Precise prediction of phase-separation key residues by machine learning.

Understanding intracellular phase separation is crucial for deciphering transcriptional control, cell fate transitions, and disease mechanisms. However, the key residues, which impact phase separation the most for protein phase separation function have remained elusive. We develop PSPHunter, which can precisely predict these key residues based on machine learning scheme. In vivo and in vitro validations demonstrate that truncating just 6 key residues in GATA3 disrupts phase separation, enhancing tumor cell migration and inhibiting growth. Glycine and its motifs are enriched in spacer and key residues, as revealed by our comprehensive analysis. PSPHunter identifies nearly 80% of disease-associated phase-separating proteins, with frequent mutated pathological residues like glycine and proline often residing in these key residues. PSPHunter thus emerges as a crucial tool to uncover key residues, facilitating insights into phase separation mechanisms governing transcriptional control, cell fate transitions, and disease development.

Carbonized Cellulose Aerogel Derived from Waste Pomelo Peel for Rapid Hemostasis of Trauma-Induced Bleeding.

Uncontrollable massive bleeding caused by trauma will cause the patient to lose a large amount of blood and drop body temperature quickly, resulting in hemorrhagic shock. This study aims to develop a hemostatic product for hemorrhage management. In this study, waste pomelo peel as raw material is chosen. It underwent processes of carbonization, purification, and freeze-drying. The obtained carbonized pomelo peel (CPP) is hydrophilic and exhibits a porous structure (nearly 80% porosity). The water/blood absorption ratio is significantly faster than the commercial Gelfoam and has a similar water/blood absorption capacity. In addition, the CPP showed a water-triggered shape-recoverable ability. Moreover, the CPP shows ideal cytocompatibility and blood compatibility in vitro and favorable tissue compatibility after long terms of subcutaneous implantation. Furthermore, CPP can absorb red blood cells and fibrin. It also can absorb platelets and activate platelets, and it is capable of achieving rapid hemostasis on the rat tail amputation and hepatectomized hemorrhage model. In addition, the CPP not only can quickly stop bleeding in the rat liver-perforation and rabbit heart uncontrolled hemorrhage models, but also promotes rat liver and rabbit heart tissue regeneration in situ. These results suggest the CPP has shown great potential for managing uncontrolled hemorrhage.

The impact of weight loss on renal function in individuals with obesity and type 2 diabetes: a comprehensive review.

Obesity and Type 2 Diabetes (T2D) are two highly prevalent diseases that exhibit a complex interplay between them. Obesity serves as a primary risk factor for the development of T2D, and conversely, individuals with T2D often exhibit comorbid obesity. Renal dysfunction emerges as a critical consequence of the convergence of obesity and Type 2 Diabetes, contributing significantly to the overall burden of complications associated with these conditions. Recognizing the profound implications of renal dysfunction in individuals contending with both obesity and Type 2 Diabetes, interventions targeting weight loss have gained prominence as potential therapeutic avenues. Weight loss not only addresses the primary risk factor of obesity but also holds the promise of mitigating the progression of Type 2 Diabetes and its associated renal complications. This comprehensive review aims to explore the impact of weight loss on renal function in individuals contending with the convergence of obesity and T2D.

Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Self-Assembled Acid-Responsive Nanosystem for Synergistic Anti-Angiogenic/Photothermal/Ferroptosis Therapy against Esophageal Cancer.

Esophageal cancer (EC) treatment via anti-angiogenic therapy faces challenges due to non-cytotoxicity and non-specific biodistribution of the anti-angiogenic agents. Hence, the quest for a synergistic treatment modality and a targeted delivery approach to effectively address EC has become imperative. In this study, an acid-responsive release nanosystem (Bev-IR820@FeIII TA) that involves the conjugation of bevacizumab, an anti-angiogenic monoclonal antibody, with TA and Fe3+ to form a metal-phenolic network, followed by loading with the near-infrared photothermal agent (IR820) to achieve combinational therapy, is designed. The construction of Bev-IR820@FeIII TA can be realized through a facile self-assembly process. The Bev-IR820@FeIII TA exhibits tumor-targeting capabilities and synergistic therapeutic effects, encompassing anti-angiogenic therapy, photothermal therapy (PTT), and ferroptosis therapy (FT). Bev-IR820@FeIII TA exhibits remarkable proficiency in delivering drugs to EC tissue through its pH-responsive release properties. Consequently, bevacizumab exerts its therapeutic effects by obstructing tumor angiogenesis, thereby impeding tumor growth. Meanwhile, PTT facilitates localized thermal ablation at the tumor site, directly eradicating EC cells. FT synergistically collaborates with PTT, giving rise to the formation of a reactive oxygen species (ROS) storm, subsequently culminating in the demise of EC cells. In summary, this amalgamated treatment modality carries substantial promise for synergistically impeding EC progression and showcases auspicious prospects for future EC treatment.

Association Between Weight Change During Adulthood and Chronic Kidney Disease: Results from a National Survey 2011-2018.

Purpose: This study aimed to investigate the intricate relationship between weight change patterns and the onset of chronic kidney disease (CKD). Although obesity is recognized as a predisposing factor for CKD, the dynamics of weight fluctuation and its impact on CKD development are not well-defined. By analyzing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2011 to 2018, we sought to elucidate the association between weight trajectories and CKD risk. Patients and Methods: We included participants aged ≥40 years, employing body mass index (BMI) measurements at three life stages-baseline, age 25, and a decade preceding baseline-to categorize weight change patterns. Logistic regression was employed to evaluate the association of these patterns with CKD onset, adjusting for potential confounders. Results: The study encompassed 12,284 participants, with 2893 individuals diagnosed with CKD. Transitioning from normal weight to obesity and staying obese throughout adulthood were found to increase the risk of developing CKD. These associations remained consistent after adjusting for covariates but were statistically insignificant after adjusting for comorbidities. Notably, individuals transitioning from obesity to normal weight from age 25 to baseline and from 10 years before baseline to baseline demonstrated significant correlations with CKD but not between age 25 and 10 years before baseline. Conclusion: Obesity, weight gain throughout adulthood, and weight loss in middle-to-late adulthood are associated with an increased risk of CKD. This emphasizes the importance of long-term weight change patterns and maintaining a healthy weight throughout adulthood.

Strategies to Improve Long-Term Outcomes for Patients with Chronic Kidney Disease in China.

Background: Chronic kidney disease (CKD) is an incurable disease requiring lifelong management. China has a high prevalence of CKD, which disproportionately affects older adults and those with chronic risk factors for CKD development. The rising prevalence of CKD in China places a substantial burden on the general population and the healthcare system. Summary: In China, there are currently many unmet needs for patients with CKD and high-risk individuals, resulting from a lack of education and support to reduce risk factors, delayed diagnoses, limited knowledge of CKD among primary-care physicians, and poor access to treatments among some patient populations. An integrated, nationwide approach is required to improve the current situation of CKD management in China. There are currently several national healthcare frameworks in place that focus on new major health policies to prevent disease and encourage people to adopt healthier lifestyles, and while they do not directly target CKD, they may have a positive indirect impact. We explore the unmet needs for patients with CKD in China and discuss the potential strategies that may be required to overcome them. Such strategies include improving physician and patient education, establishing a targeted screening programme, supporting patients to improve self-management behaviours, accelerating the creation of medical consortia and medical satellite centres, and migrating from hospital- to community-based management. In addition to policy-driven strategies, development of novel therapies will be key to providing new solutions for the long-term management of CKD. Key Messages: An integrated, nationwide approach is required, incorporating policy-driven changes to the clinical management of CKD, as well as the development of novel CKD treatments.

Causal relationship between lung diseases and risk of esophageal cancer: insights from Mendelian randomization.

BACKGROUND: An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer. METHODS: Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method. RESULTS: Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003-1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504-1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998-1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998-1.0000, p = 0.147), showed no significant correlation with esophageal cancer. CONCLUSIONS: The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma.

Simultaneous profiling of chromatin architecture and transcription in single cells.

The three-dimensional structure of chromatin plays a crucial role in development and disease, both of which are associated with transcriptional changes. However, given the heterogeneity in single-cell chromatin architecture and transcription, the regulatory relationship between the three-dimensional chromatin structure and gene expression is difficult to explain based on bulk cell populations. Here we develop a single-cell, multimodal, omics method allowing the simultaneous detection of chromatin architecture and messenger RNA expression by sequencing (single-cell transcriptome sequencing (scCARE-seq)). Applying scCARE-seq to examine chromatin architecture and transcription from 2i to serum single mouse embryonic stem cells, we observe improved separation of cell clusters compared with single-cell chromatin conformation capture. In addition, after defining the cell-cycle phase of each cell through chromatin architecture extracted by scCARE-seq, we find that periodic changes in chromatin architecture occur in parallel with transcription during the cell cycle. These findings highlight the potential of scCARE-seq to facilitate comprehensive analyses that may boost our understanding of chromatin architecture and transcription in the same single cell.

A comprehensive investigation on source apportionment and multi-directional regional transport of volatile organic compounds and ozone in urban Zhengzhou.

To understand the characteristics, source apportionment, and regional transport of volatile organic compounds (VOCs) and ozone (O3) in a typical city with severe air pollution in central China, we observed and analyzed 115 VOC species at an urban site in Zhengzhou from 29 July to 26 September 2021. During this period, observation- and emission-based approaches revealed that Zhengzhou was in a VOC-limited regime. The average concentration of total VOCs (TVOCs) was 162.25 ± 71.42 µg/m3, dominated by oxygenated VOCs (OVOCs, 34.49%), alkanes (24.29%), and aromatics (19.49%). Six VOC sources were identified using positive matrix factorization (PMF) model, including paint solvent usage (25.32%), secondary production (24.11%), industrial production (19.22%), vehicle exhaust (16.18%), biogenic emission (8.87%), and combustion (6.30%). To assess the regional contribution and source apportionment of VOCs and O3, Comprehensive Air Quality Model with Extensions (CAMx) with the Ozone Source Apportionment Technology (OSAT) was used for simulation. Results showed that the VOCs were significantly affected by local emissions (about 70%), while O3 was mainly attributed to regional and super-regional transport. Regarding multi-directional regional transport of VOCs and O3, dominant contributions were from the northeast and east-northeast directions, and O3 contributions were also predominantly from the east and east-southeast directions. In terms of source apportionment, the transportation and industrial sectors (including solvent usage) were the major contributors to O3 and VOCs. To alleviate VOCs and O3 pollution, transportation and industrial emission reduction should be strengthened, and regional coordination, especially from the northeast to east-southeast directions, should be emphasized in addition to local management.

Genetic impact on the association of sleep patterns and chronic kidney disease: A prospective cohort study of 157,175 UK Biobank participants.

OBJECTIVES: The association between sleep pattern and chronic kidney disease (CKD) incidence, and whether the association is dependent on the genetic backgrounds has not been addressed. We sought to investigate the association of multidimensional sleep pattern with CKD in consideration of genetic polymorphisms. METHODS: In this prospective cohort study of 157,175 participants from the UK Biobank, sleep patterns were derived by multiple correspondence analysis (MCA) and k-means clustering of individual sleep traits (sleep duration, insomnia, chronotype, daytime sleepiness, snoring, and night shift status). Cox proportional hazard regression was used to estimate the association between sleep patterns and CKD incidence. Gene-environment-wide interaction study (GEWIS) was performed to detect whether gene polymorphisms were modifiers on this association. RESULTS: Compared with "healthy sleep" pattern, increased CKD incidence was observed in the clusters with "long sleep duration" (hazard ratios (HR) 1.42, 95% confidence intervals (CI), 1.18-1.72) and "night shift" (HR 1.23, 95% CI, 1.05-1.45) patterns, but not with the "short sleep duration" pattern. By GEWIS, we identified 167 SNPs as suggestive effect modifiers that interacted with unhealthy sleep patterns and affected the risk of CKD. CONCLUSIONS: Unhealthy sleep patterns, with features of long sleep duration and night shift, may increase the risk of CKD. The study highlights the interaction of sleep and individual genetic risk to affect health outcomes.

MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway.

MTHFD1L, a key enzyme of folate metabolism, is seldom reported in cancer. In this study, we investigate the role of MTHFD1L in the tumorigenicity of esophageal squamous cell carcinoma (ESCC). ESCC tissue microarrays (TMAs) containing 177 samples from 109 patients were utilized to evaluate whether MTHFD1L expression, determined using immunohistochemical analysis, is a prognostic indicator for ESCC patients. The function of MTHFD1L in the migration and invasion of ESCC cells was studied with wound healing, Transwell, and three-dimensional spheroid invasion assays in vitro and a lung metastasis mouse model in vivo. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MTHFD1L. Elevated expression of MTHFD1L in ESCC tissues was significantly associated with poor differentiation and prognosis. These phenotypic assays revealed that MTHFD1L significantly promote the viability and metastasis of ESCC cell in vivo and in vitro. Further detailed analyses of the molecular mechanism demonstrated that the ESCC progression driven by MTHFD1L was through up-regulation ERK5 signaling pathways. These findings reveal that MTHFD1L is positively associated with the aggressive phenotype of ESCC by activating ERK5 signaling pathways, suggesting that MTHFD1L is a new biomarker and a potential molecular therapeutic target for ESCC.

Responses of Rice and Related Cadmium Transporter Genes to the Passivating Microbial Agent MBLHAP.

Alkali-producing microorganisms and hydroxyapatite (HAP), a chemical passivation agent, have a certain remediation effect on cadmium (Cd) -contaminated soil. They can decrease the available Cd content in the soil to a certain extent and reduce the overall Cd content of rice planted in the soil. The Cd-contaminated soil was treated with the passivating bacterial agent that had been developed. Changes in the Cd concentration of rice leaves and soil were observed. Real-time PCR was used to analyse the expression levels of Cd transport protein genes in rice. Then, we determined the activities of super-oxide dismutase (SOD), catalase (CAT) and peroxidase (POD) at different stages of rice growth. The results showed that after HAP, alkali-producing microorganisms and passivating microbial agents were applied to the Cd treated soil. The total Cd content in rice leaves was reduced by 66.80%, 80.32% and 81.35%. The expression differences of genes related to Cd transporter proteins were measured, and the results showed that the changes in gene regulation were consistent with the changes in Cd content of rice leaves. The changes in SOD activity, CAT activity and POD activity further indicated that the three enzymes could alleviate the adverse effects of Cd stress by regulating the related enzyme activities in rice. In conclusion, alkali-producing microorganisms, HAP and passivating bacterial agents can effectively reduce the toxicity of Cd to rice, and reduce the absorption and accumulation of Cd in rice leaves.

AlphaFold2 and its applications in the fields of biology and medicine.

AlphaFold2 (AF2) is an artificial intelligence (AI) system developed by DeepMind that can predict three-dimensional (3D) structures of proteins from amino acid sequences with atomic-level accuracy. Protein structure prediction is one of the most challenging problems in computational biology and chemistry, and has puzzled scientists for 50 years. The advent of AF2 presents an unprecedented progress in protein structure prediction and has attracted much attention. Subsequent release of structures of more than 200 million proteins predicted by AF2 further aroused great enthusiasm in the science community, especially in the fields of biology and medicine. AF2 is thought to have a significant impact on structural biology and research areas that need protein structure information, such as drug discovery, protein design, prediction of protein function, et al. Though the time is not long since AF2 was developed, there are already quite a few application studies of AF2 in the fields of biology and medicine, with many of them having preliminarily proved the potential of AF2. To better understand AF2 and promote its applications, we will in this article summarize the principle and system architecture of AF2 as well as the recipe of its success, and particularly focus on reviewing its applications in the fields of biology and medicine. Limitations of current AF2 prediction will also be discussed.

The Causal Association of Irritable Bowel Syndrome with Multiple Disease Outcomes: A Phenome-Wide Mendelian Randomization Study.

BACKGROUND: This study aimed to identify novel associations between irritable bowel syndrome (IBS) and a broad range of outcomes. METHODS: In total, 346,352 white participants in the U.K. Biobank were randomly divided into two halves, in which a genome-wide association study (GWAS) of IBS and a polygenic risk score (PRS) analysis of IBS using GWAS summary statistics were conducted, respectively. A phenome-wide association study (PheWAS) based on the PRS of IBS was performed to identify disease outcomes associated with IBS. Then, the causalities of these associations were tested by both one-sample (individual-level data in U.K. Biobank) and two-sample (publicly available summary statistics) Mendelian randomization (MR). Sex-stratified PheWAS-MR analyses were performed in male and female, separately. RESULTS: Our PheWAS identified five diseases associated with genetically predicted IBS. Conventional MR confirmed these causal associations between IBS and depression (OR: 1.07, 95%CI: 1.01-1.14, p = 0.02), diverticular diseases of the intestine (OR: 1.13, 95%CI: 1.08-1.19, p = 3.00 × 10-6), gastro-esophageal reflux disease (OR: 1.09, 95%CI: 1.05-1.13, p = 3.72 × 10-5), dyspepsia (OR: 1.21, 95%CI: 1.13-1.30, p = 9.28 × 10-8), and diaphragmatic hernia (OR: 1.10, 95%CI: 1.05-1.15, p = 2.75 × 10-5). The causality of these associations was observed in female only, but not men. CONCLUSIONS: Increased risks of IBS is found to cause a series of disease outcomes. Our findings support further investigation on the clinical relevance of increased IBS risks with mental and digestive disorders.

Real-time prediction of organ failures in patients with acute pancreatitis using longitudinal irregular data.

It is extremely important to identify patients with acute pancreatitis who are at high risk for developing persistent organ failures early in the course of the disease. Due to the irregularity of longitudinal data and the poor interpretability of complex models, many models used to identify acute pancreatitis patients with a high risk of organ failure tended to rely on simple statistical models and limited their application to the early stages of patient admission. With the success of recurrent neural networks in modeling longitudinal medical data and the development of interpretable algorithms, these problems can be well addressed. In this study, we developed a novel model named Multi-task and Time-aware Gated Recurrent Unit RNN (MT-GRU) to directly predict organ failure in patients with acute pancreatitis based on irregular medical EMR data. Our proposed end-to-end multi-task model achieved significantly better performance compared to two-stage models. In addition, our model not only provided an accurate early warning of organ failure for patients throughout their hospital stay, but also demonstrated individual and population-level important variables, allowing physicians to understand the scientific basis of the model for decision-making. By providing early warning of the risk of organ failure, our proposed model is expected to assist physicians in improving outcomes for patients with acute pancreatitis.

Proliferative exhausted CD8+ T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8+ T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen-presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects.

The prognostic value of sarcopenia in oesophageal cancer: A systematic review and meta-analysis.

The loss of skeletal muscle mass and function is defined as sarcopenia, which might develop in elderly patients with cancers. It has been indicated as a potential negative factor in the survival of patients with malignant tumours. The aim of this systematic review and meta-analysis was to evaluate the associations between sarcopenia and survival outcomes or postoperative complications in patients with oesophageal cancer (EC). Web of Science, Embase, Medline, and Cochrane Library databases were searched until 10 May 2022, using keywords: sarcopenia, oesophageal cancer, and prognosis. Studies investigating the prognostic value of sarcopenia on EC survival were included. Forest plots and summary effect models were used to show the result of this meta-analysis. The quality of included studies was evaluated with the Newcastle-Ottawa Scale (NOS). A total of 1436 studies were identified from the initial search of four databases, and 41 studies were included for the final quantitative analysis. This meta-analysis revealed a significant association between sarcopenia and overall survival (OS) [hazard ratios (HR):1.68, 95% confidence interval (CI):1.54-1.83, P = 0.004, I2  = 41.7%] or disease-free survival (DFS) 1.97 (HR: 1.97, 95% CI: 1.44-2.69, P = 0.007, I2  = 61.9%) of EC patients. Subgroup analysis showed that sarcopenia remained a consistent negative predictor of survival when stratified by different treatment methods, populations, or sarcopenia measurements. Sarcopenia was also a risk factor for postoperative complications with a pooled odds ratio of 1.47 (95% CI: 1.21-1.77, P = 0.094, I2  = 32.7%). The NOS scores of all included studies were ≥6, and the quality of the evidence was relatively high. The results from the study suggested that sarcopenia was significantly associated with both survival outcomes and postoperative complications in EC patients. Sarcopenia should be appropriately diagnosed and treated for improving short-term and long-term outcomes of patients with EC.