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The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including 3’-phosphoadenosine 5’-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3’-phosphoadenosine-5’-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.

IntroductionDigital twins of patients are virtual models that can create a digital patient replica to test clinical interventions in silico without exposing real patients to risk. With the increasing availability of electronic health records and sensor-derived patient data, digital twins offer significant potential for applications in the healthcare sector.MethodsThis article presents a scalable full-stack architecture for a patient simulation application driven by graph-based models. This patient simulation application enables medical practitioners and trainees to simulate the trajectory of critically ill patients with sepsis. Directed acyclic graphs are utilized to model the complex underlying causal pathways that focus on the physiological interactions and medication effects relevant to the first 6 h of critical illness. To realize the sepsis patient simulation at scale, we propose an application architecture with three core components, a cross-platform frontend application that clinicians and trainees use to run the simulation, a simulation engine hosted in the cloud on a serverless function that performs all of the computations, and a graph database that hosts the graph model utilized by the simulation engine to determine the progression of each simulation.ResultsA short case study is presented to demonstrate the viability of the proposed simulation architecture.DiscussionThe proposed patient simulation application could help train future generations of healthcare professionals and could be used to facilitate clinicians’ bedside decision-making.

Summary: Ovarian cancer is a highly lethal gynecological malignancy, emphasizing the need for effective treatment strategies. This study investigated the synergistic effects of quercetin and paclitaxel on ovarian cancer. Using SKOV3 and A2780 cell lines, we found that the combined treatment significantly enhanced cell apoptosis and inhibited invasion and migration compared to individual treatments. Then, we identified 32 common targets between quercetin/paclitaxel and ovarian cancer, with 29 genes showing differential expression between normal ovarian tissue and ovarian tumor tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that quercetin and paclitaxel modulated cancer-related pathways in ovarian cancer treatment. Mechanistic analysis further discovered that the synergistic effect was mediated by downregulating ERBB2 and BIRC5 and upregulating CASP3 expression. This study provides strong evidence that quercetin enhances the effectiveness of paclitaxel in treating ovarian cancer.

BackgroundThe duration of sleep plays a crucial role in the development of physiological functions that impact health. However, little is known about the associations between sleep duration and functional disability among older adults in China. ObjectiveThis study aimed to explore the associations between sleep duration and functional disabilities in the older population (aged≥65 years) in China. MethodsThe data for this cross-sectional study were gathered from respondents 65 years and older who participated in the 2018 survey of the China Health and Retirement Longitudinal Study, an ongoing nationwide longitudinal investigation of Chinese adults. The duration of sleep per night was obtained through face-to-face interviews. Functional disability was assessed according to activities of daily living (ADL) and instrumental activities of daily living (IADL) scales. The association between sleep duration and functional disability was assessed by multivariable generalized linear models. A restricted cubic-spline model was used to explore the dose-response relationship between sleep duration and functional disability. ResultsIn total, 5519 participants (n=2471, 44.77% men) were included in this study with a mean age of 73.67 years, including 2800 (50.73%) respondents with a functional disability, 1978 (35.83%) with ADL disability, and 2299 (41.66%) with IADL disability. After adjusting for potential confounders, the older adults reporting shorter (≤4, 5, or 6 hours) or longer (8, 9, or ≥10 hours) sleep durations per night exhibited a notably increased risk of functional disability compared to that of respondents who reported having 7 hours of sleep per night (all P

Abstract Objectives To develop and validate a magnetic resonance imaging-based (MRI) deep multiple instance learning (D-MIL) model and combine it with clinical parameters for preoperative prediction of lymph node metastasis (LNM) in operable cervical cancer. Methods A total of 392 patients with cervical cancer were retrospectively enrolled. Clinical parameters were analysed by logistical regression to construct a clinical model (M1). A ResNet50 structure is applied to extract features at the instance level without using manual annotations about the tumour region and then construct a D-MIL model (M2). A hybrid model (M3) was constructed by M1 and M2 scores. The diagnostic performance of each model was evaluated by the area under the receiver operating characteristic curve (AUC) and compared using the Delong method. Disease-free survival (DFS) was evaluated by the Kaplan‒Meier method. Results SCC-Ag, maximum lymph node short diameter (LNmax), and tumour volume were found to be independent predictors of M1 model. For the diagnosis of LNM, the AUC of the training/internal/external cohort of M1 was 0.736/0.690/0.732, the AUC of the training/internal/external cohort of M2 was 0.757/0.714/0.765, and the AUC of the training/internal/external cohort of M3 was 0.838/0.764/0.835. M3 showed better performance than M1 and M2. Through the survival analysis, patients with higher hybrid model scores had a shorter time to reach DFS. Conclusion The proposed hybrid model could be used as a personalised non-invasive tool, which is helpful for predicting LNM in operable cervical cancer. The score of the hybrid model could also reflect the DFS of operable cervical cancer. Critical relevance statement Lymph node metastasis is an important factor affecting the prognosis of cervical cancer. Preoperative prediction of lymph node status is helpful to make treatment decisions, improve prognosis, and prolong survival time. Key points • The MRI-based deep-learning model can predict the LNM in operable cervical cancer. • The hybrid model has the highest diagnostic efficiency for the LNM prediction. • The score of the hybrid model can reflect the DFS of operable cervical cancer. Graphical Abstract

The long-term excessive use of chemical fertilizers may result in soil degradation, but manure and straw application is considered to be an effective approach for alleviating this problem. The aim of this study is to examine the long-term impacts of different fertilization patterns on soil quality variables in a wheat–sweet potato rotation system. Four treatments were conducted in a field trial for a duration of twelve years, including (1) no fertilizer (control, CK); (2) application of mineral fertilizers (NPK) alone; (3) NPK with crop straw return (NPKs); (4) combined use of NPK and farmyard manure (NPKm). Thirteen physical, chemical, and biological soil parameters were measured. The results showed that the NPKm and NPKs significantly improved the proportion of macroaggregates (>0.25 mm) by 24.7% and 21.9% compared to the NPK alone, respectively. The proportion of microaggregates (0.053–0.25 mm) under the NPKm was 47.4% significantly higher than the NPKs. Additionally, the NPKm resulted in a 22.2% and 19.6% increase in the SOC content than the NPK and NPKs, respectively. In terms of soil-available K, the NPKs resulted in levels that were 42.1% and 49.6% higher than the NPKm and NPK alone, respectively. Long-term fertilization significantly decreased soil pH by 0.95–1.85 units compared to the control, whereas manure application could alleviate soil acidification, as shown when the pH increased by 10.6–18.7%. The NPKm and NPKs resulted in significantly increased soil pHs by 10.6% and 18.7% compared to the NPK alone, respectively. In addition, the NPKm and NPKs increased N-acetyl-β-D-glucosaminidase activity by 52.6% and 60.3% compared to the NPK alone. Determined by the minimum data set method, the NPKm treatment exhibited the highest soil quality index, followed by the NPKs and NPK. Our findings suggested that the combined use of chemical fertilizers with organic amendments proved beneficial for enhancing soil quality.

The perinuclear theca (PT) is a dense cytoplasmic web encapsulating the sperm nucleus. The physiological roles of PT in sperm biology and the clinical relevance of variants of PT proteins to male infertility are still largely unknown. We reveal that cylicin-1, a major constituent of the PT, is vital for male fertility in both mice and humans. Loss of cylicin-1 in mice leads to a high incidence of malformed sperm heads with acrosome detachment from the nucleus. Cylicin-1 interacts with itself, several other PT proteins, the inner acrosomal membrane (IAM) protein SPACA1, and the nuclear envelope (NE) protein FAM209 to form an ‘IAM–cylicins–NE’ sandwich structure, anchoring the acrosome to the nucleus. WES (whole exome sequencing) of more than 500 Chinese infertile men with sperm head deformities was performed and a CYLC1 variant was identified in 19 patients. Cylc1-mutant mice carrying this variant also exhibited sperm acrosome/head deformities and reduced fertility, indicating that this CYLC1 variant most likely affects human male reproduction. Furthermore, the outcomes of assisted reproduction were reported for patients harbouring the CYLC1 variant. Our findings demonstrate a critical role of cylicin-1 in the sperm acrosome–nucleus connection and suggest CYLC1 variants as potential risk factors for human male fertility.

BackgroundNonsuicidal self-injury (NSSI) among adolescents is a growing global concern. However, effective interventions for treating NSSI are limited.MethodA 36-week quasi-experimental study design of parent–child group resilience training (intervention group) for adolescents aged 12–17 years was used and compared with treatment-as-usual (control group). The primary endpoint was the frequency of NSSI assessed with the Ottawa Self-Injury Inventory (OSI), and the secondary endpoints were the levels of depression, hope, resilience, and family adaptability and cohesion as assessed by the 24-item Hamilton depression rating scale (HAMD-24), Herth Hope Scale (HHS), Connor-Davidson Resilience Scale (CD-RISC), and Family Adaptability and Cohesion Evaluation Scale, second edition (FACES-II-CV), respectively.ResultA total of 118 participants completed the trial. Both groups showed a significant reduction in NSSI frequency after 12, 24, and 36 weeks of intervention (p< 0.05), although the intervention group did not differ significantly from the control group. After 12, 24, and 36 weeks of intervention, the CD-RISC, HHS, HAMD-24, and FACES-II-CV scores in the intervention and control groups improved over baseline (p< 0.05). Furthermore, the intervention group had higher scores on the CD-RISC, HHS, and FACES-II-CV and lower scores on the HAMD-24 than the control group after 12, 24, and 36 weeks of intervention (p < 0.05).ConclusionParent–child group emotional regulation and resilience training showed promise as treatment options for NSSI among adolescents, leading to increased hope, resilience, and improved family dynamics among NSSI teens. Moreover, NSSI frequency significantly decreased in the intervention group compared to baseline.

Abstract As a universal structure in space plasma, electron holes represent an obvious signature of nonlinear process. Although the theory has a 60-year history, whether electron hole can finally accelerate ambient electrons (or ions) is quite controversial. Previous theory for one-dimensional holes predicts that net velocity change of passing electrons (or ions) occurs only if the holes have non-zero acceleration. However, the prediction has not yet been demonstrated in observations. Here, we report four electron holes whose acceleration/deceleration is obtained by fitting the spatial separations and detection time delays between different Magnetospheric Multiscale spacecraft. We find that electron hole acceleration/deceleration is related to the ion velocity distribution gradient at the hole’s velocity. We observe net velocity changes of ions passing through the accelerating/decelerating holes, in accordance with theoretical predictions. Therefore, we show that electron holes with non-zero acceleration can cause the velocity of passing ions to increase in the acceleration direction.

Abstract Background Due to the lack of corresponding clinical symptoms, small calcified gastric gastrointestinal stromal tumors (GISTs) are often overlooked in clinical practice. Therefore, there is an unmet need to define the imaging features of calcified micro-gastric GISTs to facilitate diagnosis. This study retrospectively analyzed the computed tomography (CT) features of pathologically confirmed calcified micro-gastric GISTs. Methods The medical records (gastroscopy, pre-treatment gastric CT imaging [pre- and post-contrast scans], pathology) of patients with calcified gastric GISTs

The crystallographic defects introduced after thermal deformation of near-β Ti-55511 alloy can have an important impact on the precipitation of primary α phase (αp), β grain evolution and the texture evolution during the subsequent heat treatment. The investigation indicates that the intragranular short-rod αp precipitated by strain-induced nucleation deviates from Burgers orientation relationship (BOR) by boundary splitting in 0.27–0.64, accompanied by β→αp transformation, which strictly obeys BOR during ST. In addition, the strain and strain rate can modify the αp-type after deformation. Three main αp types are Type I: 50–60°/, Type II: 40–50° or 80–90°/ and Type III: 90–100°/. The phase transformation inheritance occurs after ST based on the variant selection effect, and the αp varieties are mainly 80–90°/ and 80–90°/. Furthermore, the density of the deformation texture (000–1) [11–20] is weakened by the new αp transformation texture (0001) [-1-780] and the recrystallization texture (23-5-3) [11–22], but it is inherited at 1.23. However, the αp recrystallization texture significantly restrains the occurrence of the deformation texture inheritance phenomenon at 0.001 s−1. Moreover, the adjacent αp grains are mainly 60°/ to each other, while the β grains around αp with a relatively high degree of recrystallization are mainly 30–50°/ to each other. The first one of the static sphericalized αp is partly generated by coarsening, which is derived from the dispersed nucleus αp precipitated at the trigonal/tetragonal β sub-boundaries. The second one is by the GB separation mechanism triggered by the formation of α/α boundaries within the short-bar αp grain.

Abstract Estuaries play an important role in the global nitrous oxide budget. However, considerable uncertainties exist in estimating their nitrous oxide emissions, largely due to anthropogenic impacts, particularly wastewater discharge. Here we investigate nitrous oxide emission dynamics in the Pearl River Estuary through advanced high-resolution, real-time measurements. Results suggest that Pearl River Estuary is a strong nitrous oxide emission source (1.05 Gg yr−1; range: 0.92–1.23 Gg yr−1) with pronounced spatial heterogeneity. Wastewater discharge substantially impacts emissions by introducing abundant nutrients, altering carbon-to-nitrogen stoichiometry, and stimulating biochemical processes. A meta-analysis further reveals the widespread enhancement of nitrous oxide emission induced by wastewater nitrogen input in global estuaries, with nitrous oxide emission factors considerably lower than that suggested by the IPCC owing to progressive biological saturation. Consequently, refining emission factor estimates through comprehensive bottom-up studies is imperative to improve the understanding of estuarine contributions to the global nitrous oxide budget.

Abstract Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.

Abstract Background Spatial epidemiology plays an important role in public health. Yet, it is unclear whether the current university education in spatial epidemiology in China could meet the competency-oriented professional demands. This study aimed to understand the current situation of education and training, practical application, and potential demands in spatial epidemiology among public health postgraduates in China, and to assess the critical gaps in a future emerging infectious diseases (EID) pandemic preparedness and response. Methods This study was divided into three parts. The first part was a comparative study on spatial epidemiology education in international public health postgraduate training. The second part was a cross-sectional survey conducted among public health professionals. The third part was a nationwide cross-sectional survey conducted among public health postgraduates at Chinese universities from October 2020 to February 2021. Data was collected by the WeChat-based questionnaire star survey system and analyzed using the SPSS software. Results International education institutions had required public health postgraduates to master the essential knowledge and capacity of spatial epidemiology. A total of 198 public health professionals were surveyed, and they had a median of 4.00 (IQR 3.13–4.53) in demand degree of spatial epidemiology. A total of 1354 public health postgraduates were surveyed from 51 universities. Only 29.41% (15/51) of universities offered spatial epidemiology course. Around 8.05% (109/1354) of postgraduates had learned spatial epidemiology, and had a median of 1.05 (IQR 1.00–1.29) in learning degree and a median of 1.91 (IQR 1.05–2.78) in practical application degree of spatial epidemiology. To enhance professional capacity, 65.95% (893/1354) of postgraduates hoped that universities would deliver a credit-course of spatial epidemiology. Conclusions A huge unmet education and training demand in spatial epidemiology existed in the current education system of public health postgraduates in China. To enhance the competency-oriented professional capacity in preparedness and response to a future pandemic, it is urgent to incorporate the teaching and training of spatial epidemiology into the compulsory curriculum system of public health postgraduates in China.

The aerodynamic loads of a sedan experience significant fluctuations when passing by a sand dune at the roadside under crosswinds, which can easily cause yawing and overturning. Computational fluid dynamics (CFD) methods, based on different turbulence modeling approaches, yield different aerodynamic results for sedans. This study aims to investigate the effects of three prevailing turbulence modeling approaches (renormalization group (RNG) k-ε, large eddy simulation (LES), and improved delayed detached eddy simulation (IDDES)) on the aerodynamic characteristics of a sedan passing by a sand dune under crosswinds. The CFD dynamic mesh models are constructed using the “mosaic” mesh technique to account for the dune–air–sedan interaction. The reliability of the CFD prediction method is verified by comparing it with field test results. The predictive capabilities of the three turbulence modeling approaches are compared in terms of aerodynamic loads and flow field characteristics. The simulation of sand particle movement is conducted through the discrete phase model, aiming to assess the impact of wind–sand flow on the aerodynamic properties of sedans. Corresponding results show that the aerodynamic loads predicted by the LES model closely match (within 4.4–7.5%) the corresponding data obtained from field tests. While the IDDES and LES models demonstrate similar abilities in characterizing the wind field details, and their results exhibit maximum differences of 8.3–15.7%. Meanwhile, the maximum difference between the results obtained by the RNG k-ε and LES models ranges from 14.8% to 18.4%, attributed to its inability to capture subtle changes in the vortex structure within the flow field. This work will provide a numerical modeling reference for studies on the wind–sand flow and the aerodynamic characteristics of sedans running through the desert, and it has implications for the safe driving of sedans under extreme conditions.

Sulfate transporters (SULTRs) are essential for the transport and absorption of sulfate in plants and serve as critical transport proteins within the sulfur metabolism pathway, significantly influencing plant growth, development, and stress adaptation. A bioinformatics analysis of SULTR genes in soybean was performed, resulting in the identification and classification of twenty-eight putative GmSULTRs into four distinct groups. In this study, the characteristics of the 28 GmSULTR genes, including those involved in collinearity, gene structure, protein motifs, cis-elements, tissue expression patterns, and the response to abiotic stress and plant hormone treatments, were systematically analyzed. This study focused on conducting a preliminary functional analysis of the GmSULTR3;1a gene, wherein a high expression level of GmSULTR3;1a in the roots, stems, and leaves was induced by a sulfur deficiency and GmSULTR3;1a improved the salt tolerance. A further functional characterization revealed that GmSULTR3;1a-overexpressing soybean hairy roots had higher SO42−, GSH, and methionine (Met) contents compared with the wild-type (WT) plant. These results demonstrate that the overexpression of GmSULTR3;1a may promote the sulfur assimilation metabolism and increase the content of sulfur-containing amino acids in plants.

Mass timber construction has recently gained popularity due to its outstanding environmental benefits and building performance, which hold revolutionary potential for the construction industry. However, its impacts from the perspective of occupants have not been thoroughly explored. This study introduces an innovative empirical approach that explores the potential benefits of mass timber construction for individuals and organizations, with an emphasis on the workplace. We review the conceptual framework regarding how visual and physical exposure to timber construction materials and finishes have a positive effect on individuals and organizations at a broad level. We propose a more holistic mixed-method behavioral approach to studying occupant behavior and well-being by integrating self-reported questionnaires, objective biomarkers (heart rate variability and hair cortisol), and indoor environmental quality (IEQ) measures. Our study offers a novel research primer on the exploration of mass timber construction impacts and benefits for both office workers and construction workers. Participants from different office settings completed pre- and post-occupancy evaluation surveys to assess their experiences, including IEQ satisfaction, productivity, and health. Office workers were located in three different offices: a controlled laboratory environment, an open-plan office, and an open-plan space with a timber interior. The construction workers worked in a timber space for three months and then moved to work in a building with a concrete structure. The analysis included descriptive statistics, t-tests, ANOVA, and linear regression to compare differences between office settings and assess the relationship between environmental variables and overall satisfaction in IEQ, comfort, productivity, and health. In office workers, in terms of building image, thermal comfort, and artificial lighting, the data analysis revealed significant differences in occupants’ satisfaction levels between office settings. However, the low number of participants affected the results, and some factors were not found significant in relation to the office setting. Among tradespeople, there was no relationship between the building environment and productivity, health, or comfort. However, the results of hair cortisol testing indicated that working in a timber space can decrease the level of cortisol (stress) and have an impact on the productivity of workers. Such occupant’s perspective research is pivotal to informing policy makers, developers, business owners, construction professionals, timber industry stakeholders, environmentalists, and researchers in their decision-making processes. Fostering the future widespread adoption and advancement of mass timber construction.

Advancements in information technology have facilitated the emergence of mHealth apps as crucial tools for health management and chronic disease prevention. This research work focuses on mHealth apps for the management of diabetes by patients on their own. Given that China has the highest number of diabetes patients in the world, with 141 million people and a prevalence rate of 12.8% (mentioned in the Global Overview of Diabetes), the development of a usability research methodology to assess and validate the user-friendliness of apps is necessary. This study describes a usability evaluation model that combines task analysis methods and eye movement data. A blood glucose recording application was designed to be evaluated. The evaluation was designed based on the model, and the feasibility of the model was demonstrated by comparing the usability of the blood glucose logging application before and after a prototype modification based on the improvement suggestions derived from the evaluation. Tests showed that an improvement plan based on error logs and post-task questionnaires for task analysis improves interaction usability by about 24%, in addition to an improvement plan based on eye movement data analysis for hotspot movement acceleration that improves information access usability by about 15%. The results demonstrate that this study presents a usability evaluation model for mHealth apps that enables the effective evaluation of the usability of mHealth apps.