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Objectives: Prolonged exposure to chronic hypertension places the heart under excessive strain, resulting in myocardial remodeling. Phillyrin, derived from the natural plant Forsythia suspensa, has been found to possess cardioprotective properties. The objective of this study is to investigate the role and mechanism of phillyrin in hypertension-induced myocardial remodeling in mice. Methods: We constructed a mouse model of salt-sensitive hypertension. The mice were treated with varying doses of phillyrin, and their blood pressure, cardiac function, cardiac hypertrophy, fibrosis, inflammation, and other conditions were assessed. Key findings: Our research findings demonstrated that phillyrin has the potential to lower blood pressure, enhance cardiac function, and mitigate cardiac hypertrophy, fibrosis, and inflammatory responses in deoxycorticosterone acetate-salt hypertension mice. In hypertensive mice, there was an elevated expression of endothelin1 (ET-1) in heart tissue, which can be reduced by phillyrin. Additionally, phillyrin effectively reduced the hypertrophy of H9c2 cells induced by ET-1 stimulation. Conclusions: Our research highlights the therapeutic capabilities of phillyrin in the treatment of myocardial remodeling through the reduction of ET-1 signaling. These results contribute to the advancement of novel applications for phillyrin and establish a solid conceptual basis for future investigations in this area. [ABSTRACT FROM AUTHOR]

The development of the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) system has provided precise and efficient strategies to edit target genes and generate transgene-free crops. Significant progress has been made in the editing of protein-coding genes; however, studies on the editing of non-coding DNA with regulatory roles lags far behind. Non-coding regulatory DNAs, including those which can be transcribed into long non-coding RNAs (lncRNAs), and miRNAs, together with cis -regulatory elements (CREs), play crucial roles in regulating plant growth and development. Therefore, the combination of CRISPR/Cas technology and non-coding regulatory DNA has great potential to generate novel alleles that affect various agronomic traits of crops, thus providing valuable genetic resources for crop breeding. Herein, we review recent advances in the roles of non-coding regulatory DNA, attempts to edit non-coding regulatory DNA for crop improvement, and potential application of novel editing tools in modulating non-coding regulatory DNA. Finally, the existing problems, possible solutions, and future applications of gene editing of non-coding regulatory DNA in modern crop breeding practice are also discussed. [ABSTRACT FROM AUTHOR]

Background The evidence-base for mass tuberculosis screening among persons with diabetes (PWD) is poor. We evaluated the yield and costs of mass screening among PWD in eastern China. Methods We included individuals with type 2 diabetes from 38 townships in Jiangsu Province. Screening comprised of physical examinations, symptom screening, and chest X-rays; smear and culture testing were performed through clinical triage. We assessed the yield and number needed to screen (NNS) to detect 1 tuberculosis case among all PWD, those with symptoms, and with suggestive chest X-rays. Unit costing was collected to estimate screening costs and to calculate cost per case detected. We performed a systematic review of other mass tuberculosis screening programs concentrated on PWD. Results Of 89 549 screened PWD, 160 were diagnosed with tuberculosis (179 cases per 100 000 persons; 95% confidence interval [CI]: 153–205). The NNS was 560 (95% CI: 513–606), 248 (95% CI: 217–279), and 36 (95% CI: 24–48) among all participants, with abnormal chest X-rays, and symptoms. The cost per case was high overall (US$13 930) but lower with symptoms (US$1037) and high fasting blood glucose levels (US$6807). From systematic review, the pooled NNS to detect one case among all PWD (regardless of symptoms or chest X-ray results) in high- versus low-burden settings was 93 (95% CI: 70–141) versus 395 (95% CI: 283–649). Conclusions A mass tuberculosis screening program focused on PWD was feasible however, the overall yield was low and not cost-efficient. Risk-stratified approaches may be practical among PWD in low- and medium tuberculosis burden settings. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. Hence, a multi-target drug would improve treatment efficacy. We applied a new multi-scale predictive modelling framework that integrates machine learning with biophysics and systems pharmacology to screen drugs for Alzheimer's disease using patients' tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer's disease. Ibudilast is a multi-target drug, as it is a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist. In addition, we predict that ibudilast inhibits off-target kinases (e.g. IRAK1 and GSG2). In Japan and other Asian countries, ibudilast is approved for treating asthma and stroke due to its anti-inflammatory potential. Based on these previous studies and on our predictions, we tested for the first time the efficacy of ibudilast in Fisher transgenic 344-AD rats. This transgenic rat model is unique as it exhibits hippocampal-dependent spatial learning and memory deficits and Alzheimer's disease pathology, including hippocampal amyloid plaques, tau paired-helical filaments, neuronal loss and microgliosis, in a progressive age-dependent manner that mimics the pathology observed in Alzheimer's disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer's disease pathology. We demonstrate that ibudilast-treatment of transgenic rats mitigated hippocampal-dependent spatial memory deficits, as well as hippocampal (hilar subregion) amyloid plaque and tau paired-helical filament load, and microgliosis compared to untreated transgenic rat. Neuronal density analysed across all hippocampal regions was similar in ibudilast-treated transgenic compared to untreated transgenic rats. Interestingly, RNA sequencing analysis of hippocampal tissue showed that ibudilast-treatment affects gene expression levels of the TLR and ubiquitin-proteasome pathways differentially in male and female transgenic rats. Based on the TLR4 signalling pathway, our RNA sequencing data suggest that ibudilast-treatment inhibits IRAK1 activity by increasing expression of its negative regulator IRAK3, and/or by altering TRAF6 and other TLR-related ubiquitin ligase and conjugase levels. Our results support that ibudilast can serve as a repurposed drug that targets multiple pathways including TLR signalling and the ubiquitin/proteasome pathway to reduce cognitive deficits and pathology relevant to Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Deciphering 3D genome conformation is important for understanding gene regulation and cellular function at a spatial level. The recent advances of single cell Hi-C technologies have enabled the profiling of the 3D architecture of DNA within individual cell, which allows us to study the cell-to-cell variability of 3D chromatin organization. Computational approaches are in urgent need to comprehensively analyze the sparse and heterogeneous single cell Hi-C data. Here, we proposed scDEC-Hi-C, a new framework for single cell Hi-C analysis with deep generative neural networks. scDEC-Hi-C outperforms existing methods in terms of single cell Hi-C data clustering and imputation. Moreover, the generative power of scDEC-Hi-C could help unveil the differences of chromatin architecture across cell types. We expect that scDEC-Hi-C could shed light on deepening our understanding of the complex mechanism underlying the formation of chromatin contacts. [ABSTRACT FROM AUTHOR]

Inonotus obliquus is a medicinal fungus with potential for use in various health applications. To better utilize this fungus, this study focused on epidermis and internal tissues of five sclerotia from different regions in Jilin, Inner Mongolia, and Heilongjiang, examining their polyphenols, polysaccharides, flavonoids, and total triterpenes contents. And evaluated the extracts from sclerotia for their total antioxidant capacity and scavenging ability of DPPH free radicals. The study also isolated the associated fungi from the epidermis and internal tissues of three sclerotia. Results revealed that the polyphenol content was higher in the epidermis than in internal tissue of every sclerotium. However, flavonoid and total triterpenoid content was lower in the epidermis of every sclerotium. The polysaccharide content was no significant in different parts of three sclerotia, but the epidermal polysaccharide content in two sclerotia was significantly higher than in internal tissues. The internal tissue extracts from tested sclerotia exhibited better scavenging ability of DPPH free radicals than those from the epidermis. There was no significant difference in total antioxidant capacity among different parts of three sclerotia, and the internal tissues' total antioxidant capacity in two sclerotia was higher than the epidermis. The number and species of associated fungi in the internal tissues were far less than that in the epidermis. The study suggests separating the epidermis and internal tissue for medicinal use. The research provides insights into the bioactive components and associated fungi of I. obliquus to inform its practical application in medicine. [ABSTRACT FROM AUTHOR]

This article offers, for the first time, a comprehensive survey of all accessible (28) Chinese cases in which Chinese judges or lawyers invoked the Unidroit Principles of International Commercial Contracts (PICC) as applicable law or otherwise made a reference to the PICC. The survey has a particular focus on the use of the PICC to interpret or supplement domestic law, which is widely assumed to have no direct impact on the decisions of local courts. Through a detailed analysis that explores the often-times subtle connection between the PICC and judicial reasoning in Chinese courtrooms, the survey rebuts the 'no direct impact' thesis and demonstrates and expounds a range of significant roles the PICC may play in this respect. In doing so, this article also illustrates the case-guiding effect of previously little-known case comments—the dominant vehicle by which Chinese judges presently make the above use of the PICC. [ABSTRACT FROM AUTHOR]

Motivation Single-cell technologies play a crucial role in revolutionizing biological research over the past decade, which strengthens our understanding in cell differentiation, development and regulation from a single-cell level perspective. Single-cell RNA sequencing (scRNA-seq) is one of the most common single cell technologies, which enables probing transcriptional states in thousands of cells in one experiment. Identification of cell types from scRNA-seq measurements is a fundamental and crucial question to answer. Most previous studies directly take gene expression as input while ignoring the comprehensive gene–gene interactions. Results We propose scGraph, an automatic cell identification algorithm leveraging gene interaction relationships to enhance the performance of the cell-type identification. scGraph is based on a graph neural network to aggregate the information of interacting genes. In a series of experiments, we demonstrate that scGraph is accurate and outperforms eight comparison methods in the task of cell-type identification. Moreover, scGraph automatically learns the gene interaction relationships from biological data and the pathway enrichment analysis shows consistent findings with previous analysis, providing insights on the analysis of regulatory mechanism. Availability and implementation scGraph is freely available at https://github.com/QijinYin/scGraph and https://figshare.com/articles/software/scGraph/17157743. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults. Methods We conducted 2 randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received an EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A bacillus Calmette Guerin (BCG) model was established to assess the diagnosis of tuberculosis infection using an EC skin test. Results In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive EC skin test at 1.0 μg/0.1 mL or 0.5 μg/0.1 mL. The area under the curve was 0.95 (95% confidence interval [CI],.91–.97) for the EC skin test at 1.0 μg/0.1 mL at 24–72 hours. Compared with the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI, 77.8–97.2 vs 86.5, 95% CI, 79.5–93.4) and specificity (98.9, 95% CI, 96.0–99.9 vs 96.1, 95% CI, 93.5–97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0–100.0). No serious adverse events related to the EC skin test were observed. Conclusions The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0 μg/0.1 mL, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination. Clinical Trials Registration NCT02389322 and NCT02336542. [ABSTRACT FROM AUTHOR]

Background There are large knowledge gaps on the transmission dynamics of Mycobacterium tuberculosis in settings where both tuberculosis and human immunodeficiency virus (HIV) are endemic. We aimed to assess the infectiousness of tuberculosis patients coinfected with HIV. Methods We systematically searched for studies of contacts of both HIV-positive and HIV-negative tuberculosis index cases. Our primary outcome was Mycobacterium tuberculosis infection in contacts. Data on sputum smear and lung cavitation status of index cases were extracted from each study to assess effect modification. Secondary outcomes included prevalent tuberculosis and HIV in contacts of HIV-positive and HIV-negative index cases. Results Of 5255 original citations identified, 32 studies met inclusion criteria, including 25 studies investigating M. tuberculosis infection (Nparticipants = 36 893), 13 on tuberculosis (Nparticipants = 18 853), and 12 on HIV positivity (Nparticipants = 18 424). Risk of M. tuberculosis infection was lower in contacts of HIV-positive index cases (odds ratio [OR], 0.67, 95% confidence interval [CI],.58–.77) but was heterogeneous (I 2 = 75.1%). Two factors modified this relationship: the lung cavitary status of the index case and immunosuppression (measured through CD4 counts or HIV or acquired immunodeficiency syndrome diagnoses) among index people living with HIV. Rates of HIV were consistently higher in contacts of coinfected index cases (OR, 4.9; 95% CI, 3.0–8.0). This was modified by whether the study was in sub-Saharan Africa (OR, 2.8; 95% CI, 1.6–4.9) or in another global region (OR, 9.8; 95% CI, 5.9–16.3). Conclusions Tuberculosis patients coinfected with HIV are less infectious than HIV-uninfected cases when they have severe immunosuppression or paucibacillary disease. Contacts of coinfected index cases are almost 5 times more likely to also have HIV. [ABSTRACT FROM AUTHOR]

Background: Malaria is a life-threatening disease worldwide, but lacks studies on its incidence at the global level. We aimed to describe global trends and regional diversities in incidence of malaria infection, to make global tailored implications for malaria prevention.Methods: We used the data from the Global Burden of Disease Study 2019. The age-standardized incidence rate (ASR) and absolute number of malaria episodes showed the epidemic status of malaria infection. The estimated annual percentage change of ASR and changes in malaria episodes quantified the malaria incidence trends. The connection between ASRs and traveller number indicated infection risk for travellers.Results: Globally, the malaria ASR decreased by an average 0.80% (95% confidence interval 0.58-1.02%) per year from 1990 to 2019; however, it slightly increased from 3195.32 per 100 000 in 2015 to 3247.02 per 100 000 in 2019. The incidence rate of children under 5 was higher than other age groups. A total of 40 countries had higher ASRs in 2019 than in 2015, with the largest expansion in Cabo Verde (from 2.02 per 100 000 to 597.00 per 100 000). After 2015, the ASRs in high-middle, middle and low-middle Socio-demographic Index regions began to rise and the uptrends remained in 2019. Central, Western and Eastern Sub-Saharan Africa had the highest ASRs since 1990, and traveller number in Eastern and Western Sub-Saharan Africa increased by 31.24 and 7.58%, respectively, from 2017 to 2018. Especially, most countries with ASR over 10 000 per 100 000 had increase in traveller number from 2017 to 2018, with the highest change by 89.56% in Mozambique.Conclusions: Malaria is still a public health threat for locals and travellers in Sub-Saharan Africa and other malaria-endemic areas, especially for children under 5. There were unexpected global uptrends of malaria ASRs from 2015 to 2019. More studies are needed to achieve the goal of malaria elimination. [ABSTRACT FROM AUTHOR]

Background Discordance between the QuantiFERON-TB Gold In-tube (QFT) and tuberculin skin test (TST) is not well understood. We aimed to identify the factors that determine discordance between the TST and QFT when compared to either TST+QFT+ or TST-QFT- results in a medium tuberculosis (TB) burden setting. Methods We conducted a population-based study in Eastern China and administered TSTs and QFTs to participants. We calculated kappa values while constructing multivariable logistic regression models to evaluate predictors of test discordance. We analyzed the predictive value of discordant and concordant test results for progression to TB over 6 years of follow-up. Results Overall, 5405 participants were enrolled; 2043 (37.8%) and 1104 (20.4%) were TST and QFT positive, respectively. There was fair agreement between the TST and the QFT (kappa values between 0.30–0.39 at different TST cutoffs). Agreement was lower among participants vaccinated with Bacillus Calmette-Guerin (BCG; κ, 0.17 versus 0.47 in nonvaccinated participants). TST+QFT- results were associated with decreasing age, smoking, undiagnosed diabetes, and BCG vaccination (adjusted odds ratio, 1.45; 95% confidence interval [CI], 1.11–1.90). TST-QFT+ results were associated with increasing age, male sex, smoking, and diagnosed diabetes. Compared to participants with TST-QFT- results, QFT+ and TST+QFT+ participants were 6.3 (95% CI, 1.9–20.4) and 7.5 (95%CI, 2.3–25.1) times more likely to progress to TB, respectively. Conclusions In this population-based study of over 5000 participants from a medium TB burden region, the test agreement between QFT and TST was fair overall and we found multiple novel predictors of discordant QFT/TST results. QFT provides a substantial improvement to the TST among these populations and was multi-fold better at predicting progression to TB. [ABSTRACT FROM AUTHOR]

Motivation Accurate prediction of cancer drug response (CDR) is challenging due to the uncertainty of drug efficacy and heterogeneity of cancer patients. Strong evidences have implicated the high dependence of CDR on tumor genomic and transcriptomic profiles of individual patients. Precise identification of CDR is crucial in both guiding anti-cancer drug design and understanding cancer biology. Results In this study, we present DeepCDR which integrates multi-omics profiles of cancer cells and explores intrinsic chemical structures of drugs for predicting CDR. Specifically, DeepCDR is a hybrid graph convolutional network consisting of a uniform graph convolutional network and multiple subnetworks. Unlike prior studies modeling hand-crafted features of drugs, DeepCDR automatically learns the latent representation of topological structures among atoms and bonds of drugs. Extensive experiments showed that DeepCDR outperformed state-of-the-art methods in both classification and regression settings under various data settings. We also evaluated the contribution of different types of omics profiles for assessing drug response. Furthermore, we provided an exploratory strategy for identifying potential cancer-associated genes concerning specific cancer types. Our results highlighted the predictive power of DeepCDR and its potential translational value in guiding disease-specific drug design. Availability and implementation DeepCDR is freely available at https://github.com/kimmo1019/DeepCDR. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

This comment highlights the major civil or commercial (mostly contract) law provisions in 24 judicial documents newly released by the Supreme People's Court or High People's Courts in China in response to the outbreak of COVID-19 and assesses the significance of key changes to the pre-pandemic law. It concludes by noting the increased role of the doctrine of the change of circumstances and the 'contract purpose' test, the emphasis placed on consensual solutions (by way of mediation and contract renegotiation), and the flexibility and relatively clearer guidance afforded to lower courts in their adjudication of disputes arising in connection with COVID-19. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic may impede global tuberculosis elimination goals. In Jiangsu Province, China, tuberculosis notifications dropped 52% in 2020 compared to 2015–2019. Treatment completion and screening for drug resistance decreased continuously in 2020. Urgent attention must be paid to tuberculosis control efforts during and after the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Gene flow between species may cause variations in branch length and topology of gene tree, which are beyond the expected variations from ancestral processes. These additional variations make it difficult to estimate parameters during speciation with gene flow, as the pattern of these additional variations differs with the relationship between isolation and migration. As far as we know, most methods rely on the assumption about the relationship between isolation and migration by a given model, such as the isolation-with-migration model, when estimating parameters during speciation with gene flow. In this article, we develop a multispecies coalescent approach which does not rely on any assumption about the relationship between isolation and migration when estimating parameters and is called mstree. mstree is available at https://github.com/liujunfengtop/MStree/ and uses some mathematical inequalities among several factors, which include the species divergence time, the ancestral population size, and the number of gene trees, to estimate parameters during speciation with gene flow. Using simulations, we show that the estimated values of ancestral population sizes and species divergence times are close to the true values when analyzing the simulation data sets, which are generated based on the isolation-with-initial-migration model, secondary contact model, and isolation-with-migration model. Therefore, our method is able to estimate ancestral population sizes and speciation times in the presence of different modes of gene flow and may be helpful to test different theories of speciation. [ABSTRACT FROM AUTHOR]

Motivation Advances in high-throughput genotyping and sequencing technologies during recent years have revealed essential roles of non-coding regions in gene regulation. Genome-wide association studies (GWAS) suggested that a large proportion of risk variants are located in non-coding regions and remain unexplained by current expression quantitative trait loci catalogs. Interpreting the causal effects of these genetic modifications is crucial but difficult owing to our limited knowledge of how regulatory elements function. Although several computational methods have been designed to prioritize regulatory variants that substantially impact human phenotypes, few of them achieve consistently high performance even when large-scale multi-omic data are integrated. Results We propose a novel multi-task framework based on Bayesian deep neural networks, MtBNN, to quantify the deleterious impact of single nucleotide polymorphisms in non-coding genomic regions. With the high-efficiency provided by the multi-task Bayesian framework to integrate information from different sources, MtBNN is capable of extracting features from genomic sequences of large-scale chromatin-profiling data, such as chromatin accessibility and transcript factor binding affinities, and calculating the distribution of the probability that a non-coding variant disrupts regulatory activities. A series of comprehensive experiments show that MtBNN quantifies the functional impact of cis-regulatory variations with high accuracy, including expression quantitative trait locus, DNase I sensitivity quantitative trait locus and functional genetic variants located within ATAC-peaks that affect the accessibility of the corresponding peak and achieves significantly better performance than the existing methods. Moreover, MtBNN has applications in the discovery of potentially causal disease-associated single-nucleotide polymorphisms (SNPs), thus helping fine-map the GWAS SNPs. Availability and implementation Code can be downloaded from https://github.com/Zoesgithub/MtBNN. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Hi-C is a genome-wide technology for investigating 3D chromatin conformation by measuring physical contacts between pairs of genomic regions. The resolution of Hi-C data directly impacts the effectiveness and accuracy of downstream analysis such as identifying topologically associating domains (TADs) and meaningful chromatin loops. High resolution Hi-C data are valuable resources which implicate the relationship between 3D genome conformation and function, especially linking distal regulatory elements to their target genes. However, high resolution Hi-C data across various tissues and cell types are not always available due to the high sequencing cost. It is therefore indispensable to develop computational approaches for enhancing the resolution of Hi-C data. Results We proposed hicGAN, an open-sourced framework, for inferring high resolution Hi-C data from low resolution Hi-C data with generative adversarial networks (GANs). To the best of our knowledge, this is the first study to apply GANs to 3D genome analysis. We demonstrate that hicGAN effectively enhances the resolution of low resolution Hi-C data by generating matrices that are highly consistent with the original high resolution Hi-C matrices. A typical scenario of usage for our approach is to enhance low resolution Hi-C data in new cell types, especially where the high resolution Hi-C data are not available. Our study not only presents a novel approach for enhancing Hi-C data resolution, but also provides fascinating insights into disclosing complex mechanism underlying the formation of chromatin contacts. Availability and implementation We release hicGAN as an open-sourced software at https://github.com/kimmo1019/hicGAN. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Focusing on two recent decisions handed down by the highest authority in the United Kingdom and Australia, this article attempts to critically review the common law rule dealing with contractual penalties through a comparison with its 'functional equivalent' under Chinese law. In the above two decisions, the UK and Australian courts effectively tightened the test for a penalty clause by making it harder for a contracting party to escape from the provision of the contract. However, the decision to retain the penalty jurisdiction remains a controversial one, and the historical and comparative analysis offered by the UK Supreme Court to justify the retention is particularly tenuous. In this regard, a comparison with Chinese law, which bears diametrical differences from the common law in both systematic design and under-structure, helps to bring out the incoherency between rule and rationale under the common law. By tracing the different historical origins and paths of evolution of both the common law and Chinese rules, the article offers a full-fledged comparison that penetrates the surface of legal texts and challenges the long-held assumption that the penalty jurisdiction exercises a fairness control by reference to the time when the contract is made. It concludes that the true rationale of allowing judicial intervention in agreed damage clauses lies in the existence of a discretionary power to achieve remedial justice and that the common law penalty rule should be abolished given its inability to adapt to this rationale. [ABSTRACT FROM AUTHOR]

Motivation: A majority of known genetic variants associated with human-inherited diseases lie in non-coding regions that lack adequate interpretation, making it indispensable to systematically discover functional sites at the whole genome level and precisely decipher their implications in a comprehensive manner. Although computational approaches have been complementing high- throughput biological experiments towards the annotation of the human genome, it still remains a big challenge to accurately annotate regulatory elements in the context of a specific cell type via automatic learning of the DNA sequence code from large-scale sequencing data. Indeed, the development of an accurate and interpretable model to learn the DNA sequence signature and further enable the identification of causative genetic variants has become essential in both genomic and genetic studies. Results: We proposed Deopen, a hybrid framework mainly based on a deep convolutional neural network, to automatically learn the regulatory code of DNA sequences and predict chromatin accessibility. In a series of comparison with existing methods, we show the superior performance of our model in not only the classification of accessible regions against background sequences sampled at random, but also the regression of DNase-seq signals. Besides, we further visualize the convolutional kernels and show the match of identified sequence signatures and known motifs. We finally demonstrate the sensitivity of our model in finding causative noncoding variants in the analysis of a breast cancer dataset. We expect to see wide applications of Deopen with either public or in-house chromatin accessibility data in the annotation of the human genome and the identification of non-coding variants associated with diseases. [ABSTRACT FROM AUTHOR]

Starch composition and the amount in endosperm, both of which contribute dramatically to seed yield, cooking quality, and taste in cereals, are determined by a series of complex biochemical reactions. However, the mechanism regulating starch biosynthesis in cereal seeds is not well understood. This study showed that OsbZIP58, a bZIP transcription factor, is a key transcriptional regulator controlling starch synthesis in rice endosperm. OsbZIP58 was expressed mainly in endosperm during active starch synthesis. osbzip58 null mutants displayed abnormal seed morphology with altered starch accumulation in the white belly region and decreased amounts of total starch and amylose. Moreover, osbzip58 had a higher proportion of short chains and a lower proportion of intermediate chains of amylopectin. Furthermore, OsbZIP58 was shown to bind directly to the promoters of six starch-synthesizing genes, OsAGPL3, Wx, OsSSIIa, SBE1, OsBEIIb, and ISA2, and to regulate their expression. These findings indicate that OsbZIP58 functions as a key regulator of starch synthesis in rice seeds and provide new insights into seed quality control. [ABSTRACT FROM AUTHOR]

Background. Syphilis has made a rapid resurgence in China, especially among high-risk groups including female sex workers (FSWs).Methods. Two cities in each of 3 provinces in South China were chosen and allocated to intervention or control arms. The intervention consisted of enhancing community-based syphilis screening outreach intervention with comprehensive sexually transmitted infection services at designated clinics while the control maintained routine intervention activities. Generalized linear modeling was used to examine effect of the intervention on incident syphilis infection.Results. A total of 8275 women were eligible, and 3597 women enrolled (n = 2011 in control arm, n = 1586 in intervention arm) in the study. The median follow-up duration was 375 days (interquartile range, 267–475). Syphilis incidence density in the intervention group was reduced by 70% (95% confidence interval, 53%–81%) compared with the incidence in the control arm. The syphilis prevention intervention benefits were robust among FSWs at low-tier venues, individuals with less than high school education, migrants, and women who did not report condom use during the last episode of sex.Conclusions. Integrated sexually transmitted infection and human immunodeficiency virus prevention strategies substantially reduce syphilis incidence among FSWs, especially among those at low-tier venues. This intervention suggests the need for scaling up comprehensive FSW programs in China. [ABSTRACT FROM PUBLISHER]

This article investigates whether market competition enhances the incentives of Chinese industrial firms to avoid corporate income tax. We estimate the effects of competition on the relationship between firms’ reported accounting profits and their imputed profits based on the national income account. To cope with measurement errors and potential endogeneity, we use instrumental variables, exogenous policy shocks and other robustness analysis. We find robust and consistent evidence that firms in more competitive environments engage in more tax avoidance activities. Moreover, all else equal, firms in relatively disadvantageous positions demonstrate stronger incentives to avoid corporate income tax. [ABSTRACT FROM AUTHOR]

Aims: The maladaptive response to biomechanical stress is a fundamental response in heart disease. Loss of the 3′-lipid phosphatase, phosphatase and tensin homolog deleted on chromosome ten (PTEN), is associated with increased phosphorylation of Akt/protein kinase B and glycogen synthase kinase-β. We hypothesize that these key changes will halt the development of pathological hypertrophy and the progression to heart failure in response to pressure overload. [ABSTRACT FROM PUBLISHER]