RAVAR: a curated repository for rare variant-trait associations.

Rare variants contribute significantly to the genetic causes of complex traits, as they can have much larger effects than common variants and account for much of the missing heritability in genome-wide association studies. The emergence of UK Biobank scale datasets and accurate gene-level rare variant-trait association testing methods have dramatically increased the number of rare variant associations that have been detected. However, no systematic collection of these associations has been carried out to date, especially at the gene level. To address the issue, we present the Rare Variant Association Repository (RAVAR), a comprehensive collection of rare variant associations. RAVAR includes 95 047 high-quality rare variant associations (76186 gene-level and 18 861 variant-level associations) for 4429 reported traits which are manually curated from 245 publications. RAVAR is the first resource to collect and curate published rare variant associations in an interactive web interface with integrated visualization, search, and download features. Detailed gene and SNP information are provided for each association, and users can conveniently search for related studies by exploring the EFO tree structure and interactive Manhattan plots. RAVAR could vastly improve the accessibility of rare variant studies. RAVAR is freely available for all users without login requirement at http://www.ravar.bio.

AGF-PPIS: A protein-protein interaction site predictor based on an attention mechanism and graph convolutional networks.

Protein-protein interactions play an important role in various biological processes. Interaction among proteins has a wide range of applications. Therefore, the correct identification of protein-protein interactions sites is crucial. In this paper, we propose a novel predictor for protein-protein interactions sites, AGF-PPIS, where we utilize a multi-head self-attention mechanism (introducing a graph structure), graph convolutional network, and feed-forward neural network. We use the Euclidean distance between each protein residue to generate the corresponding protein graph as the input of AGF-PPIS. On the independent test dataset Test_60, AGF-PPIS achieves superior performance over comparative methods in terms of seven different evaluation metrics (ACC, precision, recall, F1-score, MCC, AUROC, AUPRC), which fully demonstrates the validity and superiority of the proposed AGF-PPIS model. The source codes and the steps for usage of AGF-PPIS are available at https://github.com/fxh1001/AGF-PPIS.

msBERT-Promoter: a multi-scale ensemble predictor based on BERT pre-trained model for the two-stage prediction of DNA promoters and their strengths.

BACKGROUND: A promoter is a specific sequence in DNA that has transcriptional regulatory functions, playing a role in initiating gene expression. Identifying promoters and their strengths can provide valuable information related to human diseases. In recent years, computational methods have gained prominence as an effective means for identifying promoter, offering a more efficient alternative to labor-intensive biological approaches. RESULTS: In this study, a two-stage integrated predictor called "msBERT-Promoter" is proposed for identifying promoters and predicting their strengths. The model incorporates multi-scale sequence information through a tokenization strategy and fine-tunes the DNABERT model. Soft voting is then used to fuse the multi-scale information, effectively addressing the issue of insufficient DNA sequence information extraction in traditional models. To the best of our knowledge, this is the first time an integrated approach has been used in the DNABERT model for promoter identification and strength prediction. Our model achieves accuracy rates of 96.2% for promoter identification and 79.8% for promoter strength prediction, significantly outperforming existing methods. Furthermore, through attention mechanism analysis, we demonstrate that our model can effectively combine local and global sequence information, enhancing its interpretability. CONCLUSIONS: msBERT-Promoter provides an effective tool that successfully captures sequence-related attributes of DNA promoters and can accurately identify promoters and predict their strengths. This work paves a new path for the application of artificial intelligence in traditional biology.

webTWAS: a resource for disease candidate susceptibility genes identified by transcriptome-wide association study.

The development of transcriptome-wide association studies (TWAS) has enabled researchers to better identify and interpret causal genes in many diseases. However, there are currently no resources providing a comprehensive listing of gene-disease associations discovered by TWAS from published GWAS summary statistics. TWAS analyses are also difficult to conduct due to the complexity of TWAS software pipelines. To address these issues, we introduce a new resource called webTWAS, which integrates a database of the most comprehensive disease GWAS datasets currently available with credible sets of potential causal genes identified by multiple TWAS software packages. Specifically, a total of 235 064 gene-diseases associations for a wide range of human diseases are prioritized from 1298 high-quality downloadable European GWAS summary statistics. Associations are calculated with seven different statistical models based on three popular and representative TWAS software packages. Users can explore associations at the gene or disease level, and easily search for related studies or diseases using the MeSH disease tree. Since the effects of diseases are highly tissue-specific, webTWAS applies tissue-specific enrichment analysis to identify significant tissues. A user-friendly web server is also available to run custom TWAS analyses on user-provided GWAS summary statistics data. webTWAS is freely available at http://www.webtwas.net.

Fatigue, sleep and physical activity in postoperative patients with pituitary adenomas: A survey.

BACKGROUND: The condition and correlation of fatigue, sleep and physical activity in postoperative patients with pituitary adenomas remain unclear. This survey aimed to evaluate the current status and influencing factors of fatigue, sleep and physical activity in postoperative patients with pituitary adenomas. METHODS: Patients undergoing pituitary adenoma resection in two tertiary hospitals from November 2019 to November 2021 were included. The general data questionnaire, Multidimensional Fatigue Inventory (MFI-20), Pittsburgh Sleep Quality Index (PSQI) and international physical activity questionnaire were used for data analysis. RESULTS: In total, 184 patients with pituitary adenomas were included. The postoperative patients with pituitary adenomas had a high level of fatigue. In total, 34 (18.5%) patients had low level of physical activity, 76(41.3%) patients had medium level of physical activity and 74 (40.2%) had high level of physical activity. Postoperative time, PSQI, physical activity level and gender were the influencing factors of fatigue in patients with pituitary adenomas (all P < 0.05). CONCLUSIONS: Postoperative patients with pituitary adenomas have a higher level of fatigue, and it is related to reduced sleep quality and activity. Relevant nursing measures should be taken according to the influencing factors of fatigue to reduce the fatigue of postoperative patients with pituitary adenomas.

Goals and approaches for each processing step for single-cell RNA sequencing data.

Single-cell RNA sequencing (scRNA-seq) has enabled researchers to study gene expression at the cellular level. However, due to the extremely low levels of transcripts in a single cell and technical losses during reverse transcription, gene expression at a single-cell resolution is usually noisy and highly dimensional; thus, statistical analyses of single-cell data are a challenge. Although many scRNA-seq data analysis tools are currently available, a gold standard pipeline is not available for all datasets. Therefore, a general understanding of bioinformatics and associated computational issues would facilitate the selection of appropriate tools for a given set of data. In this review, we provide an overview of the goals and most popular computational analysis tools for the quality control, normalization, imputation, feature selection and dimension reduction of scRNA-seq data.

Anticancer peptides prediction with deep representation learning features.

Anticancer peptides constitute one of the most promising therapeutic agents for combating common human cancers. Using wet experiments to verify whether a peptide displays anticancer characteristics is time-consuming and costly. Hence, in this study, we proposed a computational method named identify anticancer peptides via deep representation learning features (iACP-DRLF) using light gradient boosting machine algorithm and deep representation learning features. Two kinds of sequence embedding technologies were used, namely soft symmetric alignment embedding and unified representation (UniRep) embedding, both of which involved deep neural network models based on long short-term memory networks and their derived networks. The results showed that the use of deep representation learning features greatly improved the capability of the models to discriminate anticancer peptides from other peptides. Also, UMAP (uniform manifold approximation and projection for dimension reduction) and SHAP (shapley additive explanations) analysis proved that UniRep have an advantage over other features for anticancer peptide identification. The python script and pretrained models could be downloaded from https://github.com/zhibinlv/iACP-DRLF or from http://public.aibiochem.net/iACP-DRLF/.

Critical downstream analysis steps for single-cell RNA sequencing data.

Single-cell RNA sequencing (scRNA-seq) has enabled us to study biological questions at the single-cell level. Currently, many analysis tools are available to better utilize these relatively noisy data. In this review, we summarize the most widely used methods for critical downstream analysis steps (i.e. clustering, trajectory inference, cell-type annotation and integrating datasets). The advantages and limitations are comprehensively discussed, and we provide suggestions for choosing proper methods in different situations. We hope this paper will be useful for scRNA-seq data analysts and bioinformatics tool developers.

webSCST: an interactive web application for single-cell RNA-sequencing data and spatial transcriptomic data integration.

SUMMARY: Integrative analysis of single-cell RNA-sequencing (scRNA-seq) data with spatial data for the same species and organ would provide each cell sample with a predictive spatial location, which would facilitate biological study. However, publicly available spatial sequencing datasets for specific species and organs are rare and are often displayed in different formats. In this study, we introduce a new web-based scRNA-seq analysis tool, webSCST, that integrates well-organized spatial transcriptome sequencing datasets categorized by species and organs, provides a user-friendly interface for raw single-cell processing with popular integration methods and allows users to submit their raw scRNA-seq data once to obtain predicted spatial locations for each cell type. AVAILABILITY AND IMPLEMENTATION: webSCST implemented in shiny with all major browsers supported is available at http://www.webscst.com. webSCST is also freely available as an R package at https://github.com/swsoyee/webSCST.

Protein-DNA/RNA interactions: Machine intelligence tools and approaches in the era of artificial intelligence and big data.

With the development of artificial intelligence (AI) technologies and the availability of large amounts of biological data, computational methods for proteomics have undergone a developmental process from traditional machine learning to deep learning. This review focuses on computational approaches and tools for the prediction of protein-DNA/RNA interactions using machine intelligence techniques. We provide an overview of the development progress of computational methods and summarize the advantages and shortcomings of these methods. We further compiled applications in tasks related to the protein-DNA/RNA interactions, and pointed out possible future application trends. Moreover, biological sequence-digitizing representation strategies used in different types of computational methods are also summarized and discussed.

Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.

The Heterotrophic Bacterium Cupriavidus pinatubonensis JMP134 Oxidizes Sulfide to Sulfate with Thiosulfate as a Key Intermediate.

Heterotrophic bacteria actively participate in the biogeochemical cycle of sulfur on Earth. The heterotrophic bacterium Cupriavidus pinatubonensis JMP134 contains several enzymes involved in sulfur oxidation, but how these enzymes work together to oxidize sulfide in the bacterium has not been studied. Using gene-deletion and whole-cell assays, we determined that the bacterium uses sulfide:quinone oxidoreductase to oxidize sulfide to polysulfide, which is further oxidized to sulfite by persulfide dioxygenase. Sulfite spontaneously reacts with polysulfide to produce thiosulfate. The sulfur-oxidizing (Sox) system oxidizes thiosulfate to sulfate. Flavocytochrome c sulfide dehydrogenase enhances thiosulfate oxidation by the Sox system but couples with the Sox system for sulfide oxidation to sulfate in the absence of sulfide:quinone oxidoreductase. Thus, C. pinatubonensis JMP134 contains a main pathway and a contingent pathway for sulfide oxidation.IMPORTANCE We establish a new pathway of sulfide oxidation with thiosulfate as a key intermediate in Cupriavidus pinatubonensis JMP134. The bacterium mainly oxidizes sulfide by using sulfide:quinone oxidoreductase, persulfide dioxygenase, and the Sox system with thiosulfate as a key intermediate. Although the purified and reconstituted Sox system oxidizes sulfide, its rate of sulfide oxidation in C. pinatubonensis JMP134 is too low to be physiologically relevant. The findings reveal how these sulfur-oxidizing enzymes participate in sulfide oxidation in a single bacterium.

Capsaicin combined with ice stimulation improves swallowing function in patients with dysphagia after stroke: A randomised controlled trial.

BACKGROUND: Dysphagia is a common condition after stroke, and it is associated with many complications. Early and effective treatments are essential to the prognosis of patients with dysphagia. We aimed to evaluate the effects and safety of capsaicin combined with ice stimulation in patients with dysphagia after stroke. METHODS: Patients with dysphagia admitted to our hospital from December 2017 to December 2019 were included. The control group received the ice stimulation, and the experimental group received the combined capsaicin and ice stimulation. The grade of water swallowing test (WST), standard swallowing assessment (SSA) scores and the serum substance P level was compared between control (ice only) and experimental group (capsaicin plus ice). RESULTS: No differences before treatment and significance following treatment in each group (before and after) and between groups (capsaicin plus ice vs ice only) were found (all P > .05); the SSA scores were significantly reduced after intervention for both groups (all P < .001), and after intervention, SSA score in experimental group was significantly less than that of control group (P < .001). After intervention, the number of patients graded as WST level I-II in experimental group was significantly more than that of control group (P < .001); the serum substance P level was significantly increased after intervention for both groups (all P < .05), and after intervention, the serum substance P level in experimental group was significantly higher than that of control group (P = .007). CONCLUSIONS: The combined use of capsaicin with ice stimulation is beneficial to the recovery of swallowing function of patients with dysphagia, which should be included into the clinical practice.

Photodegradation of 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P) in coastal seawaters: Important role of DOM.

Benzotriazole UV stabilizers (BT-UVs) have attracted concerns due to their ubiquitous occurrence in the aquatic environment, and their bioaccumulative and toxic properties. However, little is known about their aquatic environmental degradation behavior. In this study, photodegradation of a representative of BT-UVs, 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P), was investigated under simulated sunlight irradiation. Results show that UV-P photodegrades slower under neutral conditions (neutral form) than under acidic or alkaline conditions (cationic and anionic forms). Indirect photodegradation is a dominant elimination pathway of UV-P in coastal seawaters. Dissolved organic matter (DOM) from seawaters accelerate the photodegradation rates mainly through excited triplet DOM (3DOM⁎), and the roles of singlet oxygen and hydroxyl radical are negligible in the matrixes. DOM from seawaters impacted by mariculture exhibits higher steady-state concentration of 3DOM⁎ ([3DOM⁎]) relative to those from pristine seawaters, leading to higher photosensitizing effects on the photodegradation. Halide ions inhibit the DOM-sensitized photodegradation of UV-P by decreasing [3DOM⁎]. Photodegradation half-lives of UV-P are estimated to range from 24.38 to 49.66 hr in field water bodies of the Yellow River estuary. These results are of importance for assessing environmental fate and risk UV-P in coastal water bodies.

Roles of citric acid in conjunction with saline nebulization in experimental tracheostomy in guinea pigs.

PURPOSE: Tracheostomy usually accompanied by the impairment of cough reflex, which may affect the clearance of secretions and result in the occurrence and development of pulmonary inflammation. Previous research has demonstrated that citric acid could effectively evoke cough. However, there are limited data available on this topic specific to the cough stimulation method, and the roles of citric acid in tracheostomy still remain obscure. The aims of present study were to identify the potential roles of citric acid in conjunction with saline nebulization in tracheostomy in guinea pigs. MATERIALS AND METHODS: Experimental tracheostomy model was induced in guinea pigs, and different nebulization interventions were implemented. The expression of P-selectin and platelet count were analyzed by flow cytometer and automatic globulimeter, the histological changes in trachea and lung tissue were assessed by hematoxylin and eosin staining, and the inflammatory cytokines and substance P (SP) levels in bronchoalveolar lavage fluid were evaluated by enzyme-linked immunosorbent assay. RESULTS: Tracheostomy resulted in the disorder of trachea mucosa and cilia, the inflammatory cell infiltration in lung tissue, the increase of IL-6, TNF-α levels and the decrease of SP level. Citric acid alone increase the SP level, and the joint action of citric acid and saline nebulization further showed significantly beneficial effects on pathological, inflammatory changes and SP level. CONCLUSIONS: Citric acid combined with saline nebulization contributes to the alleviation of tracheotomy-induced tracheal damage and pulmonary inflammation in an experimental tracheostomy model in guinea pigs. This may provide novel insights into the inflammation management and cough recovery after tracheostomy.

The physician-nurse collaboration in feeding critically ill patients: A multicenter survey.

AIMS: Describe physician-nurse collaboration in feeding critically ill patients and explore the influence factors related to this collaboration, which can provide information for clinical practice and future studies. BACKGROUND: Appropriate nutrition support is essential and significant for critically ill patients, and the importance of physician-nurse collaboration in other fields has been confirmed, yet there are limited studies put insights into the status of physician-nurse collaboration in feeding critically ill patients. METHODS: A cross-sectional survey with a covering of 15 hospitals was conducted. A 21-item questionnaire was administered to physicians and nurses in critical care units. Descriptive statistics, univariate and multiple stepwise regression analysis were performed to evaluate the physician-nurse collaboration in feeding critically ill patients. RESULTS: A total of 331 respondents completed the questionnaire. Nurses and physicians were found to have differing perceptions of the physician-nurse collaboration in feeding critically ill patients, with nurses reporting lower levels of collaboration. Nurses consistently gave more negative responses on every survey question compared with physicians. Age, education and clinical experience significantly influenced the nurses' perceptions of cooperation, and age, education, ICU type, and seniority affected the physicians' perceptions of collaboration. CONCLUSIONS: Physicians, nurses and hospital administrators should highlight the physician-nurse collaboration in feeding critically ill patients and reinforce the cooperation based on potential influencing factors. Further research is required to establish feasible cooperative protocol and evaluate the effectiveness of the approach.

Recombinant Escherichia coli with sulfide:quinone oxidoreductase and persulfide dioxygenase rapidly oxidises sulfide to sulfite and thiosulfate via a new pathway.

Many heterotrophic bacteria contain sulfide:quinone oxidoreductase (SQR) and persulfide dioxygenase (PDO) genes. It is unclear how these enzymes cooperate to oxidise sulfide in bacteria. Cupriavidus pinatubonensis JMP134 contains a gene cluster of sqr and pdo, and their functions were analysed in Escherichia coli. Recombinant E. coli cells with SQR and PDO rapidly oxidised sulfide to thiosulfate and sulfite. The SQR also contains a DUF442 domain that was shown to have rhodanese activities. E. coli cells with PDO and SQR-C94S, an active site mutant of the rhodanese domain, oxidised sulfide to thiosulfate with transitory accumulation of polysulfides. Cellular and enzymatic evidence showed that DUF442 speeds up the reaction of polysulfides with glutathione to produce glutathione persulfide (GSSH). Thus, SQR oxidises sulfide to polysulfides; rhodanese enhances the reaction of polysulfides with glutathione to produce GSSH; PDO oxidises GSSH to sulfite; sulfite spontaneously reacts with polysulfides to generate thiosulfate. The pathway is different from the proposed mitochondrial pathway because it has polysulfides, that is, disulfide and trisulfide, as intermediates. The data demonstrated that heterotrophic bacteria with SQR and PDO can rapidly oxidise sulfide to thiosulfate and sulfite, providing the foundation for using heterotrophic bacteria with SQR and PDO for sulfide bioremediation.

The role of osmolality in saline fluid nebulization after tracheostomy: time for changing?

BACKGROUND: Saline fluid nebulization is highly recommend to combat the complications following tracheostomy, yet the understandings on the role of osmolality in saline solution for nebulization remain unclear. OBJECTIVES: To investigate the biological changes in the early stage after tracheostomy, to verify the efficacy of saline fluid nebulization and explore the potential role of osmolality of saline nebulization after tracheostomy. METHODS: Sprague-Dawley rats undergone tracheostomy were taken for study model, the sputum viscosity was detected by rotational viscometer, the expressions of TNF-α, AQP4 in bronchoalveolar lavage fluid were assessed by western blot analysis, and the histological changes in endothelium were evaluated by HE staining and scanning electron microscopy (SEM). RESULTS: Study results revealed that tracheostomy gave rise to the increase of sputum viscosity, TNF-α and AQP4 expression, mucosa and cilia damage, yet the saline fluid nebulization could significantly decrease the changes of those indicators, besides, the hypertonic, isotonic and hypertonic saline nebulization produced different efficacy. CONCLUSIONS: Osmolality plays an important role in the saline fluid nebulization after tracheostomy, and 3% saline fluid nebulization seems to be more beneficial, further studies on the role of osmolality in saline fluid nebulization are warranted.

Pressure Combined with Ischemia/Reperfusion Injury Induces Deep Tissue Injury via Endoplasmic Reticulum Stress in a Rat Pressure Ulcer Model.

Pressure ulcer is a complex and significant health problem in long-term bedridden patients, and there is currently no effective treatment or efficient prevention method. Furthermore, the molecular mechanisms and pathogenesis contributing to the deep injury of pressure ulcers are unclear. The aim of the study was to explore the role of endoplasmic reticulum (ER) stress and Akt/GSK3ß signaling in pressure ulcers. A model of pressure-induced deep tissue injury in adult Sprague-Dawley rats was established. Rats were treated with 2-h compression and subsequent 0.5-h release for various cycles. After recovery, the tissue in the compressed regions was collected for further analysis. The compressed muscle tissues showed clear cellular degenerative features. First, the expression levels of ER stress proteins GRP78, CHOP, and caspase-12 were generally increased compared to those in the control. Phosphorylated Akt and phosphorylated GSK3ß were upregulated in the beginning of muscle compression, and immediately significantly decreased at the initiation of ischemia-reperfusion injury in compressed muscles tissue. These data show that ER stress may be involved in the underlying mechanisms of cell degeneration after pressure ulcers and that the Akt/GSK3ß signal pathway may play an important role in deep tissue injury induced by pressure and ischemia/reperfusion.

Ubiquitin D is an independent prognostic marker for survival in stage IIB-IIC colon cancer patients treated with 5-fluoruracil-based adjuvant chemotherapy.

BACKGROUND: Postoperative 5-fluoruracil (5-FU)-based adjuvant chemotherapy is recommended for stage II colon cancer patients with high conventional risk factors; however, some of these patients still experience tumor recurrence. Identifying novel biomarkers to distinguish the risk of tumor recurrence after surgery is vital for improving their prognoses. We previously showed that ubiquitin D (UBD) can predict the prognosis of colon cancer; however, there are limited data on whether UBD is an independent prognostic factor for stage II patients treated with 5-FU-based adjuvant chemotherapy. METHODS: Quantitative real-time PCR and Western blot analyses were used to examine UBD expression in randomly selected stage II patients' tumor tissues. UBD expression and p65 distribution were assessed using immunohistochemistry in paraffin-embedded specimens from the 101 tumor recurrence patients and 178 nonrelapse patients who received postoperative 5-FU-based adjuvant chemotherapy. RESULTS: UBD expression, both at transcriptional and posttranscriptional levels, was higher in relapse tumors (P < 0.001). Immunohistochemistry staining of UBD and p65 showed significant differences between the two groups (P < 0.001). Patients with tumor tissues that UBD-positive expression alone or in combination with p65 nuclei translocation recurred early had a significantly shorter survival time (P < 0.001), especially in stage IIB-IIC patients. UBD-positive expression accompanied with p65 nuclei translocation was a significant independent predictive high risk factor for overall survival (HR 8.76; 95% CI, 5.35-14.27; P = 0.004) and disease-free survival (HR 5.70; 95% CI, 1.43-11.55; P = 0.016). CONCLUSION: UBD may help to identify recurrent risk in stage IIB-IIC colon cancer patients and further predict which patients benefit from postoperative 5-FU-based adjuvant chemotherapy.