Foundation of China (81903371); Special Found on Prevention and Control of New Coronary Pneumonia in Guangdong Universities (2020KZDZX1047). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study process and contents were reviewed and approved by the Institutional Review Board of the National Center for AIDS/STD Control and Prevention (NCAIDS) and Center for Disease Control and Prevention (CDC) in China. The study was carried out in accordance with relevant guidelines.

Background: Asymptomatic carriers were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) without developing symptoms, which might be a

Background: This study conducted in mainland China was aimed to explore the cognition, psychological state, anxiety and depression level of college students dur

Objective To identify candidate urinary protein biomarkers to distinguish medulloblastoma (MB) patients from healthy patients or benign brain disease control patients. Methods The tandem mass tag (TMT)-labeled quantitative proteomics approach was used to identify differential proteins in the urinary proteome of 9 pre- and postsurgery MB patients and 9 healthy control patients, respectively. Ingenuity pathway analysis was used for functional annotation of differential proteins. The biomarker candidates were validated by the parallel reaction monitoring (PRM) method in 112 samples (29 pre- and postsurgery MB patients, 26 healthy control patients, and 28 benign brain disease control patients). Receiver operating characteristic (ROC) curves were developed to evaluate candidate biomarkers. Results A total of 114 differential proteins were found. Bioinformatic analysis revealed that the urinary proteome could reflect changes in MB. Seventeen candidate biomarkers were validated by PRM. The combination of CADH1, FGFR4 and FIBB could be used to discriminate MB patients from healthy control patients with an area under the curve (AUC) of 0.973, and the combination of CADH1 and FIBB showed good discriminative power for differentiating MB from benign brain disease with an AUC of 0.884. Conclusion This report describes the first application of a TMT-PRM workflow to identify and validate MB–specific biomarkers in urine. These findings might contribute to the application of urinary proteomics for detecting and monitoring MB. Biological significance Medulloblastoma (MB) is among the most common pediatric brain malignancies. This tumor has a highly aggressive clinical course with a high tendency for relapses. Magnetic resonance imaging (MRI) is the major means of diagnosis and for radiographic surveillance after surgery. In MRI, sedation is often required in young children, which could expose them to a series of risks, including airway obstruction and even death. Aside from MRI, there is no reliable biomarker for clinical screening or monitoring of the disease. These facts introduce the clinical need of noninvasive biomarkers for early screening or monitoring of MB. This study is focused on the investigation of a marker panel based on urinary proteome, as a tool for the detection of MB in selected patients at risk. Upon evaluation of the marker model in an independent blinded set of 112 samples, the panel (CADH1, FGFR4 and FIBB) could be used to discriminate MB patients from healthy control patients with an area under the curve (AUC) of 0.973, and the combination of CADH1 and FIBB showed good discriminative power for differentiating MB from benign brain disease with an AUC of 0.884.

Plasma metabolomics and lipidomics have been commonly used for biomarker discovery for the rich metabolic information they provide. Studies in white and Japanese populations suggested that gender and age can affect circulating plasma metabolite profiles; however, the Chinese population has not been surveyed. In our study, we profiled Chinese plasma metabolome and lipidome in a cohort of 534 healthy adults and reported an overview of metabolic characteristics in the Chinese population. Inter-individual analysis showed that inter-individual variations of the plasma metabolome and lipidome were 0.645 and 0.568, respectively. Further differential analysis indicated that gender and age would affect the metabolic status. Metabolic pathways such as fatty-acid metabolism, nicotinate and nicotinamide metabolism, steroidogenesis process and tryptophan metabolism were found to vary with gender and age. Comparison of metabolism characteristics between Chinese and other western population suggested that plasma metabolomics could reflect regional and ethnic differences, to some extent. Further, using the above strategy, renal cell carcinoma (RCC) biomarkers were explored based on age- and gender-matched healthy subjects, 34 patients with benign kidney lesions and 143 patients with RCC. Metabolic and lipid profiling of the plasma could significantly differentiate cancer cases from healthy controls and benign controls, with an area under the curve (AUC) of 0.971 and 0.839, respectively. Our study provides an overview of plasma metabolic characteristics in a Chinese population and suggests that plasma metabolomics and lipidomics are useful strategies for biomarker discovery. Funding Statement: This work was supported by National Basic Research Program of China (Nos. 2013CB530805 and 2014CBA02005), Major collaborative innovation projects (No. 2017-I2M-1-009), Key Basic Research Program of the Ministry of Science and Technology of China (No. 2013FY114100), the National Natural Science Foundation of China (No. 30970650, 31200614, 31400669, 81371515 and 81670611), Beijing Natural Science Foundation (No. 5132028), Basic scientific research (2017PT310004) and Biologic Medicine Information Center, National Scientific Data Sharing Platform for Population and Health. Declaration of Interests: The authors declare no conflict of interests. Ethics Approval Statement: This study was approved by the Institutional Review Board of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences.

Problem definition: We study the impact of bonus strategies on gig platforms and their welfare implications. We consider two types of bonus strategies used by gig platforms: 1) fixed bonus that is paid in addition to commissions as long as a service provider participates, and 2) contingent bonus that is paid only if a service provider participates consistently over time. Academic/practical relevance: The success of a gig platform is crucially driven by its ability to retain service providers. However, gig workers are independent contractors whose working schedules are not fully controlled by the platform. To overcome this challenge, gig platforms in reality have commonly relied on bonus strategies to drive participation of gig workers. Methodology: We develop a game theory model to study platform competition with bonus strategies. Results: Our analysis shows that the two types of bonuses will arise in equilibrium under different market conditions. First, when labor supply is thick relative to demand, fixed bonus will be offered. In this case, fixed bonus improves platform profit by eliminating a prisoner’s dilemma that arises when the platforms compete only on commissions. However, social welfare will be reduced because platform competition is softened. Second, when labor supply is thin relative to demand, contingent bonus will be offered. In this case, contingent bonus reduces platform profit because it intensifies platform competition and traps the platforms in a prisoner’s dilemma where they are forced to offer too much bonus. It further causes inefficiency in matching labor supply with demand and hence reduces social welfare. Managerial implications: First, bonus competition can lead to opposite impacts on gig platforms depending on the market condition. Second, social planners should be cautious about gig platforms’ use of bonus strategies in general.

Heterogeneous single atom catalysts (SACs) with atomically-dispersed active metal centres represent an intermediary between heterogeneous and homogeneous catalysis. However, the design of SACs for homogeneous processes remains challenging. In the present work, a porous organic polymer with aminopyridine functionalities was designed so as to fabricate a stable, atomically-dispersed Ir catalyst. This Ir-based SAC exhibits excellent catalytic activity during the liquid phase hydrogenation of CO2 to formate. The associated turnover number is as high as 25,135, representing the best performance yet for a heterogeneous conversion reaction. Spectral characterization and density functional theory modelling demonstrate that the architecture of the Ir single atom active site is analogous to that of a homogeneous mononuclear Ir pincer complex catalyst. As a result, a catalytic mechanism similar to that over a homogeneous Ir catalyst occurs during CO2 hydrogenation with this quasi-homogeneous Ir-based SAC. This work suggests a promising basis for the design of efficient SACs for the once-dominant homogeneous catalytic processes.