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Abstract While the ruminant gut archaeome regulates the gut microbiota and hydrogen balance, it is also a major producer of the greenhouse gas methane. However, ruminant gut archaeome diversity within the gastrointestinal tract (GIT) of ruminant animals worldwide remains largely underexplored. Here, we construct a catalogue of 998 unique archaeal genomes recovered from the GITs of ruminants, utilizing 2270 metagenomic samples across 10 different ruminant species. Most of the archaeal genomes (669/998 = 67.03%) belong to Methanobacteriaceae and Methanomethylophilaceae (198/998 = 19.84%). We recover 47/279 previously undescribed archaeal genomes at the strain level with completeness of >80% and contamination of

Abstract Purposes T cells play a crucial role as regulators of anti-tumor activity within the tumor microenvironment (TME) and are closely associated with the progression of osteosarcoma (OS). Nevertheless, the specific role of T cell-related genes (TCRGs) in the pathogenesis of OS remains unclear. Methods First, we processed single-cell RNA sequencing (scRNA-seq) data of OS from the public databases and performed cell annotation. We identified highly variable genes in each cell type using the "FindAllMarkers" function, explored the distribution of different clusters, and investigated inter-cellular communication patterns via the "CellChat" framework. Then, we used multivariate Cox analysis to construct a TCRG and developed a nomogram to predict survival probabilities for OS patients. Finally, we validated the aforementioned results using various cell lines and investigated the immune cell infiltration, expression of immune checkpoints, chemotherapy sensitivity, and the efficacy of targeted therapies across different risk groups. Results From the scRNA-seq data, we identified 3,000 highly variable genes, presented the top 10 genes, and validated the expression of core genes across different cell lines.Moreover, our analysis delved into interactions between T cells and other cell types. Our analyses constructed a predictive T cell-related signature (TCRS) that incorporated these prognostic TCRGs, showing a clear prognostic separation between the high-risk and low-risk OS patient groups in multiple cohorts. Survival analysis indicated better outcomes for patients classified in the high-risk group. The low-risk group exhibited elevated levels of CD4 memory resting T cells, contrasting with the higher levels of macrophage M0 observed in the high-risk group via the CIBERSORT algorithm. Furthermore, we observed that the low-risk group exhibitedAQ1 significant up-regulation of immune checkpoint genes (ICGs) and lower Tumour Immune Dysfunction and Exclusion (TIDE) scores, suggesting that they may be suitable for immunotherapy. Conversely, the high-risk group appeared more responsive to chemotherapy and targeted therapies, according to our drug sensitivity analysis. Conclusion In conclusion, our study identified TCRGs, constructed and validated a TCRS for OS, and assessed immune response and drug sensitivity in different risk groups of OS patients. These findings provide novel insights into personalized treatment strategies for OS, potentially guiding more effective therapeutic interventions.

Abstract Background The rumen microbiome plays an essential role in maintaining ruminants’ growth and performance even under extreme environmental conditions, however, which factors influence rumen microbiome stability when ruminants are reared in such habitats throughout the year is unclear. Hence, the rumen microbiome of yak (less domesticated) and cattle (domesticated) reared on the Qinghai-Tibetan Plateau through the year were assessed to evaluate temporal changes in their composition, function, and stability. Results Rumen fermentation characteristics and pH significantly shifted across seasons in both cattle and yak, but the patterns differed between the two ruminant species. Ruminal enzyme activity varied with season, and production of xylanase and cellulase was greater in yak compared to cattle in both fall and winter. The rumen bacterial community varied with season in both yak and cattle, with higher alpha diversity and similarity (beta diversity) in yak than cattle. The diversity indices of eukaryotic community did not change with season in both ruminant species, but higher similarity was observed in yak. In addition, the similarity of rumen microbiome functional community was higher in yak than cattle across seasons. Moreover, yak rumen microbiome encoded more genes (GH2 and GH3) related to cellulose and hemicellulose degradation compared to cattle, and a new enzyme family (GH160) gene involved in oligosaccharides was uniquely detected in yak rumen. The season affected microbiome attenuation and buffering values (stability), with higher buffering value in yak rumen microbiome than cattle. Positive correlations between antimicrobial resistance gene (dfrF) and CAZyme family (GH113) and microbiome stability were identified in yak, but such relationship was negatively correlated in cattle. Conclusions The findings of the potential of cellulose degradation, the relationship between rumen microbial stability and the abundance of functional genes varied differently across seasons and between yak and cattle provide insight into the mechanisms that may underpin their divergent adaptation patterns to the harsh climate of the Qinghai-Tibetan Plateau. These results lay a solid foundation for developing strategies to maintain and improve rumen microbiome stability and dig out the potential candidates for manufacturing lignocellulolytic enzymes in the yak rumen to enhance ruminants’ performance under extreme environmental conditions.

Abstract Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC.

Abstract Colonizing in the gastrointestinal tract, Escherichia coli confronts diverse acidic challenges and evolves intricate acid resistance strategies for its survival. The lysine-mediated decarboxylation (Cad) system, featuring lysine decarboxylase CadA, lysine/cadaverine antiporter CadB, and transcriptional activator CadC, plays a crucial role in E. coli’s adaptation to moderate acidic stress. While the activation of the one-component system CadC and subsequent upregulation of cadBA operon in response to acid and lysine presence have been proposed, the molecular mechanisms governing the transition of CadC from an inactive to an active state remain elusive. Under neutral conditions, CadC is inhibited by forming a complex with lysine-specific permease LysP, stabilized in this inactive state by a disulfide bond. Our study unveils that, in an acidic environment, the disulfide bond in CadC is reduced by the disulfide bond isomerase DsbC, exposing R184 to periplasmic proteases, namely DegQ and DegP. Cleavage at R184 by DegQ and DegP generates an active N-terminal DNA-binding domain of CadC, which binds to the cadBA promoter, resulting in the upregulated transcription of the cadA and cadB genes. Upon activation, CadA decarboxylates lysine, producing cadaverine, subsequently transported extracellularly by CadB. We propose that accumulating cadaverine gradually binds to the CadC pH-sensing domain, preventing cleavage and activation of CadC as a feedback mechanism. The identification of DegP, DegQ, and DsbC completes a comprehensive roadmap for the activation and regulation of the Cad system in response to moderate acidic stress in E. coli.

Abstract Background Seed germination is a key process in the plant life cycle that affects the vegetative and reproductive stages of plants. Although the JAZ gene family has been characterized in many plants, the relationship between the JAZ gene and seed germination is still unclear. Results We identified two members of the JAZ family from wheat, TaTIFY3B and TaTIFY10A. TaTIFY3B and TaTIFY10A were localized in both the cell membrane and nucleus. Spatio-temporal expression analysis of TaTIFY3B and TaTIFY10A in wheat revealed that these genes are essential for the preharvest sprouting (PHS) stage of seed development, with expression levels significantly decreasing during the ripening period. Transgenic rice plants overexpressing wheat TaTIFY3B and TaTIFY10A improved seed germination rates. Transgenic Arabidopsis plants overexpressing wheat TaTIFY10A improved seed germination rates and promoted flowering. In addition, abscisic acid (ABA) and jasmonic acid (JA) were found to induce TaTIFY3B and TaTIFY10A expression. Under different ABA concentrations, the seed germination rates of transgenic rice and Arabidopsis overexpressing TaTIFY3B and TaTIFY10A are superior to wild-type (WT) and mutant plants, and the root lengths of Arabidopsis overexpressing TaTIFY3B and TaTIFY10A also change. Under different JA concentrations, there is no difference in the seed germination rate of rice overexpressing TaTIFY3B and TaTIFY10A compared to WT and mutant plants, but there is a significant difference in the seed germination rate and root length of overexpressing Arabidopsis compared to WT and mutant plants. Under different concentrations of salt and drought treatments, the seed germination rate and root length of overexpressing Arabidopsis of TaTIFY3B and TaTIFY10A are affected. Conclusions This study offers a novel perspective for understanding the molecular basis of pre-harvest sprouting and provides potential candidate genes for controlling wheat seed germination.

Abstract Switchgrass (Panicum virgatum L.) is a perennial C4 warm-season grass known for its high-biomass yield and wide environmental adaptability, making it an ideal bioenergy crop. Despite its potential, switchgrass seedlings grow slowly, often losing out to weeds in field conditions and producing limited biomass in the first year of planting. Furthermore, during the reproductive growth stage, the above-ground biomass rapidly increases in lignin content, creating a significant saccharification barrier. Previous studies have identified rhythm-related genes TOC1 and LHY as crucial to the slow seedling development in switchgrass, yet the precise regulatory functions of these genes remain largely unexplored. In this study, the genes TOC1 and LHY were characterized within the tetraploid genome of switchgrass. Gene expression analysis revealed that PvTOC1 and PvLHY exhibit circadian patterns under normal growth conditions, with opposing expression levels over time. PvTOC1 genes were predominantly expressed in florets, vascular bundles, and seeds, while PvLHY genes showed higher expression in stems, leaf sheaths, and nodes. Overexpression of PvTOC1 from the N chromosome group (PvTOC1-N) or PvLHY from the K chromosome group (PvLHY-K) in Arabidopsis thaliana led to alterations in circadian rhythm and hormone metabolism, resulting in shorter roots, delayed flowering, and decreased resistance to oxidative stress. These transgenic lines exhibited reduced sensitivity to hormones and hormone inhibitors, and displayed altered gene expression in the biosynthesis and signal transduction pathways of abscisic acid (ABA), gibberellin (GA), 3-indoleacetic acid (IAA), and strigolactone (SL). These findings highlight roles of PvTOC1-N and PvLHY-K in plant development and offer a theoretical foundation for genetic improvements in switchgrass and other crops.

Airborne radar receivers that utilize subarray processing face challenges owing to the complex space-time coupling distribution caused by grating-lobe clutter. This results in multiple performance notches in the main beam, which severely affects target detection performance. To address this issue, we analyze the characteristics of grating-lobe clutter distribution in subarray processing and propose an approach for space-time clutter suppression based on the design of a receiving subarray beam pattern. Our approach leverages an overlapping subarray scheme to form wide nulls in the regions between subarrays where grating-lobe clutter is prevalent through beam pattern design. This design facilitates grating-lobe clutter pre-filtering between subarrays. Furthermore, we develop a subarray-level space-time processor that avoids the grating-lobe clutter coupling diffusion in the space-time two-dimensional plane by performing clutter pre-filtering within each subarray. This strategy enhances clutter suppression and moving-target-detection capabilities. Simulation results verify that the proposed method can remarkably improve the output signal to clutter plus noise ratio loss performance in grating-lobe clutter regions.

(1) Background: Over the past few decades, Jiangsu Province, China, has witnessed a remarkable surge in the incidence of prostate cancer (PCa), accompanied by notable demographic shifts; (2) Methods: PCa data for Jiangsu Province from 2009 to 2019 were obtained from the Jiangsu Cancer Registry. We calculated crude and age-specific incidence rates (ASIRs), average age at onset, and age-specific composition ratios. Standardization was performed based on the Segi’s world population. Birth cohorts (1929–2019) were analyzed to assess PCa incidence by birth year. Trend analysis was conducted using the Joinpoint Regression Model, and average annual percent changes (AAPCs) with corresponding 95% confidence interval (CI) were computed. A linear regression model was used to analyze the relationship between the average age at diagnosis and calendar years; (3) Results: The ASIRs of PCa in Jiangsu Province increased significantly, with an AAPC of 11.25% (95%CI: 10.09%, 12.42%) from 2009 to 2019. This increase was observed across all age groups, particularly among those aged 0–59 years. Birth cohort analysis revealed a rising trend with earlier birth years showing higher incidence, notably in the 1959 cohort. In rural areas, the age-standardized average age at onset of PCa decreased from 75.45 years in 2009 to 73.39 years in 2019, and the peak age group shifted from 75–79 years in 2009 to 70–74 years in 2019; (4) Conclusions: The rising incidence of PCa in Jiangsu Province, along with an increased proportion of cases in younger age groups, highlights the need for targeted interventions.

Objectives: Colistin is known as the last resort antibiotic to treat the infections caused by multidrug resistant foodborne pathogens. The emergence and widespread dissemination of plasmid-mediated colistin resistance gene mcr-1 in the Escherichia coli (E. coli) incurs potential threat to public health. Here, we investigated the epidemiology, transmission dynamics, and genetic characterization of mcr-1 harbouring E. coli isolates from poultry originated in Hebei Province, China. Methods: A total of 297 faecal samples were collected from the two large poultry farms in Hebei Province, China. The samples were processed for E. coli identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing. Then, the mcr-1 gene harbouring E. coli strains were identified by polymerase chain reaction and subjected to antimicrobial susceptibility testing by broth microdilution assay. The genomic characterization of the isolates was done by whole genome sequencing using the various bioinformatics tools, and multi-locus sequence typing was done by sequence analysis of the seven housekeeping genes. The conjugation experiment was done to check the transferability of mcr-1 along with the plasmid stability testing. Results: A total of six mcr-1 E. coli isolates with minimum inhibitory concentration of 4 μg/mL were identified from 297 samples (2.02%). The mcr-1 harbouring E. coli were identified as multidrug resistant and belonged to ST101 (n = 4) and ST410 (n = 2). The genetic environment of mcr-1 presented its position on IncHI2 plasmid in 4 isolates and p0111 in 2 isolates, which is a rarely reported plasmid type for mcr-1. Moreover, both type of plasmids was transferable to recipient J53, and mcr-1 was flanked by 3 mobile elements ISApl1, Tn3, and IS26 forming a novel backbone Tn3–IS26-mcr-1– pap2-ISApl1 on the p0111 plasmid. The phylogenetic analysis shared a common lineage with mcr-1 harbouring isolates from the environment, humans, and animals, which indicate its horizontal spread among the diverse sources, species, and hosts. Conclusion: This study recommends the one health approach for future surveillance across multiple sources and bacterial species to adopt relevant measures and reduce global resistance crises.

This study examines the relationship between reputational threat and altruistic behavior in children aged 6-11 and explores how social inhibition and group relationships affect this behavior. Study 1 involved 204 children and found that age and reputational threat influence altruism, with age 8 being a key turning point. Study 2 focused on 130 nine-year-olds and showed that children with low social inhibition engage in more altruistic acts, regardless of reputational threat. Study 3, with 151 participants, analyzed the effects of group dynamics based on left-behind status. Non-left-behind children preferred out-group altruism, while left-behind children showed in-group preference under reputational threat, with no difference in its absence. Left-behind children were generally more altruistic. The findings highlight age 8 as crucial for reputation strategies and suggest that reputational threat, social inhibition, and group dynamics shape altruistic behavior. This research offers insights into the positive qualities of left-behind children, informing their development and education.

Abstract Deep learning models have been developed for various predictions in glioma; yet, they were constrained by manual segmentation, task-specific design, or a lack of biological interpretation. Herein, we aimed to develop an end-to-end multi-task deep learning (MDL) pipeline that can simultaneously predict molecular alterations and histological grade (auxiliary tasks), as well as prognosis (primary task) in gliomas. Further, we aimed to provide the biological mechanisms underlying the model’s predictions. We collected multiscale data including baseline MRI images from 2776 glioma patients across two private (FAHZU and HPPH, n = 1931) and three public datasets (TCGA, n = 213; UCSF, n = 410; and EGD, n = 222). We trained and internally validated the MDL model using our private datasets, and externally validated it using the three public datasets. We used the model-predicted deep prognosis score (DPS) to stratify patients into low-DPS and high-DPS subtypes. Additionally, a radio-multiomics analysis was conducted to elucidate the biological basis of the DPS. In the external validation cohorts, the MDL model achieved average areas under the curve of 0.892–0.903, 0.710–0.894, and 0.850–0.879 for predicting IDH mutation status, 1p/19q co-deletion status, and tumor grade, respectively. Moreover, the MDL model yielded a C-index of 0.723 in the TCGA and 0.671 in the UCSF for the prediction of overall survival. The DPS exhibits significant correlations with activated oncogenic pathways, immune infiltration patterns, specific protein expression, DNA methylation, tumor mutation burden, and tumor-stroma ratio. Accordingly, our work presents an accurate and biologically meaningful tool for predicting molecular subtypes, tumor grade, and survival outcomes in gliomas, which provides personalized clinical decision-making in a global and non-invasive manner.

Abstract Background People with the metabolically obese normal weight (MONW) phenotype have been confirmed to significantly increase the risk of unfavorable health consequences. This study aimed to investigate the relationships between traditional and novel anthropometric indices with the MONW phenotype and compare the predictive ability of different anthropometric indices in identifying individuals with the MONW phenotype. Methods This cross-sectional study involved a total of 26,332 participants aged 18 years or older with a normal weight from Nanjing, China. Sociodemographic information, biochemical measurements, and anthropometric indices were collected. The novel body fat anthropometric indices included body shape index (ABSI), body roundness index (BRI), abdominal volume index (AVI), weight-adjusted-waist index (WWI), body adiposity index (BAI), conicity index (CI), waist-hip-height ratio (WHHR), as well as traditional indices such as waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR).The prevalence ratio (PR) from modified poisson regression and area under the receiver-operating characteristic curve (AUC) were conducted to compare the association and predictive capacity of different obesity indicators for the MONW phenotype. All analyses were stratified by sex. Results Modified poisson regression analyses revealed that weight, WC, HC, BMI, WHR, WHtR, ABSI, BRI, AVI, WWI, BAI, CI, and WHHR were independently associated with higher risk of the MONW phenotype, regardless of whether they were treated as a continuous or categorical variable (P

Abstract A large number of slopes appear along the line during railway construction, which will pose a threat to railway safety operation. Slope monitoring plays an important role in ensuring the safety of railway operation. Aiming at the difficulties of sensor multiplexing, low accuracy, and large disturbance by trains, this paper proposes a railway slope monitoring method based on integrated fusion detection of inclination and vibration. Instability and failure characteristics of the K3 slope in Shuohuang Railway and dynamic characteristics under the excitation of the train load are analyzed by the finite element method (FEM) analysis. Based on the above analysis, a slope monitoring system is established utilizing the self-developed dual-parameter fiber Bragg grating (FBG) sensor. The monitoring data of the past four years show that the slope is in a relatively stable state at present. The monitoring data are consistent with the results of the FEM. The feasibility of the damage identification method based on inclination and vibration characteristics is verified, which provides a new method for railway slope monitoring.

Abstract The current-driven movement of magnetic skyrmions along a nanostripe is essential for the advancement and functionality of a new category of spintronic devices resembling racetracks. Despite extensive research into skyrmion dynamics, experimental verification of current-induced motion of ultra-small skyrmions within an ultrathin nanostripe is still pending. Here, we unveil the motion of individual 80 nm-size skyrmions in an FeGe track with an ultrathin width of 100 nm. The skyrmions can move steadily along the track over a broad range of current densities by using controlled pulse durations of as low as 2 ns. The potential landscape, arising from the magnetic edge twists in such a geometrically confined system, introduces skyrmion inertia and ensures efficient motion with a vanishing skyrmion Hall angle. Our results showcase the steady motion of skyrmions in an ultrathin track, offering a practical pathway for implementing skyrmion-based spintronic devices.

Abstract Background An increasing body of evidence suggests that home-based exercise (HBE) therapy has significant therapeutic effects on knee osteoarthritis (KOA) and hip osteoarthritis (HipOA), and it has advantages such as cost savings, strong operability, and good compliance compared with hospitalization and exercise courses. Objective To evaluate the efficacy of HBE in the treatment of KOA and HipOA. Methods A systematic search was conducted in PubMed, Cochrane, Web of Science, and Embase to collect randomized controlled trials. The retrieval time was from database establishment until March 6, 2024. Stata 15.1 software was used for data analysis. Results A total of 16 randomized controlled trials involving 3,015participants were included, with 1,519 participants in the intervention group and 1,496 in the control group. The meta-analysis showed that, compared to the control group, HBE can significantly improve pain [SMD=-0.38, 95% CI (-0.58, -0.18); P = 0.001], joint function [SMD=-0.60, 95% CI (-1.01, -0.19); P = 0.004], balance ability [SMD=-0.67, 95% CI (-1.00, -0.34); P = 0.001], mobility (ADL) [SMD = 0.51, 95% CI (0.19, 0.82); P = 0.002] in patients with KOA and HipOA. There is no statistical difference in the improvement of joint stiffness [WMD = -0.80, 95% CI (-1.61, 0.01); P = 0.052]. In addition, subgroup analysis showed that HBE significantly improved pain, joint function, and balance ability in KOA patients compared with the control group. HipOA patients showed significant improvement in pain and joint function; However, HBE only improved activity ability in patients with comorbidities of KOA and HipOA. Conclusion HBE can effectively alleviate pain, improve joint function, and enhance physical function in patients with KOA and HipOA. However, more high-quality randomized controlled trials (RCTs) with large sample sizes and long-term interventions are needed to validate the efficacy of HBE due to limitations in the methodology and consistency of indicator outcomes in the included RCTs. Registration number We’ve registered with PROSPERO, and the number is CRD42023443085.

Abstract Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/β-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of β-catenin, thereby further enhancing Wnt/β-catenin signaling. Pharmacological inhibition of Wnt/β-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/β-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings.

Purpose: To investigate the safety and efficacy of intensity modulated carbon ion radiation therapy (IM-CIRT) using pencil beam scanning technology for patients with unresectable sacrococcygeal chordoma (SC). Methods and Materials: A total of 35 patients with unresectable SC were retrospectively analyzed, including 54.3% (19/35) recurrent cases. In 68.6% (24/35) cases, tumor was located in S2 or above, and all cases were treated with hypofractionated IM-CIRT. The median dose was 70.4 Gy (range, 69-80 Gy) (relative biologic effectiveness) in 16 fractions (range, 16-23 fractions), typically delivered over 5 fractions per week. Results: The 3-year overall survival, cause-specific survival, progression-free survival, locoregional progression–free survival, and distant metastasis–free survival rates with a median follow-up time of 42 months (range, 12-91 months) for the entire cohort were 93.2%, 96.3%, 61.8%, 80%, and 77.3%, respectively. Multivariate analysis revealed that gross tumor volume (hazard ratio, 3.807; 95% CI, 1.044-13.887; P = .043) was the only significant prognostic factor for progression-free survival and the dose for the gross tumor volume ≥70.4 Gy (relative biologic effectiveness) was relevant with significantly better locoregional progression–free survival (hazard ratio, 0.190; 95% CI, 0.038-0.940; P = .042). No significant prognostic factor for overall survival, cause-specific survival, and distant metastasis–free survival and no severe (ie, grade ≥3) acute toxicity were identified. Severe late toxicities occurred in 3 patients (8.57%): pain (1 patient), motor neuropathy (1 patient), and skin ulcer (1 patient). Furthermore, no severe toxicity related to urinary function or defecation was observed following IM-CIRT. Pain grades improved or remained unchanged in 85.7% of patients. Conclusions: IM-CIRT produced acceptable 3-year outcomes without substantial late adverse effects, especially urinary and anorectal complications for SC, and did not appear to increase pain. IM-CIRT at high doses using hypofractionated radiation therapy may improve outcomes for local control and seems to be feasible even for postoperative recurrent SC.

Ovarian cancer is a common cancer for females, and the incidence and mortality rates are on the rise. Many treatment strategies have been developed for ovarian cancer, including chemotherapy and immunotherapy, but they are often ineffective and prone to drug resistance. Protein ubiquitination is an important class of post-translation modifications that have been found to be associated with various human diseases and cancer development. Recent studies have revealed that protein ubiquitination is involved in the progression of ovarian cancer and plays an important role in the tumor immune process. Moreover, the combination of ubiquitinase/deubiquitinase inhibitors and cancer immunotherapy approaches can effectively reduce treatment resistance and improve treatment efficacy, which provides new ideas for cancer treatment. Herein, we review the role of protein ubiquitination in relation to ovarian cancer immunotherapy and recent advances in the use of ubiquitinase/deubiquitinase inhibitors in combination with cancer immunotherapy.

Abstract Lung diseases are one of the leading causes of global mortality. Advances in induced pluripotent stem cell (iPSC) differentiation have enabled the creation of bronchiolar and alveolar lung organoids, advancing research on lung conditions. Traditional Matrigel encapsulation, reliant on the spontaneous assembly and propagation of cells with limited external intervention, often results in variability and low reproducibility. The absence of hyaluronic acid (HA) in Matrigel, a key lung extracellular matrix component, limits bronchiolar and alveolar cell differentiation, reducing the efficacy and reproducibility of iPSC‐derived organoid generation. To address this, a novel hybrid hydrogel combining HA and 23% Matrigel, inspired by the natural lung environment, is developed. This hydrogel offers improved biochemical support and viscoelastic properties, significantly accelerating organoid development. Within eight days, the hydrogel produces uniformly sized organoids containing both bronchiolar and alveolar epithelial cells. Increased levels of active mechanosensors and transducers, including PIEZO1, Integrin, and Myosin, suggest that the hydrogel's altered viscoelasticity triggers a mechanotransduction cascade. This bioinspired hydrogel provides a robust, fast model for biomedical research, facilitating rapid drug screening, respiratory disease treatment studies, and surfactant trafficking investigations. Furthermore, it enables the exploration of underlying biomechanical mechanisms to enhance the controllability of organoid generation and maturation.

ABSTRACT Tryptophan (TRP) metabolites have been identified as potent biomarkers for complications of type 2 diabetes mellitus (T2DM). However, it remains unclear whether the therapeutic effect of metformin in T2DM is related to the modulation of TRP metabolic pathway. This study aims to investigate whether metformin affects TRP metabolism in T2DM mice through the gut microbiota. A liquid chromatography-tandem mass spectrometry method was established to determine 16 TRP metabolites in the serum, colon content, urine, and feces of T2DM mice, and the correlations between metabolites and the T2DM mice gut microbiota were performed. The method demonstrated acceptable linearity (R2 > 0.996), with the limit of quantification ranging from 0.29 to 69.444 nmol/L for 16 analytes, and the limit of detection ranging from 0.087 to 20.833 nmol/L. In T2DM mice, metformin treatment effectively restored levels of indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), and the ILA/IPA ratio, along with several aryl hydrocarbon receptor ligands in the serum, with a notable impact in the colon but not in the urine. This restoration was accompanied by a shift in the relative abundance of Dubosiella, Turicibacter, RF39, Clostridia_UCG-014, and Alistipes. Spearman’s correlation analysis revealed positive correlations between Turicibacter and Alistipes with IPA and indole-3-acetic acid. Conversely, these genera displayed negative correlations with ILA and kynurenine. In addition, our study revealed the presence of endogenous indole pathway in germ-free mice, and the impact of metformin on endogenous TRP metabolism in T2DM mice cannot be disregarded. Further research is needed to investigate the regulation of TRP metabolism by metformin.IMPORTANCEThis study provides valuable insights into the interrelationship between metformin administration, changes in the tryptophan (TRP) metabolome, and gut microbiota in type 2 diabetes mellitus (T2DM) mice. Indole-3-lactic acid (ILA)/indole-3-propionic acid (IPA) emerges as a potential biomarker for the development of T2DM and prediction of therapeutic response. While the indole metabolic pathway has long been associated exclusively with the gut microbiome, recent research has demonstrated the ability of host interleukin-4-induced-1 to metabolize TRP. The detection of indole derivatives in the serum of germ-free mice suggests the existence of inherent endogenous indole metabolic pathways. These findings deepen our understanding of metformin's efficacy in correcting TRP metabolic disorders and provide valuable directions for further investigation. Moreover, this knowledge may pave the way for the development of targeted treatment strategies for T2DM, focusing on the gut microbiome and restoration of associated TRP metabolism.

This article proposes an adaptive sliding mode control (SMC) strategy based on stochastic configuring networks (SCNs) to improve the stability of synchronous generator (SG) and virtual synchronous generator (VSG) paralleled microgrid and enhance the dynamic performance. First, derives an equivalent swing equation what coupling of inherent inertia/damping of SG and virtual inertia/damping of VSG, the parameters design problem is established to a stabilization problem of second-order uncertain nonlinear system with bounded uncertainties. Second, an adaptive sliding mode control based on variable-speed reaching law is designed to maintain the second-order nonlinear system stable, and the switch function of adaptive reaching law is improved to reduce system chattering. Then, the stochastic configuring networks is introduced to approximate the nonlinear term, and the approximation ability of SCNs is improved by designing the configuration range of input parameters of hidden layer nodes. The stability of proposed control strategy is proved by Lyapunov theory. Finally, the feasibility and effectiveness of the proposed control strategy are verified by the designed simulations and experiments.

Objective To investigate the signature genes of fatty acid metabolism and their association with immune cells in pulmonary arterial hypertension (PAH). Methods Fatty acid metabolism-related genes were obtained from the GeneCards database. In this retrospective study, a PAH-related dataset was downloaded from the Gene Expression Omnibus database and analyzed to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms, including least absolute shrinkage and selection operator (LASSO) and random forest, were used to identify the signature genes. Diagnostic efficiency was assessed by receiver operating characteristic (ROC) curve analysis and a nomogram. Immune cell infiltration was subsequently classified using CIBERSORT. Results In total, 817 DEGs were screened from the GSE33463 dataset. The data were clustered into six modules via WGCNA, and the MEdarkred module was significantly related to PAH. The LASSO and random forest algorithms identified five signature genes: ARV1, KCNJ2, PEX11B, PITPNC1 , and SCO1 . The areas under the ROC curves of these signature genes were 0.917, 0.934, 0.947, 0.963, and 0.940, respectively. CIBERSORT suggested these signature genes may participate in immune cell infiltration. Conclusions ARV1, KCNJ2, PEX11B, PITPNC1 , and SCO1 show remarkable diagnostic performance in PAH and are involved in immune cell infiltration.

Tied-arch bridges, a vital component of modern infrastructure, are susceptible to various forms of damage, particularly hangers. The detection and identification of such damages are crucial for maintaining structural integrity and safety. However, traditional methods face challenges in terms of accuracy and efficiency. This study aims to develop a refined method for hanger damage identification in tied-arch bridges, to address the limitations of existing techniques. By focusing on deflection changes at the anchoring points between the hangers and tie beams, we sought to enhance the precision of damage detection. We propose an innovative approach based on the concept of influence lines, introducing the ‘generalized deflection difference influence line'and the ‘deflection difference influence matrix’. Then proposed a new identification index for identifying the damaged hanger after matrix. An actual tied-arch bridge was used to validate the proposed approach. A detailed three-dimensional finite element model of the bridge was developed and calibrated using dynamic and static response data. Thirty different hanger-damage conditions were simulated to evaluate the effectiveness of the proposed method. Our findings reveal that the deflection difference influence matrix offers more detailed and comprehensive information on bridge distribution points than traditional methods. Our method proved effective in identifying hanger damage, irrespective of its location on the bridge. In additionally, the identification efficiency of the method can be improved by adjusting the magnitude of the applied load, with larger loads amplifying the detectability of damage. This study highlights the potential of the deflection difference influence matrix to revolutionize hanger damage identification for tied-arch bridges. Its adaptability, accuracy, and efficiency are significant advancements over existing methods. This study successfully demonstrates an innovative and reliable method for hanger damage identification.

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IntroductionHousehold health expenditure plays a crucial role in the daily spending of individuals. Meanwhile, the attention of the public to subjective well-being (SWB) is constantly increasing in China. Household health expenditure could reduce real family income, harming personal SWB. However, the aim of household health expenditure is to improve the physical condition of an individual, and improvements in individual health could enhance personal SWB. Therefore, the effect of household health expenditure on personal SWB is uncertain; hence, it is essential to assess the effects of household health expenditure on the SWB of Chinese residents.MethodsThe Chinese family panel studies database from 2016 to 2020 was applied in this study. A fixed effects model was used to examine the impact of household medical and health protection expenses on personal SWB. Fixed effects instrumental variable regression and propensity score matching were then used to conduct robustness testing.ResultsOn the basis of a fixed effects model, it was found that household medical and health protection expenditure did not improve the happiness and life satisfaction of individuals; rather, household health protection expenditure could significantly reduce personal happiness. Fixed effects instrumental variable regression and propensity score matching analysis supported these results. Household health protection expenditure had a greater negative impact on the happiness and life satisfaction of females compared with males.ConclusionHousehold health expenditure does not improve the SWB of individuals in China; this has certain significance for the formulation of relevant policies.

The planning of university campus directly impacts students’ quality of study and living, and there is a considerable amount of research on campus planning assessment, most of which uses post-occupancy evaluation methods. This paper tries to propose a new comprehensive assessment method for campus planning, which collects spatio-temporal behavioral data of students in their daily life through GPS software, then assesses the actual effect of campus planning comprehensively by analyzing the spatio-temporal behavioral characteristics of students. This paper also verifies the reliability of the student behavior characteristics analysis through questionnaire and explores the possible biases. The results indicate that, in addition to significant advantages in reliability, accuracy, and comprehensive judgment, the proposed method can visually reflect specific issues existing within tangible campus spaces and their impact on student behavior. Therefore, it can provide practical and reliable evidence for the practice of campus planning renewal. This method used in this paper is also applicable to other fixed group living spaces within a certain scale, like communities and neighborhoods.

Abstract Background Insulin resistance (IR) and obesity are established risk factors for hypertension, with triglyceride-glucose (TyG) serving as a recognized surrogate marker for IR. The aim of this study was to investigate the association between TyG-BMI and hypertension in the general population. Methods A total of 60,283 adults aged ≥18 years who underwent face-to-face questionnaires, anthropometric measurements, and laboratory examination were included in this study. Multivariable logistic regression models and receiver operating characteristic curve (ROC) were used to determine the association between TyG-BMI and hypertension. The restricted cubic spline model was used for the dose-response analysis. Results After fully adjusting for confounding variables, multivariate logistic regression model showed a stable positive association between TyG-BMI and hypertension (OR: 1.61 per SD increase; 95% CI: 1.55–1.67; P-trend

Abstract Liquid Chromatography Mass Spectrometry (LC-MS) is a powerful method for profiling complex biological samples. However, batch effects typically arise from differences in sample processing protocols, experimental conditions, and data acquisition techniques, significantly impacting the interpretability of results. Correcting batch effects is crucial for the reproducibility of omics research, but current methods are not optimal for the removal of batch effects without compressing the genuine biological variation under study. We propose a suite of Batch Effect Removal Neural Networks (BERNN) to remove batch effects in large LC-MS experiments, with the goal of maximizing sample classification performance between conditions. More importantly, these models must efficiently generalize in batches not seen during training. A comparison of batch effect correction methods across five diverse datasets demonstrated that BERNN models consistently showed the strongest sample classification performance. However, the model producing the greatest classification improvements did not always perform best in terms of batch effect removal. Finally, we show that the overcorrection of batch effects resulted in the loss of some essential biological variability. These findings highlight the importance of balancing batch effect removal while preserving valuable biological diversity in large-scale LC-MS experiments.

Abstract Background Good health self-management positively affects the health of healthcare providers and their ability to manage their patients’ health. This study explored the relationship between ehealth literacy, health self-management skills, and mental health literacy among undergraduate nursing students. Some studies have confirmed the correlation between e-health literacy and health self-management skills, while mental health literacy may be correlated with both, and this study aims to explore the relationship between the three. Methods A descriptive cross-sectional survey was conducted at a medical university in northwestern China among 385 Chinese undergraduate nursing students. Participants completed the General Information Questionnaire, the Adult Health Self-Management Skills Rating Scale, the Mental Health Literacy Rating Scale, and the eHealth Literacy Scale, and provided valid responses. The IBM SPSS 27.0 statistical software was used for data entry and descriptive analysis, t-test, ANOVA, and Pearson correlation analysis. The IBM Amos 26.0 was used to construct the mediation effect model, and the Bootstrap method was employed to test mediating effects. Results Mental health literacy, ehealth literacy, and health self-management skills of undergraduate nursing students were at a moderate to high level. Mental health literacy, ehealth literacy, and health self-management were positively correlated. Mental health literacy, particularly, played a partial mediating role of 31.1% ( 95% CI [0.307–1.418] ) between ehealth literacy and health self-management. Conclusions Undergraduate nursing students’ mental health literacy partially mediates the link between eHealth literacy and health self-management skills. Schools should emphasize the development of nursing students’ e-health literacy and mental health literacy in order to improve their health self-management skills, which will not only bring about a better health outcome for the students, but will also benefit the health of the social population.

Abstract Background Cardiovascular disease (CVD) is a major global health threat, particularly in China, contributing to over 40% of deaths. While sleep behaviors, sedentary behaviors, and physical activities are recognized as independent lifestyle risk factors for CVD, there remains limited understanding of specific movement behavior patterns and their CVD risks, especially considering sex-specific differences. This study examines movement behavior patterns among Chinese adults (40–75) and their associations with cardiovascular risk, with a focus on sleep, physical activity (PA), and sedentary behavior (SB). Methods Data pertaining to 13,465 male participants and 15,613 female participants, collected from the Chronic Disease and Risk Factor Surveillance Survey in Nanjing from February 2020 to December 2022. The latent class analysis method was employed to identify underlying movement patterns across sexes. Multinomial logistic regression models assessed CVD risk, and the China-PAR model calculated 10-year risk. Results Three male and four female movement patterns emerged. Active Movers (17.10% males, 5.93% females) adhered to PA recommendations but had poorer sleep quality. Moderate Achievers (61.42% males, 45.32% females) demonstrated moderate behavior. Sedentary Sleepers (21.48% males, 10.20% females) exhibited minimal PA but good sleep. Female Moderate Physical Activity (MPA) Dominant Movers demonstrated a prevalent adherence to recommended MPA levels. Active movers had the lowest CVD risk. After adjusting for potential confounders, moderate achievers (OR = 1.462, 95% CI 1.212, 1.764) and sedentary sleepers (OR = 1.504, 95% CI 1.211, 1.868) were both identified as being associated with a high-risk of cardiovascular diseases (CVDs) compared to active movers in males, demonstrating a similar trend for intermediate risk. Such associations were not statistically significant among females. Conclusions Our study revealed sex-specific movement patterns associated with CVD risks among middle-aged Chinese adults. We suggest that adopting an active movement behavior pattern, characterized by meeting or exceeding recommended levels of vigorous physical activity (VPA) and reducing sedentary behavior, is beneficial for all middle-aged adults, particularly males. An active lifestyle could help counteract the adverse effects of relatively poor sleep quality on the risk of developing CVD in this population. Integrating sleep, PA, and SB information provides a holistic framework for understanding and mitigating CVD risks.

Abstract Heavy metal contamination is an urgent ecological governance problem in mining areas. In order to seek for a green and environmentally friendly reagent with better plant restoration effect to solve the problem of low efficiency in plant restoration in heavy metal pollution soil. In this study, we evaluated the effects of three biodegradable chelating agents, namely citric acid (CA), fulvic acid (FA) and polyaspartic acid (PASP), on the physicochemical properties of copper tailings, growth of ryegrass (Lolium perenne L.) and heavy metal accumulation therein. The results showed that the chelating agent application improved the physicochemical properties of copper tailings, increased the biomass of ryegrass and enriched more Cu and Cd in copper tailings. In the control group, the main existing forms of Cu and Cd were oxidizable state, followed by residual, weak acid soluble and reducible states. After the CA, FA or PASP application, Cu and Cd were converted from the residual and oxidizable states to the reducible and weak acid soluble states, whose bioavailability in copper tailings were thus enhanced. Besides, the chelating agent incorporation improved the Cu and Cd extraction efficiencies of ryegrass from copper tailings, as manifested by increased root and stem contents of Cu and Cd by 30.29–103.42%, 11.43–74.29%, 2.98–110.98% and 11.11–111.11%, respectively, in comparison with the control group. In the presence of multiple heavy metals, CA, FA or PASP showed selectivity regarding the ryegrass extraction of heavy metals from copper tailings. PCA analysis revealed that the CA-4 and PASP-7 treatment had great remediation potentials against Cu and Cd in copper tailings, respectively, as manifested by increases in Cu and Cd contents in ryegrass by 90.98% and 74.29% compared to the CK group.

Black tea is the most important in the world tea production, and is very popular in the world tea market. China has abundant tea resources, especially unused tea leaves in summer and autumn, and there are a few new ways to develop them, such as processing black tea or deep processed products. Application of exogenous enzymes with good functional characteristics, can improve the quality of summer and autumn black teas, and their deep processed products. This article reviews that, the current status and existing problems of exogenous enzymes application in black tea processing in recent years, as well as the types and acting mechanisms of frequently-used exogenous enzymes, transformation of tea components catalyzed by exogenous enzymes during withering, rolling, and fermentation in black tea processing. Utilizing exogenous enzymes to promote the synthesis of theaflavins, a unique component of black tea, and the quality changes in deep-processing of black tea, are also summarized. Exploring the enzymatic processing methods, could promote the efficient utilization of tea resources, and regulate quality of summer and autumn black tea, as well as their deep-processed products, in the future.

An integrated computer software system for macromolecular crystallography (MX) data collection at the BL02U1 and BL10U2 beamlines of the Shanghai Synchrotron Radiation Facility is described. The system, Finback, implements a set of features designed for the automated MX beamlines, and is marked with a user-friendly web-based graphical user interface (GUI) for interactive data collection. The Finback client GUI can run on modern browsers and has been developed using several modern web technologies including WebSocket, WebGL, WebWorker and WebAssembly. Finback supports multiple concurrent sessions, so on-site and remote users can access the beamline simultaneously. Finback also cooperates with the deployed experimental data and information management system, the relevant experimental parameters and results are automatically deposited to a database.

Held every four years, the International Workshop on Tropical Cyclone (IWTC) organized by the World Meteorological Organization has been a global leading conference in the field of tropical cyclone. In preparation for the 10th IWTC (IWTC-10) in December 2022, a summary of research advances of landfalling tropical cyclone (LTC) rainfall during past four years of 2019–2022 has been prepared. Some of the latest research advances has been summarized in Lamers et al. (2023), which reviewed the latest forecast and disaster prevention methods related to TC precipitation. As a supplement, this article mainly focuses on the recent advances in LTC asymmetric rainfall evolution mechanisms and forecast verification results over China. Some new findings have been made in the LTC inner-core size relationship with the asymmetric rainfall distribution. Some major advances focused on asymmetric microphysical characteristics in the TC rainbands. Current simulation and forecast performances of LTC precipitation have been analyzed, and different forecast error sources for rainfall during different landfall stages of TC were compared. To estimate the risk of TC rainfall hazards in China, a parameterized Tropical Cyclone Precipitation Model was reviewed as well in this article.

With the virus continuing to evolve, very virulent IBDV (vvIBDV) and novel variant IBDV (nvIBDV) have become the predominant epidemic strains in China, exacerbated by the widespread use of attenuated vaccine strains (attIBDV), making a complex infection situation of IBDV in the field. Therefore, developing a rapid and accurate high-resolution melting curve quantitative reverse transcription PCR (HRM-qRT-PCR) for the identification and pathotyping of IBDV is crucial for clinical monitoring and disease control. Extensive data analysis and genome-screening of the three dominant IBDV pathotypes identified a specific region (nucleotides 2450–2603 in segment A) with distinct GC content as the detection target. Experimental testing of HRM-qRT-PCR revealed distinct melting curves and high sensitivity, with the detection limits of 61.2 copies/μL, 61.1 copies/μL and 67.5 copies/μL for vvIBDV, nvIBDV and attIBDV, respectively. The method exhibited excellent specificity, with no inter-genotypes cross-reactivity among the three pathotypes and no reactivity to other common avian pathogens. Applied to samples with double and triple co-infections of different IBDV pathotypes, the method displayed specific melting peaks corresponding to the viruses present in the samples, with an accuracy rate of 100 %. This method precisely identifies and differentiates all the single or co-infected samples, generating distinct peaks corresponding to the Tm values of each virus pathotype in traditional melting curve plots. Furthermore, the method overcomes the limitations of traditional pathotyping methods, requiring only one reaction to achieve rapid viral pathotyping and facilitating quantitative analysis of viruses within the samples. This study introduces an innovative HRM-qRT-PCR method, offering new technology to rapid and accurate identification, pathotyping and quantification of vvIBDV, nvIBDV, and attIBDV. With strong discriminatory power, user-friendliness and a short processing time, this method is highly attractive for the rapid IBDV pathotyping in real-time large-scale epidemiological surveillance during outbreaks.

Visual geo-localization using prior map of known environments has extensive applications in the fields such as self-driving, augmented reality and navigation. Currently, such prior maps are usually constructed by visual SLAM or SFM. However, the recent advances in LiDAR SLAM technology with RGB camera demonstrate great potential in efficient and accurate prior map construction and visual geo-localization. In this research, we developed a novel prior map construction approach which seamlessly integrates a handheld LiDAR SLAM system, a global LiDAR localization algorithm and a sparse set of terrestrial LiDAR scans as accurate control within a factor graph optimization framework. The developed LiDAR SLAM system augmented by terrestrial LiDAR scans achieves an improved mapping accuracy of 8 cm under GNSS-denied conditions in the areas over 50,000 m2 while the state-of-art FAST-LIO2 alone fails and produces a mapping error over 30 m. The results show that a competitive accuracy of visual geo-localization on a mobile phone using the constructed prior map is achieved (i.e. 60 and 76 cm in two tests respectively). Finally, this work also demonstrates a novel LiDAR point cloud fusion method that produces optimized and consistent coarse-to-fine 3D reconstruction in large and complex scenes.

ABSTRACT: This study aimed to probe if xylooligosaccharide (XOS) could act as an antimetabolite to impact the cell cycle and antibiotic tolerance of avian pathogenic Escherichia coli (APEC). We firstly measured the bacteriostasis of XOS against APEC O78 and its effect on the growth of APEC O78 growing on different medium. Afterwards, the effects of XOS on xylose operon activation along with the cell cycle and antibiotic tolerance of APEC O78 were analyzed. The results showed that XOS caused no inhibitory circle against APEC O78 and did not affect (P > 0.05) the growth of APEC O78 growing on LB medium. Besides, APEC O78 was unable to grow on M9 medium (carbon-free) added with XOS. However, XOS exerted a similar role as xylose in increasing (P < 0.05) the expression of certain xylose operon genes including xylose isomerase (XylA)-encoding gene (xylA) and xylose-binding periplasmic protein (XylF)-encoding gene (xylF) in APEC O78. The molecular docking simulation revealed that the major monomer components (xylobiose, xylotriose and xylotetraose) of XOS had stable binding potentials to both XylA and XylF proteins of E. coli, as supported by the low binding free energy and the formation of considerable hydrogen bonds between them. The subsequent analysis showed that XOS altered certain cell cycle-related genes expression, especially elevated (P < 0.05) nrdB expression and decreased ihfB expression to a degree. Moreover, XOS played a similar role as 2-deoxy-glucose (a glucose analogue serving as a typical antimetabolite) in lowering (P < 0.05) the number of ampicillin-tolerant APEC O78. Collectively, XOS had no direct bacteriostasis against APEC and could not be metabolized/utilized by APEC O78. However, it might become an analogue of xylose and then activate xylose transport- and metabolism-related proteins in APEC O78, thus functioning as a potential antimetabolite and exerting antimetabolic actions. This could at least partially interpret the observed roles of XOS in interfering with the cell cycle and diminishing the antibiotic tolerance of APEC O78. The above findings expand the knowledges about the functions of XOS and provide a basis for exploring novel strategies to reduce the antibiotic tolerance of APEC.

Objectives: The aim of this study was to investigate the mechanism of itaconate’s potential effect in diabetic kidney disease.Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138–147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

ABSTRACTFlagella play a crucial role in the invasion process of Salmonella and function as a significant antigen that triggers host pyroptosis. Regulation of flagellar biogenesis is essential for both pathogenicity and immune escape of Salmonella. We identified the conserved and unknown function protein STM0435 as a new flagellar regulator. The ∆stm0435 strain exhibited higher pathogenicity in both cellular and animal infection experiments than the wild-type Salmonella. Proteomic and transcriptomic analyses demonstrated dramatic increases in almost all flagellar genes in the ∆stm0435 strain compared to wild-type Salmonella. In a surface plasmon resonance assay, purified STM0435 protein-bound c-di-GMP had an affinity of ~8.383 µM. The crystal structures of apo-STM0435 and STM0435&c-di-GMP complex were determined. Structural analysis revealed that R33, R137, and D138 of STM0435 were essential for c-di-GMP binding. A Salmonella with STM1987 (GGDEF protein) or STM4264 (EAL protein) overexpression exhibits completely different motility behaviours, indicating that the binding of c-di-GMP to STM0435 promotes its inhibitory effect on Salmonella flagellar biogenesis.

Novel variant infectious bursal disease virus (nvIBDV) is an emerging genotype (A2dB1b) that can cause severe and prolonged immunosuppression in young chickens. Despite current commercial vaccines being proven to lack complete protection against nvIBDV, it remains unclear whether the oil emulsion inactivated vaccines (OEVs) of the homologous and heterologous virus or booster immunization can provide effective protection. In this study, OEVs with two types of nvIBDV isolates QZ191002 (A-nv/B-nv) and YL160304 (A-nv/B-HLJ0504-like) were prepared and evaluated the protective effects of OEVs plus the booster immunizations with different current commercial vaccines against the challenge of nvIBDVs. The results from vaccination-challenge experiments showed that nvIBDV could break through the protection provided by only one immunization dose of the commercial vaccines, with the protection rates ranging from 40% to 60%. Interestingly, even with booster immunization with different commercial vaccines, the protection rates could only be increased to 60%–80%. As expected, only the OEVs of the homologous virus could provide 100% protection against the homologous nvIBDV, which could induce high-level specific antibodies, ameliorate target organ damage, and significantly reduce the viral load of the bursal in the challenged chickens. Notably, YL160304-OEV performed better than QZ191002-OEV, providing 100% protection not only against the challenge of homologous strain but also against that of heterologous QZ191002 strain. Antibody levels of the immunized chickens gradually increased after a short decline and reached the highest level on the age of 28 days. Similarly, the percentages of lymphocytes CD4+, CD8+ T, and B in peripheral blood lymphocytes (PBLs) were significantly increased on 21 d and 28 d. Notably, despite the nvIBDV, OEVs initially induced a delayed responses in the early stages but ultimately reach higher levels of CD4+ and CD8+ T lymphocytes. The results of study suggest that even booster immunization with different commercial vaccines cannot provide complete protection against nvIBDV, while the OEVs made by the nvIBDVs can provide full protection. Moreover, YL160304-OEV exhibits a broader protective spectrum against different nvIBDV strains, making it a potential candidate for the development of new vaccine.

BackgroundPrevious studies based on resting-state functional magnetic resonance imaging(rs-fMRI) and voxel-based morphometry (VBM) have demonstrated significant abnormalities in brain structure and resting-state functional brain activity in patients with early-onset schizophrenia (EOS), compared with healthy controls (HCs), and these alterations were closely related to the pathogenesis of EOS. However, previous studies suffer from the limitations of small sample sizes and high heterogeneity of results. Therefore, the present study aimed to effectively integrate previous studies to identify common and specific brain functional and structural abnormalities in patients with EOS.MethodsThe PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), and WanFang databases were systematically searched to identify publications on abnormalities in resting-state regional functional brain activity and gray matter volume (GMV) in patients with EOS. Then, we utilized the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software to conduct a whole-brain voxel meta-analysis of VBM and rs-fMRI studies, respectively, and followed by multimodal overlapping on this basis to comprehensively identify brain structural and functional abnormalities in patients with EOS.ResultsA total of 27 original studies (28 datasets) were included in the present meta-analysis, including 12 studies (13 datasets) related to resting-state functional brain activity (496 EOS patients, 395 HCs) and 15 studies (15 datasets) related to GMV (458 EOS patients, 531 HCs). Overall, in the functional meta-analysis, patients with EOS showed significantly increased resting-state functional brain activity in the left middle frontal gyrus (extending to the triangular part of the left inferior frontal gyrus) and the right caudate nucleus. On the other hand, in the structural meta-analysis, patients with EOS showed significantly decreased GMV in the right superior temporal gyrus (extending to the right rolandic operculum), the right middle temporal gyrus, and the temporal pole (superior temporal gyrus).ConclusionThis meta-analysis revealed that some regions in the EOS exhibited significant structural or functional abnormalities, such as the temporal gyri, prefrontal cortex, and striatum. These findings may help deepen our understanding of the underlying pathophysiological mechanisms of EOS and provide potential biomarkers for the diagnosis or treatment of EOS.