Search

Abstract Background The complex interactions between host genetics and the gut microbiome are well documented. However, the specific impacts of gene expression patterns and microbial composition on each other remain to be further explored. Results Here, we investigated this complex interplay in a sizable population of 705 hens, employing integrative analyses to examine the relationships among the host genome, mucosal gene expression, and gut microbiota. Specific microbial taxa, such as the cecal family Christensenellaceae, which showed a heritability of 0.365, were strongly correlated with host genomic variants. We proposed a novel concept of regulatability ( $${r}_{b}^{2}$$ r b 2 ), which was derived from h 2, to quantify the cumulative effects of gene expression on the given phenotypes. The duodenal mucosal transcriptome emerged as a potent influencer of duodenal microbial taxa, with much higher $${r}_{b}^{2}$$ r b 2 values (0.17 ± 0.01, mean ± SE) than h 2 values (0.02 ± 0.00). A comparative analysis of chickens and humans revealed similar average microbiability values of genes (0.18 vs. 0.20) and significant differences in average $${r}_{b}^{2}$$ r b 2 values of microbes (0.17 vs. 0.04). Besides, cis ( $${h}_{\text{cis}}^{2}$$ h cis 2 ) and trans heritability ( $${h}_{\text{trans}}^{2}$$ h trans 2 ) were estimated to assess the effects of genetic variations inside and outside the cis window of the gene on its expression. Higher $${h}_{\text{trans}}^{2}$$ h trans 2 values than $${h}_{\text{cis}}^{2}$$ h cis 2 values and a greater prevalence of trans-regulated genes than cis-regulated genes underscored the significant role of loci outside the cis window in shaping gene expression levels. Furthermore, our exploration of the regulatory effects of duodenal mucosal genes and the microbiota on 18 complex traits enhanced our understanding of the regulatory mechanisms, in which the CHST14 gene and its regulatory relationships with Lactobacillus salivarius jointly facilitated the deposition of abdominal fat by modulating the concentration of bile salt hydrolase, and further triglycerides, total cholesterol, and free fatty acids absorption and metabolism. Conclusions Our findings highlighted a novel concept of $${r}_{b}^{2}$$ r b 2 to quantify the phenotypic variance attributed to gene expression and emphasize the superior role of intestinal mucosal gene expressions over host genomic variations in elucidating host‒microbe interactions for complex traits. This understanding could assist in devising strategies to modulate host–microbe interactions, ultimately improving economic traits in chickens. Graphical Abstract The host genome, hepatic and duodenal transcriptomes, and gut microbiome were integrated to elucidate the regulatory mechanisms underlying the complex phenotypes of chickens. Heritability estimation and GWASs from the genome, regulatability estimation from the transcriptome, and microbiability estimation from the microbiome were collectively calculated for the host phenotypes. By integrating genome and transcriptome data, the cis- and trans-heritability of genes were estimated, and methods such as eQTL mapping and SMR were used to elucidate the genetic regulatory mechanisms of phenotypes. By integrating genome and microbiome data, we conducted microbial heritability estimation and GWASs to explore the extent to which the host genome shapes the microbiota. By integrating transcriptome and microbiome data, we estimated the microbiability of genes and the regulatability of the microbiota, exploring the degree of interaction between host gene expression and the gut microbiota. By combining all the analytical methods mentioned above, a more advanced and comprehensive understanding of the extent and manner of host and microbiota interactions that regulate host phenotypes can be achieved. Video Abstract

Abstract Background The global rise in multidrug-resistant Acinetobacter baumannii infections poses a significant healthcare challenge. Bacteriophage offer a promising alternative to antibiotics for treating A. baumannii infections. Phage tail fiber and spike proteins are essential for host recognition, with some exhibiting depolymerase activity that aids in degrading the bacterial cell wall, facilitating infection. Detailed studies of the functional domains responsible for depolymerase activity and receptor-binding in phage tail fiber/spike proteins are a crucial step toward developing effective phage treatments. Results A total of 32 functional domains were identified across 313 tail fiber and spike proteins from 204 publicly available Acinetobacter baumannii phages using InterPro and AlphaFold3. Domains associated with depolymerase function were Pectin lyase-like domain (PLD), phage_tailspike_middle domain (PTMD), Transglycosidases domain (TGD), and SGNH hydrolase domain (SHD). These domains were primarily found in phages from the Autographiviridae family, specifically within the Friunavirus genus. The predominant PLD domain displayed high variability, with its sequence conserved only in a 25-amino-acid region among two closely related fiber/spike protein lineages. All enzymatic domains exhibit high sequence diversity yet retain structural stability, which is essential for enzymatic function. As for receptor-binding domains, four types of pyocin_knob domains (PKD) were initially identified, characterized by unique β-sheet and α-helix configurations. Each type of PKD exhibited distinct potential receptor-binding sites, primarily located within the α-helix region, and was closely associated with the Obolenskvirus genus, as well as the Autographiviridae and Straboviridae families. The G3DSA:2.60.40.3940 domain, exhibiting minor structural variations, was predominantly found in phages of the Obolenskvirus genus. Additionally, a novel Obo-β-sandwich structure, identified as a potential receptor-binding domain, was discovered within Obolenskvirus genus cluster. The structural diversity of these receptor-binding domains accounts for their interactions with various receptors. Conclusions This research deepens the understanding of the relationship between A. baumannii phage genera and the functional domains within their tail fiber/spike proteins, emphasizing the compatibility between structural characteristics and functional roles. The data obtained could serve as a reference for the targeted modification of phages or their tail fiber/spike proteins, enhancing their therapeutic applications.

Abstract Background Polyps containing bizarre stromal cells are occasionally observed in the lower gynecologic tract, including the vagina, cervix, and endometrium, predominantly in perimenopausal or postmenopausal patients. These cases have traditionally been considered benign without subsequent recurrence or malignancy. Case presentation We describe a rare instance of a rapid enlarging endometrial polyp characterized by atypical stromal cells in a 76-year-old postmenopausal woman, who presented with vaginal bleeding. Histologically, the polyp was noted for its abundance of atypical stromal cells interspersed among thick-walled vascular channels. Higher magnification revealed eosinophilic cytoplasm in the stromal cells, which exhibited both mono- and multinucleation, hyperchromasia with coarse chromatin, and an absence of conspicuous nucleoli and mitotic figures. A consensus among two of three consulting expert gynecological pathologists supported a benign endometrial polyp diagnosis; however, one pathologist raised the possibility of adenosarcoma, highlighting the diagnostic dilemma these unique lesions present. Despite a hysterectomy recommendation, the patient chose monitoring over immediate surgery. Persistent vaginal bleeding led to her return six months later, whereupon a 7-cm polypoid lesion in the endometrial cavity was found and removed via hysterectomy. The histopathology mirrored the initial findings, showing no myometrial invasion, prompting a re-evaluation of the presumed benign nature of the polyp given its rapid growth. Remarkably, RNA sequencing analysis of the polyp detected a JAK2::NFIB gene fusion, a novel finding for endometrial polyps with atypical stromal cells, the clinical implications of which remain to be elucidated. Conclusion The rapid recurrence of the polyp within six months raises new questions about the true biological nature of these entities and the relevance of gene fusions like JAK2::NFIB in their pathogenesis, meriting further investigation.

Abstract Radiotherapy (RT) is the primary treatment modality for nasopharyngeal carcinoma (NPC). However, the tumor microenvironment (TME)-induced radioresistance often compromises its therapeutic efficacy. Herein, we propose an innovative bidirectional radiosensitization strategy for NPC. Specifically, we have encapsulated metformin (Met) and copper sulfide nanoparticles (CuS NPs) within injectable DNA supramolecular hydrogels (DSH) to create a novel radiosensitizer, Met-CuS@DSH. This radiosensitizer not only effectively reverses tumor hypoxia to promote reactive oxygen species (ROS) generation but also significantly inhibits glutathione (GSH)-mediated ROS scavenging, thereby achieving bidirectional radiosensitization by enhancing ROS production and suppressing its scavenging. This strategy significantly improves the therapeutic effect of NPC while reducing the RT dose (3 Gy in total), which provides a promising approach for overcoming the radioresistance of NPC caused by TME. Graphical Abstract

Abstract Background The importance of parathyroid gland preservation in thyroid surgery has been well recognized; however, the rapid identification of the parathyroid gland, particularly the inferior parathyroid gland (IPG), remains challenging. This study aimed to evaluate the effectiveness of retrograde inferior parathyroid protection technique (RIPPT) based on thymus preservation. Methods A total of 236 patients were enrolled in this study between August 2019 and December 2020. RIPPT was employed to identify and protect the inferior parathyroid gland (IPG), and its identification rate and the anatomical variations were analyzed. The parathyroid hormone (PTH) and serum calcium levels were compared between patients who underwent IPG orthotopic retention and those who received IPG auto-transplantation, stratified by the anatomical type of the IPG. Results In total, the IPG identification rate was 97.88% (231/236), and the auto-transplantation rate was 74.46% (172/231). The anatomical relationship between IPG and thymus was observed in 77.97% of patients (184/236). Additionally, PTH levels were higher in patients with IPG orthotopic retention compared to those with IPG auto-transplantation both on postoperative day 1 (POD1) and at 6 months. PTH levels were also higher in patients with superior parathyroid gland (SPG) and IPG orthotopic retention compared to those who underwent both auto-transplantation procedures. Conclusion Retrograde inferior parathyroid protection technique (RIPPT) underscores the importance of protecting inferior parathyroid gland (IPG) in thyroid surgery and has been demonstrated to be effective in the rapid identification and functional preservation of IPG, based on short-term outcomes. Clinical trial number Not applicable.

Abstract Neuroinflammation induced by activation of microglial is a vital contributor to progression of Parkinson’s disease (PD), emerging evidences suggested that ferroptosis played a pivotal role in microglial activation and subsequent dopaminergic neuron loss. Nevertheless, the fundamental pathogenesis of that ferroptosis contributes to PD is not yet sufficiently understood. Based on GEO dataset, ferroptosis related genes were found to be enriched in PD patients and MPTP mouse model of PD, among them, ATF4 was found to be dramatically differentially expressed. In our study, ectopic expression of ATF4 augmented MPP+-induced cytotoxic and activation of BV2 cells with upregulated intracellular L-ROS, TLR4 and pNF-κB. Ectopic ATF4 effectively promoted transformation of microglial into M1 pro-inflammatory phenotype. 17β-estradiol (E2) attenuated expression of ATF4 in BV2 cells, silence of ATF4 enhanced protective effect of E2 on MPP+-treated BV2 cells. In MPTP-induced PD mouse model, administration of E2 further abated expression of ATF4 and inhibited expressions of pro-inflammatory cytokines and activation of TLR4/NF-κB pathway. Overall, E2 effectively counteracted TLR4/NF-κB signaling pathway by restraining ATF4 and inhibited inflammatory response triggered by ferroptosis, ultimately exerted anti-PD effects.

Abstract As big data technologies continue to evolve, recommendation systems have found broad application in domains such as online retail and social networking platforms. However, centralized recommendation systems raise numerous data privacy concerns. Federated learning addresses these concerns by allowing model training on client devices and aggregating model parameters without sharing raw data. Nevertheless, federated learning faces critical challenges related to feature extraction efficiency and noise sensitivity, limiting its application in e-commerce recommendation systems where data heterogeneity and high-dimensional features are prevalent. To address these gaps, this paper introduces a novel multi-view federated learning framework, Fed-FR-MVD, designed to enhance feature extraction efficiency and improve recommendation accuracy in e-commerce applications. Fed-FR-MVD integrates a FR mechanism within a multi-view structure, incorporating both item and user perspectives to improve feature representation and robustness. This approach yields a 12%–18% increase in recommendation accuracy across various performance metrics compared to single-view and other multi-view methods. By addressing data heterogeneity and optimizing feature utilization through dynamic rescaling, Fed-FR-MVD effectively mitigates the impact of noisy data, with performance maintained across noise levels of 5%–15%. Experimental results demonstrate that Fed-FR-MVD fills a key research gap by providing a more resilient and efficient framework for federated recommendation systems in privacy-sensitive and data-diverse e-commerce environments.

Abstract Atopic dermatitis (AD) is an immune-related skin disease with a genetic background. Numerous loci have been identified associated with AD to better comprehend its complicated genetic mechanisms by genome‑wide association studies (GWASs). However, current studies reveal the underlying mechanisms of these loci in the pathogenesis of AD inadequately. Therefore, we integrated the GWAS statistics of AD with plasma proteins to explore candidate proteins correlated with the pathogenesis of AD based on protein-centered omics studies. Herein, we adopted the updated AD GWAS statistics (N = 864,982) and the dataset of plasma protein quantitative trait loci (pQTLs), comprising 1,348 proteins from individuals of European descent. We first conducted the AD-related proteome-wide association studies (PWASs) (N = 7,213) by integrating pQTLs with the AD GWAS statistics and identified twenty-six significant plasma proteins by PWAS (FDR

Abstract The involvement of the androgen receptor (AR) pathway in developing epithelial ovarian cancer is increasingly acknowledged. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. This study was initiated by investigating the impact of flutamide on miRNA expression in women at high risk (HR) for ovarian cancer. Ovarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women as well as low-risk (LR) women controls. We performed miRNA sequencing on these 3 sample cohorts and observed that flutamide normalized miRNA levels in HR tissues, notably upregulating the miR-449 family to levels seen in LR tissues. In subsequent tests in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey), flutamide also increased miR-449a and miR-449b-5p levels. Introducing mimics of these miRNAs reduced the mRNA and protein levels of AR and colony-stimulating factor 1 receptor (CSF1R, also known as c-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. Ovarian cancer cell migration was inhibited upon introducing miR-449a and miR-449b-5p mimics. Together, our study suggests a novel dual-inhibitory mechanism of flutamide on the AR pathway (AR expression suppression in addition to direct androgen antagonism) and supports its chemopreventive potential in ovarian cancer, especially for HR patients with low miR-449 expression.

Objective The objective of this study was to identify the N6-methyladenosine (m6A)-circHECA molecule in secondary hair follicles (SHFs) of cashmere goats, and generate its potential regulatory network, as well as explore the potential relationship between transcriptional pattern of m6A-circHECA and promoter methylation of its host gene (HECA). Methods The validation of circHECA m6A sites was performed using methylation immunoprecipitation (Me-RIP) along with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technique. The nucleus and cytoplasm localizations of m6A-circHECA were performed using SHF stem cells of cashmere goats with RT-qPCR analysis. Based on in-silico analysis, the regulatory networks of m6A-circHECA were generated with related signal pathway enrichment. The methylation level of promoter region of m6A-circHECA host gene (HECA) was assessed by the bisulfite sequencing PCR (BSP-PCR) technique. Results The m6A-circHECA was confirmed to contain four m6A modification sites including m6A-213, m6A-297, m6A-780, and m6A-927, and it was detected mainly in cytoplasm of the SHF stem cells of cashmere goats. The integrated regulatory network analysis showed directly or indirectly complex regulatory relationships between m6A-circHECA of cashmere goats and its potential target molecules: miRNAs, mRNAs, and proteins. The regulatory network and pathway enrichment indicated that m6A-circHECA might play multiple roles in the SHF physiology process of cashmere goats through directly or indirectly interacting or regulating its potential target molecules. A higher methylation level of promoter region of HECA gene in SHFs of cashmere goats might cause the lower expression of m6A-circHECA. Conclusion The m6A-circHECA might play multiple roles in SHF physiology process of cashmere goats through miRNA mediated pathways along with directly or indirectly interaction with its target proteins. The promoter methylation of m6A-circHECA host gene (HECA) most likely was implicated in its expression inhibition in SHFs of cashmere goats.

Abstract Fluorouracil-based chemotherapy responses in colorectal cancer (CRC) patients vary widely, highlighting the role of pharmacogenomics in developing better predictive models. We analyzed 379 CRC patients receiving fluorouracil-based chemotherapy, collecting data on fluorouracil metabolism-related SNPs (TYMS, MTHFR, DPYD, RRM1), blood inflammatory markers, and clinical status. Six machine learning models—K-nearest neighbors, support vector machine, gradient boosting decision trees (GBDT), eXtreme Gradient Boosting (XGBoost), LightGBM, and random forest—were compared against multivariate logistic regression and a deep learning model (i.e., multilayer perceptron, MLP). Feature importance analysis highlighted seven predictors: histological grade, N and M staging, monocyte count, platelet-to-lymphocyte ratio, MTHFR rs1801131, and RRM1 rs11030918. In a five-fold cross-validation, XGBoost and GBDT exhibited superior performance, with Area Under Curve (AUC) of 0.88 ± 0.02. XGBoost excelled in identifying favorable prognosis (recall = 0.939). GBDT demonstrated balance in recognizing both categories, with a recall for favorable prognosis of 0.908 and a precision for unfavorable prognosis of 0.863. MLP had a similar AUC (0.87) with high precision for favorable prognosis (recall = 0.946). In external validation, XGBoost model achieved an accuracy of 0.79. An online prognostic tool based on XGBoost was developed, integrating metabolism-related SNPs and inflammatory markers, enhancing CRC treatment precision and supporting tailored chemotherapy.

OBJECTIVES Ascending to altitudes >2500 m may lead to acute mountain sickness (AMS). METHODS The demographics, height, weight, body mass index (BMI), smoking, and alcohol consumption of 104 healthy controls were collected in Chengdu (500 m). Heart rate (HR), saturation of pulse oxygen (SpO2), and AMS-related symptoms were collected in Hoh Xil (4200 m). A headache with Lake Louise score ≥3 was defined as AMS. RESULTS The incidence of AMS was 60.58%. AMS group had a lower SpO2 and higher HR than non-AMS group. Alcohol consumption seemed a risk factor for AMS. There was no difference in the BMI, age, height, weight, and smoking between AMS and non-AMS groups. The most common AMS symptom was headache, followed by dyspnea, insomnia, dizziness, lassitude, and anorexia. Women were prone to suffer from dizziness. The value of SpO2 and HR was improved both in AMS and non-AMS groups after hypoxia acclimatization, and the value showed greater improvement in AMS group. Oxygen therapy decreased the AMS-induced tachycardia, which had no any effect on SpO2 and symptom alleviating time. CONCLUSION Lower SpO2 and higher HR following exposure to high altitude were associated with AMS susceptibility. The anthropometric data changes were larger in AMS group than non-AMS group before and after hypoxia acclimatization.

Focusing on the theoretical logic of Chinese government sports expenditure promoting public participation in sports, this study takes 31 provinces (cities, autonomous regions) in China as research objects and uses fsQCA to explore the configurational pathways of government sports expenditure affecting public participation in sports. Using the fuzzy set qualitative comparative analysis (fsQCA) method, and taking the Sports Industry Statistical Yearbook (2020 data) as the data source, this paper discusses how government sports expenditure can improve the level of public participation in sports through different combinations of driving factors. The results show that there are four effective condition combination paths, which can be summarized as the dual-core drive of “technological innovation + sports culture promotion and dissemination” and the “key housing support guarantee type” path, both of which are particularly crucial for improving public participation in physical activity. The findings of this study emphasize the importance of diversified investment in government sports expenditure for enhancing public participation in physical activity, suggesting that the government should adopt a cross-departmental resource integration strategy to build a comprehensive ecosystem supporting physical activity participation.

The multi-administration of recombinant adeno-associated virus (rAAV) is limited largely by immunological barriers. Herein, a novel strategy, named rAAV pseudo-lipid nanoparticle combined with triamcinolone acetonide (LNP-rAAV + TAC), has been described in mice. We showed successful but low efficient triple trafficking by LNP-rAAV2 carrying EGFP, human factor IX (hFIX), and luciferase (luc), due to its encapsulation characteristic. Additionally, sustained TAC treatment, which dose-dependently downregulated the anti-rAAV2 antibodies, permitted rAAV2 re-administration at dosages of ≥45 mg/kg/3 days. Furthermore, to improve the efficiency and safety, LNP-rAAV + TAC was evaluated, using LNP-rAAV2 carrying EGFP, hFIX, and luc co-treating with 45 mg/kg/3 days TAC before and after treatment with LNP-rAAV2 injections. Notable neutralizing antibody reductions of 37.8-fold and 12.7-fold were observed by the combinatorial strategy compared with the independent LNP encapsulation and TAC treatment approaches. The plasma hFIX protein was enhanced to 15.1 μg/mL and the liver bioluminescence was elevated to 1.4 × 108 p/s/cm2/sr following the second and third administrations, with weaker levels in LNP encapsulation (1.9 μg/mL, 2.1 × 104 p/s/cm2/sr) and TAC treatment (3.0 μg/mL, 6.1 × 104 p/s/cm2/sr) groups. Thus, this combination strategy is an attractive candidate for enabling multi-dosing of rAAV vector and warrants further study on the underlying mechanism.

BackgroundThe exploration of genetic signatures within the ovarian cancer (OC) tumor microenvironment (TME) remains limited. M2-like tumor-associated macrophages (M2-like TAMs) are pivotal in OC progression and therapy. This study aims to establish a novel prognostic signature and identify M2-like TAM-related biomarkers in OC using RNAseq-based transcriptome analysis.MethodsPrognostic M2-like TAM-related genes were identified through univariate Cox regression, consensus clustering, and LASSO regression. Immune landscape analysis was conducted to assess immune cell composition and immune checkpoint genes in high- and low-risk groups. Subsequently, in vitro cell experiments and OC cohorts were performed.ResultsGene set enrichment analysis revealed that GNA15 is involved in immune responses like leukocyte transendothelial migration and FcγR-mediated phagocytosis. GNA15 was up-regulated in cisplatin-resistant OC cells, and its in vitro down-regulation decreased cell proliferation. An eight-gene prognostic model, including M2-like TAM-related genes, independently predicted poor outcomes in OC. GNA15 emerged as a hub gene positively correlated with M2-like TAMs infiltration, predicting unfavorable outcomes across OC cohorts. Moreover, GNA15 expression correlated positively with CD163 expression, suggesting its role in macrophage polarization.ConclusionGNA15 plays an immunosuppressive role in OC progression linked to M2-like TAMs polarization and stands as a potential prognostic marker in OC.

Northern ecosystems, encompassing boreal forests, tundra, and permafrost areas, are increasingly affected by the amplified impacts of climate change. These ecosystems play a crucial role in determining the global carbon budget. To improve our understanding of carbon uptake in these regions, we evaluate the effectiveness of employing the physically-based Plant Phenology Index (PPI) to estimate gross primary productivity across ten different ecosystems. Based on eddy-covariance measurements from 65 sites, the vegetation index (VI)-driven GPP models (six different algorithms) are calibrated and validated. Our findings highlight that the Michaelis–Menten algorithm has the best performance and PPI is superior to the other five VIs, including NDVI, NIRv, EVI-2, NDPI, and NDGI, at predicting gross primary productivity (GPP) rates on a weekly scale (with an average R2 of 0.64 and RMSE of 1.70 g C m−2 d−1), regardless of short-term environmental constraints on photosynthesis. Through our scaled-up analysis, we estimate the annual GPP of the vast 37 million km2 study region to be around 22 Pg C yr−1, aligning with other recently developed products such as GOSIF-GPP, FluxSat-GPP, and FLUXCOM-X GPP. Derived from a climate-independent approach, the PPI-GPP product offers distinct advantages in exploring relationships between climate variables and terrestrial ecosystem productivity and phenology. Furthermore, this product holds significant value for assessing forestry and agricultural production in northern regions and for benchmarking terrestrial biosphere models and Earth system models.

Context: Urban areas are increasingly susceptible to extreme flooding events, posing significant challenges to residents’ safety and well-being. In this context, understanding the relationship between urban landscape patterns (ULP) and residents’ perceptions of safety (RPS) is crucial for effective flood disaster management. Objectives: This study explores the relationship between ULP and RPS during extreme flooding events, using Zhengzhou city as a case study. The goal is to offer strategic insights for managing extreme flood disasters. Methods: Surveying 1329 residents impacted by urban flooding in Zhengzhou, this study employed the Gradient Boosting Decision Tree (GBDT) model to examine the nonlinear relationship between ULP and RPS amidst extreme flood disasters. Results: Results indicate: (1) ULP significantly impacts RPS, with a relative importance of 44.8%, particularly influenced by the Largest Patch Index (LPI), Landscape Connectivity Index (CONTAG), and Patch Density (PD); (2) The effect of landscape pattern indices on RPS reveals a complex nonlinear relationship, exhibiting various patterns such as ’stage-wise negative correlation,’ ’U-shaped,’ and ’inverted V-shaped’ with noticeable threshold effects. The interaction effect also shows that the internal interplay of the ULP indicator, along with its interactions with flood-relevant contextual variables, significantly enhances RPS. (3) As covariates, flood impact and emergency resource accessibility also influence RPS with nonlinear trends. Conclusions: This study offers a new perspective on the relationship between ULP and RPS, emphasizing the critical role of flood response strategies tailored to ULP differences in enhancing RPS.

Proteins in egg whites play vital roles in embryonic development. Simultaneously, protein modification is affected by the surrounding environment, which ultimately affects the structure and function of proteins. Here, we measured the phenotypes of eggs at different time points during storage and incubation and used 4D label-free quantitative proteomics technology and liquid chromatography/tandem mass spectrometry (LC-MS/MS)-technique to identify the differential proteins and N-glycosylation sites in egg whites during storage and incubation. We found that the differential N-glycoproteins in the early stage of storage were mainly related to protein structure changes, antibacterial activity, and cell proliferation, and that there were more protease inhibitors in egg whites, which decreased in the later stage of storage. Finally, eleven possible protein markers and N-glycosylation sites were identified to significantly change during storage and may exert an effect on hatchability, including the proteins involved in antibacterial activity (OVOA-N855, CLU-N154, ogchi-N82, PIGR-N290, WFDC2-N120), protein structure (LOC776816), and cell proliferation (ASAH1-N173). This study provides substantial insights into the physical and molecular compositional changes in egg whites under different storage times and revealed their potential effect on chick embryo development.

Abstract Background Hippocampal disruptions represent potential neuropathological biomarkers in depressed adolescents with cognitive dysfunctions. Given heterogeneous outcomes of whole-hippocampus analyses, we investigated subregional abnormalities in depressed adolescents and their associations with symptom severity and cognitive dysfunctions. Methods MethodsSeventy-nine first-episode depressive patients (ag = 15.54 ± 1.83) and 71 healthy controls (age = 16.18 ± 2.85) were included. All participants underwent T1 and T2 imaging, completed depressive severity assessments, and performed cognitive assessments on memory, emotional recognition, cognitive control, and attention. Freesurfer was used to segment each hippocampus into 12 subfields. Multivariable analyses of variance were performed to identify overall and disease severity-related abnormalities in patients. LASSO regression was also conducted to explore the associations between hippocampal subfields and patients’ cognitive abilities. Results Depressed adolescents showed decreases in dentate gyrus, CA1, CA2/3, CA4, fimbria, tail, and molecular layer. Analyses of overall symptom severity, duration, self-harm behavior, and suicidality suggested that severity-related decreases mainly manifested in CA regions and involved surrounding subfields with disease severity increases. LASSO regression indicated that hippocampal subfield abnormalities had the strongest associations with memory impairments, with CA regions and dentate gyrus showing the highest weights. Conclusions Hippocampal abnormalities are widespread in depressed adolescents and such abnormalities may spread from CA regions to surrounding areas as the disease progresses. Abnormalities in CA regions and dentate gyrus among these subfields primarily link with memory impairments in patients. These results demonstrate that hippocampal subsections may serve as useful biomarkers of depression progression in adolescents, offering new directions for early clinical intervention.

Abstract Background Dengue virus (DENV) is the most widespread arbovirus. The World Health Organization (WHO) declared dengue one of the top 10 global health threats in 2019. However, it has been underrepresented in bibliometric analyses. This study employs bibliometric analysis to identify research hotspots and trends, offering a comprehensive overview of the current research dynamics in this field. Results We present a report spanning from 1995 to 2023 that provides a unique longitudinal analysis of Dengue virus (DENV) research, revealing significant trends and shifts not extensively covered in previous literature. A total of 10,767 DENV-related documents were considered, with a notable increase in publications, peaking at 747 articles in 2021. Plos Neglected Tropical Diseases has become the leading journal in Dengue virus research, publishing 791 articles in this field—the highest number recorded. Our bibliometric analysis provides a comprehensive mapping of DENV research across multiple dimensions, including vector ecology, virology, and emerging therapies. The study delineates a complex network of immune response genes, including IFNA1, DDX58, IFNB1, STAT1, IRF3, and NFKB1, highlighting significant trends and emerging themes, particularly the impacts of climate change and new outbreaks on disease transmission. Our findings detail the progress and current status of key vaccine candidates, including the licensed Dengvaxia, newer vaccines such as Qdenga and TV003, and updated clinical trials. The study underscores significant advancements in antiviral therapies and vector control strategies for dengue, highlighting innovative drug candidates such as AT-752 and JNJ-1802, and the potential of drug repurposing with agents like Ribavirin, Remdesivir, and Lopinavir. Additionally, it discusses biological control methods, including the introduction of Wolbachia-infected mosquitoes and gene-editing technologies. Conclusion This bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV.

Abstract Background Feed efficiency is a crucial economic trait in poultry industry. Both host genetics and gut microbiota influence feed efficiency. However, the associations between gut microbiota and host genetics, as well as their combined contributions to feed efficiency in laying hens during the late laying period, remain largely unclear. Methods In total, 686 laying hens were used for whole-genome resequencing and liver transcriptome sequencing. 16S rRNA gene sequencing was conducted on gut chyme (duodenum, jejunum, ileum, and cecum) and fecal samples from 705 individuals. Bioinformatic analysis was performed by integrating the genome, transcriptome, and microbiome to screen for key genetic variations, genes, and gut microbiota associated with feed efficiency. Results The heritability of feed conversion ratio (FCR) and residual feed intake (RFI) was determined to be 0.28 and 0.48, respectively. The ileal and fecal microbiota accounted for 15% and 10% of the FCR variance, while the jejunal, cecal, and fecal microbiota accounted for 20%, 11%, and 10% of the RFI variance. Through SMR analysis based on summary data from liver eQTL mapping and GWAS, we further identified four protein-coding genes, SUCLA2, TNFSF13B, SERTM1, and MARVELD3, that influence feed efficiency in laying hens. The SUCLA2 and TNFSF13B genes were significantly associated with SNP 1:25664581 and SNP rs312433097, respectively. SERTM1 showed significant associations with rs730958360 and 1:33542680 and is a potential causal gene associated with the abundance of Corynebacteriaceae in feces. MARVELD3 was significantly associated with the 1:135348198 and was significantly correlated with the abundance of Enterococcus in ileum. Specifically, a lower abundance of Enterococcus in ileum and a higher abundance of Corynebacteriaceae in feces were associated with better feed efficiency. Conclusions This study confirms that both host genetics and gut microbiota can drive variations in feed efficiency. A small portion of the gut microbiota often interacts with host genes, collectively enhancing feed efficiency. Therefore, targeting both the gut microbiota and host genetic variation by supporting more efficient taxa and selective breeding could improve feed efficiency in laying hens during the late laying period.

Abstract Simultaneous achievement of lightweight, ultrahigh strength, large fracture strain, and high damping capability is challenging because some of these mechanical properties are mutually exclusive. Here, we utilize self-assembled polymeric carbon precursor materials in combination with scalable nano-imprinting lithography to produce nanoporous carbon nanopillars. Remarkably, nanoporosity induced via sacrificial template significantly reduces the mass density of amorphous carbon to 0.66 ~ 0.82 g cm−3 while the yield and fracture strengths of nanoporous carbon nanopillars are higher than those of most engineering materials with the similar mass density. Moreover, these nanopillars display both elastic and plastic behavior with large fracture strain. A reversible part of the sp2-to-sp3 transition produces large elastic strain and a high loss factor (up to 0.033) comparable to Ni-Ti shape memory alloys. The irreversible part of the sp2-to-sp3 transition enables plastic deformation, leading to a large fracture strain of up to 35%. These findings are substantiated using simulation studies. None of the existing structural materials exhibit a comparable combination of mass density, strength, deformability, and damping capability. Hence, the results of this study illustrate the potential of both dense and nanoporous amorphous carbon materials as superior structural nanomaterials.

Abstract The orf virus (ORFV) poses a serious threat to the health of domestic small ruminants (i.e., sheep and goats) and humans on a global scale, causing around $150 million in annual losses to livestock industry. However, the host factors involved in ORFV infection and replication are still elusive. In this study, we compared the RNA-seq profiles of ORFV-infected or non-infected sheep testicular interstitial cells (STICs) and identified a novel host gene, potassium voltage-gated channel subfamily E member 4 (KCNE4), as a key host factor involved in the ORFV infection. Both RNA-seq data and RT-qPCR assay revealed a significant increase in the expression of KCNE4 in the infected STICs from 9 to 48 h post infection (hpi). On the other hand, the RT-qPCR assay detected a decrease in ORFV copy number in both the STICs transfected by KCNE4 siRNA and the KCNE4 knockout (KO) HeLa cells after the ORFV infection, together with a reduced fluorescence ratio of ORFV-GFP in the KO HeLa cells at 24 hpi, indicating KCNE4 to be critical for the ORFV infection. Furthermore, the attachment and internalization assays showed decreased ORFV attachment, internalization, replication, and release by the KO HeLa cells, demonstrating a potential inhibition of ORFV entry into the cells by KCNE4. Pretreatment with the KCNE4 inhibitors such as quinidine and fluoxetine significantly repressed the ORFV infection. All our findings reveal KCNE4 as a novel host regulator of the ORFV entry and replication, shedding new insight into the interactive mechanism of ORFV infection. The study also highlights the K+ channels as possible druggable targets to impede viral infection and disease.

Abstract Objective This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system. Methods The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. Results Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. Conclusion Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Highlights Oxygen-vacancy-rich SiC@MoO3 nanocomposite with strong reflection loss (− 50.49 dB at 1.27 mm thickness) and broadband absorption band (8.72 GHz at 2.68 mm thickness) were constructed via in situ etching strategy. The presence of oxygen vacancy leads to an increased conductive loss and defect-induced dipole polarization, which plays significant role in attenuating the incident electromagnetic wave.

Abstract Drug resistance to chemotherapy in cancers remains significant clinical challenges. CD44 modulates cellular adhesion, migration and growth, which plays a pivotal role in driving cancer resistance and even recurrence. Despite ongoing efforts, accurate, safe, and real-time dynamic monitoring techniques for CD44 expression remain inadequate in guiding the management of drug-resistant cancer treatment. In this study, we developed a nano-quenching and recovery detector of CD44 (Cy3-AptCD44@BPNSs) for visualizing cancer drug resistance. The fluorescence recovery of the detector is directly related to the CD44 expression level on cancer cells, which can be used to indicate the degree of drug resistance. It’s confirmed that downregulating CD44 expression on cancer cells results in a corresponding decrease in the fluorescence intensity of the detector, which enables precise and dynamic monitoring of CD44. In addition, the Cy3-AptCD44@BPNSs also exhibited specificity in detecting CD44. This visualizing strategy may open up a wide range of possibilities for rapid recognition to cancer drug resistance, which is more efficient and flexible.

For low-productivity gas wells, insufficient formation pressure leads to issues like liquid loading and decreased gas production rates. Intermittent production, where wells are periodically shut-in and open, is a common approach to address these problems. This strategy allows formation pressure recovery during the shut-in period, which leads to a higher gas rate during the production period to carry liquids out of the wellbore. However, unreasonable operating schedules can result in problems such as insufficient formation pressure recovery and issues of liquid loading. Therefore, an optimization method for intermittent gas wells based on particle swarm optimization (PSO) algorithm and deep-learning model is proposed. The PSO algorithm determines the optimal schedule, while the deep-learning model forecasts key cycle parameters for these potential schedules. A total of 110,000 key cycle parameters dataset extracted from high-frequency raw data of 304 wells is used in the model training process. The test results show that the trained model accurately predicted all selected key cycle parameters, with R2 values ranging from 0.91 to 0.99. Finally, the optimization method was applied to 100 wells in the gas field for real-time validation. Field application results show a success rate exceeding 95%, demonstrating the effectiveness of the proposed method for real-time production optimization of low-productivity gas wells under intermittent production.

In this study, we examined the effects of different residual feed intakes (RFIs) on nutrient digestibility and the microbiota of the digestive tract of Dexin fine-wool sheep. Fifty 70-day-old Dexin fine-wool meat lambs were selected as the experimental group and fed in a single pen for 100 days. Based on their mid-term metabolic weight, 100-day average daily weight gain and daily feed intake, the male Dexin lambs were divided into a low-RFI group (13), a mid-RFI group (18), and a high-RFI group (11). Six male Dexin lambs were selected from each group to collect feces, rumen digesta and solid digesta. Rectal feces were collected from three lambs in each group. The results showed that the digestibility of dry matter and crude protein by sheep in the L-RFI group was than that in the H-RFI group (P < 0.05). Within the microbial population, f_Anaerovoracaceae, g_Christensenellaceae_R_7_group, p_Proteobacteria, and g_Roseburia were significantly correlated with RFI. Energy metabolism, metabolism of amino acids and carbohydrates, transport and catabolism, and cell migration pathways were upregulated in the L-RFI group. The differences in the microbiota of the digestive tract of sheep with different RFIs were reflected in the presence of some key bacterial genera rather than changes in the overall microbial diversity.

Background: Population-based estimates of brain metastases in follicular thyroid cancer (FTC) patients with or without distant metastases (DMs) at diagnosis are lacking. Objective: To study the prevalence of brain metastases in FTC patients and compare gender disparity. Methods: DMs are defined as bone, lung and brain metastases. Using the SEER database, we identified 5116 patients diagnosed with FTC between 2010 and 2019. The incidences of brain metastases were calculated for the entire cohort and among patients with bone/lung metastases. Cohorts were stratified by gender and age. Results: 4.8% (245) had DMs at diagnosis, primarily in the form of bone metastases (3.6%), followed by lung metastases (2.4%). The incidence of brain metastases at initial diagnosis was only 0.37% (17 females and 2 males) but occurred in 8.2 and 6.1% of patients with bone metastases and lung metastases, respectively. Median survival for patients with brain metastases was only 8.0 months (95% CI: 4.1–11.9). Interestingly, female patients with bone metastases exhibited a significantly higher incidence of brain metastases compared to males (12.0 vs 1.5%), with a notable odds ratio (OR) of 8.971 (95% CI: 1.152–69.835) in univariate analysis. Multivariate logistic regression analysis confirmed that being female (OR: 10.08, 95% CI: 1.243–81.748) was the sole statistically significant risk factor for brain metastases in FTC patients with bone metastases at diagnosis. Conclusion: An incidence of brain metastases is observed in newly diagnosed FTC patients with DMs, especially in females with bone involvement. Our findings advocate for the early detection of brain metastases in female FTC patients with concurrent bone metastases at diagnosis.

The body size traits are major traits in livestock, which intuitively displays the development of the animal’s bones and muscles. This study used PCR amplification, Sanger sequencing, KASPar genotyping, and quantitative real-time reverse transcription PCR (qRT-PCR) to analyze the Single-nucleotide polymorphism and expression characteristics of Argonaute RISC catalytic component 2 (AGO2) and Plectin (PLEC) genes in Hu sheep. Two intron mutations were found in Hu sheep, which were AGO2 g.51700 A > C and PLEC g.23157 C > T, respectively. Through association analysis of two mutation sites and body size traits, it was found that AGO2 g.51700 A > C mainly affects the chest and cannon circumference of Hu sheep of while PLEC g.23157 C mainly affects body height and body length. The combined genotypes of AGO2 and PLEC genes with body size traits showed SNPs at the AGO2 g.51700 A > C and PLEC g.23157 C > T loci significantly improved the body size traits of Hu sheep. In addition, the AGO2 gene has the highest expression levels in the heart, rumen, and tail fat, and the PLEC gene is highly expressed in the heart. These two loci can provide new research ideas for improving the body size traits of Hu sheep.

Abstract Chemodynamic therapy (CDT) has shown promising antitumor effects in various malignant tumors. However, its application for glioblastoma (GBM) is significantly hindered by the challenge of delivering CDT agents across the blood‐brain barrier (BBB) and achieving efficient tumor targeting. To overcome these obstacles, this study presents a novel DNA nanomachine (Cu@tFNAs‐G‐A NM) by loading copper ions (Cu2+) onto tetrahedral framework nucleic acids (tFNAs) functionalized with dual DNA aptamers. The dual DNA aptamers (GS24 for BBB penetration and AS1411 for tumor targeting) empowered Cu@tFNAs‐G‐A NM with the ability to effectively penetrate the BBB and selectively accumulate in tumor cells. Upon internalization, the loaded Cu2+ reacted with tumor‐overexpressed reductive glutathione (GSH) and hydrogen peroxide (H2O2), generating hydroxyl radicals (·OH) and inducing tumor cell death. Additionally, Cu@tFNAs‐G‐A NM was found to be rapidly cleared from the brain and normal tissues within 24 h, minimizing potential systemic toxic side effects. These findings demonstrate the promising potential of Cu@tFNAs‐G‐A NM for effective CDT against GBM and open up new avenues for the development of targeted therapies for GBM.

Mammary glands Hyperplasia (MGH) is a benign condition common in middle-aged women. This study addresses the therapeutic effects of various deer antler medicinal materials on MGH, a topic of increasing interest. The research compares the anti-MGH effects of these materials and investigates their mechanisms. Results indicate that deer antler materials inhibited abnormal proliferation in MCF-10 A cells and improved conditions in MGH rats particularly, Cervus nippon antler (CNA) showed the most significant effects. CNA treatment reduced nipple diameter, improved organ index, and alleviated pathological hyperplasia. It also decreased lobules and alveoli in mammary glands, reduced ductal dilation, and regulated sex hormone levels and receptor expression in MGH rats' serum. Transcriptomic analyses revealed that CNA lowers expression of RANKL, NF-κB, and Cyclin D1 in mammary tissue, inhibiting progress through the G1/S phase of mammary cells and inhibiting proliferation. These findings suggest that CNA could be an effective treatment for MGH, warranting further exploration of its mechanisms and applications in breast disease.

Accurately simulating stomatal behavior is crucial for understanding water, carbon, and energy fluxes between land and atmosphere. Given the significant impact of plastic film mulching on water and temperature, it is essential to incorporate water and temperature modifications into stomatal conductance models under these conditions. In this study, we evaluated three commonly used stomatal conductance models: Ball-Woodrow-Berry (BWB), Ball-Berry-Leuning (BBL), and unified stomatal optimization (USO), to simulate the stomatal conductance of spring maize with or without mulching. We introduced modifications based on air temperature, canopy temperature, and water-temperature synergistic factors. Our results indicate that the USO model performed best, followed by the BBL and BWB models. Introducing temperature response functions improved simulation accuracy, with water-temperature synergistic models (-Tc&T) outperforming others. Models modified by canopy temperature (-Tc) outperformed those modified by air temperature (-Ta). Specifically, for the BWB model, the -Ta, -Tc, and -Tc&T modifications decreased root mean square error (RMSE) by 11.5–33.3 %, 19.2–50.6 %, and 29.5–56.7 %, respectively. For the BBL model, these reductions were 6.0–30.4 %, 20.9–48.1 %, and 25.4–52.9 %, respectively. For the USO model, the reductions were 7.9–55.2 %, 11.1–56.3 %, and 27.8–64.4 %, respectively. By comparing the simulated stomatal conductance curves with the 95 % confidence intervals (CI) of the observed data, we determined that the water-temperature synergistic model is optimal for various temperature conditions, followed by the Tc-modified and Ta-modified models. This study enhances our understanding of stomatal conductance under different temperature conditions and offers a foundation for accurately simulating carbon and water cycles in agricultural ecosystems under diverse water and temperature conditions.

North China is one of China’s most severely warming and drying regions, and understanding the dynamics of forest carbon sinks in North China is critical for forest management in response to climate change. This study examined the spatial and temporal dynamics of forest carbon sinks in North China from 2000 to 2020 using carbon cycle process and soil respiration data, and explored the relationship between the sinks’ spatial and temporal dynamics and changes in major climatic factors, particularly the effects of droughts on the forest sinks. The results showed that forest net ecosystem productivity (NEP) in North China increased significantly at 7.0 gC·m−2·yr−1 over the last 21 years, mainly concentrated along Yanshan (e.g. Hebei Province) and Qinling (e.g. south-central Shaanxi Province) area. Shaanxi had the fastest NEP growth rate, while Henan had the slowest. The spatial distribution of forest NEP in North China decreased with increasing latitude, and the increase in NEP from 2000 to 2010 attained 115 gC·m−2 was higher than that from 2010 to 2020. Moisture is the main climatic factor affecting forest carbon sinks in North China, but there is some spatial heterogeneity in the response patterns to precipitation, drought, and temperature in different regions. Drought levels have dramatically impacted forests in North China, and drought losses and post-drought recovery for NEP increased as drought levels increased. Extreme drought had the greatest impact on the forest NEP, with a loss of up to 93.46 gC m−2, but the recovery from drought was much greater than the loss from drought, the entire increase might be as high as 120 gC·m−2. Forest carbon sinks in North China have superior drought resistance, recovery, and resilience. This study illustrates the impact of conservation measures like afforestation in North China through the dynamic distribution of carbon sinks and also highlights the impacts of drought events with varying severity on forest carbon sinks.

BackgroundRecent studies offer conflicting conclusions about the effectiveness of digital health interventions in changing physical activity behaviors. In addition, research focusing on digital health interventions for college students remains relatively scarce. ObjectiveThis study aims to examine the impact of digital health interventions on physical activity behaviors among college students, using objective measures as outcome indicators. MethodsIn accordance with the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a comprehensive literature search was conducted across several databases, including MEDLINE (PubMed), Web of Science, Cochrane Library, and EBSCO (CINAHL Plus with full text), to identify relevant intervention studies published up to June 6, 2023. The inclusion criteria specified studies that examined the quantitative relationships between digital health interventions and physical activity among adults aged 18 years to 29 years, focusing on light physical activity (LPA), moderate to vigorous physical activity (MVPA), sedentary time (ST), or steps. Non–randomized controlled trials were excluded. The quality of the studies was assessed using the Cochrane Risk of Bias tool. Results were synthesized both narratively and quantitatively, where applicable. When sufficient homogeneity was found among studies, a random-effects model was used for meta-analysis to account for variability. ResultsIn total, 8 studies, encompassing 569 participants, were included in the analysis. The primary outcomes measured were LPA, MVPA, ST, and steps. Among these studies, 3 reported on LPA, 5 on MVPA, 5 on ST, and 3 on steps. The meta-analysis revealed a significant increase in steps for the intervention group compared with the control group (standardized mean difference [SMD] 0.64, 95% CI 0.37-0.92; P

BackgroundThe Klotho gene is implicated in suppressing aging phenotypes and influencing age-related diseases. Previous studies have delved into its connection with different diseases, yet the association between Klotho and hearing loss has rarely been examined. A recent population study explored the relationship between serum Klotho and hearing loss, but it had certain limitations. This study aims to analyze the link between serum α-Klotho levels and hearing thresholds, as well as the risk of hearing loss.MethodsA total of 1,762 adults aged 40–69 years were selected from the 2011–2012 National Health and Nutrition Examination Survey (NHANES). Data on audiometry, serum α-Klotho levels, and relevant covariates were gathered. Statistical analyses, including linear and logistic regression, assessed the relationships of serum α-Klotho levels with hearing outcomes.ResultsIncreased serum α-Klotho levels were correlated with diminished hearing thresholds and a lower risk of hearing loss. Quartile analysis revealed a significant trend, where elevated α-Klotho levels were linked to better auditory outcomes. Adjusted models controlled for various covariates, affirming the robustness of the findings. Non-linear associations were not observed.ConclusionThis study provided novel evidence of a negative association between serum α-Klotho and hearing impairment in adults aged 40–69. Our results suggested a protective role of serum α-Klotho on adults with hearing loss.

Heterogeneous landscape environments can lead to varying effectiveness of ecological restoration techniques (ERT). Distinguishing heterogeneous landscapes for adaptive management in ecological engineering projects is key to maximizing their ecological benefits. This paper conducted a quantitative analysis of the effectiveness of different ERTs in the Effect Zone of the China-Nepal Highway. The study firstly divided the China-Nepal Highway Effect Zone into seven ecoregions using the SKATER spatial clustering algorithm. Seven spatial-physical factors, including annual average rainfall (RAIN), annual average temperature (TEMP), vegetation supply water index (VSWI), altitude, relief ratio (RR), slope (S), soil organic carbon (SOC), total nitrogen (TP), and total phosphorus (TP), are used for analysis, and watersheds are used as the smallest clustering unit. Secondly, an index system for evaluating the effectiveness of different ERTs was constructed, and the entropy weight method was used to determine the weight of each indicator. Furthermore, four evaluation methods, RSR, TOPSIS, VIKOR and FCE, were used to conduct a fuzzy Borda combined evaluation of the effectiveness of different ERTs at distinct ecoregions. The results suggest that the varying resilience of different ecoregions is likely the major reason in causing the differences in the effectiveness of ERTs. Lastly, we constructed an adaptive management system for ecological engineering projects along the China-Nepal Highway based on the spatial suitability of ERTs in each ecoregion.

Cold stress is a critical factor affecting rice production worldwide. The application of cold-resistant agents may improve the cold resistance and yield of crops. To screen for suitable cold-resistant agents for machine-transplanted early rice, the effects of uniconazole, abscisic acid, and zinc-amino acids chelate and their spraying times (seed soaking stage, one leaf and one heart stage, two leaves and one heart stage, 7 days before the transplanting stage, and regreening stage) on the yield and cold resistance of machine-transplanted early rice were investigated. Moreover, the application method (spraying amount: 750 and 1125 g ha−1; spraying time: 7 days before the transplanting stage, transplanting stage, regreening stage, and transplanting stage and regreening stage) for the most suitable cold-resistant agent was optimized. The zinc-amino acids chelate was better than the other two cold-resistant agents for promoting rice tillering and increasing the leaf area index, dry matter weight, antioxidant enzyme activities (CAT, SOD, POD) and yield (i.e., 9.22% and 7.14% higher than uniconazole and abscisic acid, respectively), especially when it was applied in the regreening stage. The examination of spraying amounts and times indicated that the zinc-amino acids chelate dosage had no significant effect on the yield and cold resistance of early rice. However, the rice yield and antioxidant enzyme activities were highest when samples were sprayed once in the transplanting stage and the regreening stage. On the basis of the study results, 750 g ha−1 zinc-amino acids chelate applications in the transplanting and regreening stages of machine-transplanted early rice plants may be ideal for increasing cold stress resistance and yield.

Abstract Engineering multimetallic nanocatalysts with the entropy‐mediated strategy to reduce reaction activation energy is regarded as an innovative and effective approach to facilitate efficient heterogeneous catalysis. Accordingly, conformational entropy‐driven high‐entropy alloys (HEAs) are emerging as a promising candidate to settle the catalytic efficiency limitations of nanozymes, attributed to their versatile active site compositions and synergistic effects. As proof of the high‐entropy nanozymes (HEzymes) concept, elaborate PdMoPtCoNi HEA nanowires (NWs) with abundant active sites and tuned electronic structures, exhibiting peroxidase‐mimicking activity comparable to that of natural horseradish peroxidase are reported. Density functional theory calculations demonstrate that the enhanced electron abundance of HEA NWs near the Fermi level (EF) is facilitated via the self‐complementation effect among the diverse transition metal sites, thereby boosting the electron transfer efficiency at the catalytic interface through the cocktail effect. Subsequently, the HEzymes are integrated with a portable electronic device that utilizes Internet of Things‐driven signal conversion and wireless transmission functions for point‐of‐care diagnosis to validate their applicability in digital biosensing of urinary biomarkers. The proposed HEzymes underscore significant potential in enhancing nanozymes catalysis through tunable electronic structures and synergistic effects, paving the way for reformative advancements in nano‐bio analysis.

BackgroundTelemedicine provides remote health care services to overcome constraints of time and space in accessing medical care. Similarly, internet hospitals in China support and provide remote health care services. Due to the COVID-19 pandemic, there has been a proliferation of internet hospitals. Many new services, including online consultations and regular online follow-up visit services, can now be accessed via internet hospitals in China. However, the accessibility, cost, and quality advantages of regular online follow-up visit services remain unclear. ObjectiveThis study aimed to evaluate the accessibility, costs, and quality of an online regular follow-up visit service provided by an internet hospital in China. By analyzing the accessibility, costs, and quality of this service from the supply and demand sides, we can summarize the practical and theoretical experiences. MethodsA mixed methods study was conducted using clinical records from 18,473 patients receiving 39,239 online regular follow-up visit services at an internet hospital in 2021, as well as interviews with 7 physicians, 2 head nurses, and 3 administrative staff members. The quantitative analysis examined patient demographics, diagnoses, prescriptions, geographic distribution, physician characteristics, accessibility (travel time and costs), and service hours. The qualitative analysis elucidated physician perspectives on ensuring the quality of online health care. ResultsPatients were predominantly middle-aged men with chronic diseases like viral hepatitis who were located near the hospital. The vast majority were from Guangdong province where the hospital is based, especially concentrated in Guangzhou city. The online regular follow-up visit service reduced travel time by 1 hour to 9 hours and costs by ¥6 to ¥991 (US $0.86-$141.32) depending on proximity, with greater savings for patients farther from the hospital. Consultation times were roughly equivalent between online and in-person visits. Physicians provided most online services during lunch breaks (12 PM to 2 PM) or after work hours (7 PM to 11 PM), indicating increased workload. The top departments providing online regular follow-up visit services were Infectious Diseases, Rheumatology, and Dermatology. The most commonly prescribed medications aligned with the prevalent chronic diagnoses. To ensure quality, physicians conducted initial in-person consultations to fully evaluate patients before allowing online regular follow-up visits, during which they communicated with patients to assess conditions and determine if in-person care was warranted. They also periodically reminded patients to come in person for more comprehensive evaluations. However, they acknowledged online visits cannot fully replace face-to-face care. ConclusionsTelemedicine services such as online regular follow-up visit services provided by internet hospitals must strictly adhere to fundamental medical principles of diagnosis, prescription, and treatment. For patients with chronic diseases, online regular follow-up visit services improve accessibility and reduce cost but cannot fully replace in-person evaluations. Physicians leverage various strategies to ensure the quality of online care.

Adenosine (Ado) is significantly elevated in the tumor microenvironment (TME) compared to normal tissues. It binds to adenosine receptors (AdoRs), suppressing tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors on dendritic cells (DCs) and macrophages, inhibiting antigen presentation. It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor (TCR) binding and signal transduction. Ado also inhibits chemokine secretion and KCa3.1 channel activity, impeding effector T cell trafficking and infiltration into the tumor site. Furthermore, Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion, upregulating immune checkpoint proteins, and enhancing immune-suppressive cell activity. Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies. Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

Abstract Background Though deep learning has consistently demonstrated advantages in the automatic interpretation of breast ultrasound images, its black-box nature hinders potential interactions with radiologists, posing obstacles for clinical deployment. Methods We proposed a domain knowledge-based interpretable deep learning system for improving breast cancer risk prediction via paired multimodal ultrasound images. The deep learning system was developed on 4320 multimodal breast ultrasound images of 1440 biopsy-confirmed lesions from 1348 prospectively enrolled patients across two hospitals between August 2019 and December 2022. The lesions were allocated to 70% training cohort, 10% validation cohort, and 20% test cohort based on case recruitment date. Results Here, we show that the interpretable deep learning system can predict breast cancer risk as accurately as experienced radiologists, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval = 0.882 – 0.921), sensitivity of 75.2%, and specificity of 91.8% on the test cohort. With the aid of the deep learning system, particularly its inherent explainable features, junior radiologists tend to achieve better clinical outcomes, while senior radiologists experience increased confidence levels. Multimodal ultrasound images augmented with domain knowledge-based reasoning cues enable an effective human-machine collaboration at a high level of prediction performance. Conclusions Such a clinically applicable deep learning system may be incorporated into future breast cancer screening and support assisted or second-read workflows.

Abstract The nuclear receptor Nur77 plays paradoxical roles in numerous cancers. However, whether Nur77 inhibits esophageal squamous cell carcinoma (ESCC) growth and affects immunological responses against ESCC has not been determined. The functional role of Nur77 in ESCC was investigated in this study using human ESCC cell lines, quantitative real-time polymerase chain reaction (PCR), cell proliferation and colony formation assays, flow cytometry analysis, western blotting and animal models. The target gene controlled by Nur77 was verified using dual-luciferase reporter assays, chromatin immunoprecipitation analysis and functional rescue experiments. To examine the clinical importance of Nur77, 72 human primary ESCC tissues were subjected to immunohistochemistry. Taken together, these findings showed that, both in vitro and in vivo, Nur77 dramatically reduced ESCC cell growth and triggered apoptosis. Nur77 directly interacts with the interferon regulatory factor 1 (IRF1) promoter to inhibit its activity in ESCC. Pharmacological induction of Nur77 using cytosporone B (CsnB) inhibited ESCC cell proliferation and promoted apoptosis both in vitro and in vivo. Furthermore, CsnB increased CD8+ T-cell infiltration and cytotoxicity to inhibit the formation of ESCC tumors in an immunocompetent mouse model. In ESCC tissues, Nur77 expression was downregulated, and IRF1 expression was increased; moreover, their expression levels were negatively related. IRF1 and Nur77 were strongly correlated with overall survival. These findings suggested that Nur77 targets and regulates the IRF1/PD-L1 axis to serve as a tumor suppressor in ESCC. Graphical abstract of the regulatory mechanism of Nur77 overexpression downregulates IRF1 in the inhibition of ESCC progression and enhance anti-PD-1 therapy efficacy.

The Asteraceae are widely distributed throughout the world, with diverse functions and large genomes. Many of these genes remain undiscovered and unstudied. In this study, we discovered a new gene ClNUM1 in Chrysanthemum lavandulifolium and studied its function. In this study, bioinformatics, RT-qPCR, paraffin sectioning, and tobacco transgenics were utilized to bioinformatically analyze and functionally study the three variable splice variants of the unknown gene ClNUM1 cloned from C. lavandulifolium. The results showed that ClNUM1.1 and ClNUM1.2 had selective 3′ splicing and selective 5′ splicing, and ClNUM1.3 had selective 5′ splicing. When the corresponding transgenic tobacco plants were subjected to abiotic stress treatment, in the tobacco seedlings, the ClNUM1.1 gene and the ClNUM1.2 gene enhanced salt and low-temperature tolerance and the ClNUM1.3 gene enhanced low-temperature tolerance; in mature tobacco plants, the ClNUM1.1 gene was able to enhance salt and low-temperature tolerance, and the ClNUM1.2 and ClNUM1.3 genes were able to enhance low-temperature tolerance. In summary, there are differences in the functions of the different splice variants and the different seedling stages of transgenic tobacco, but all of them enhanced the resistance of tobacco to a certain extent. The analysis and functional characterization of the ClNUM1 gene provided new potential genes and research directions for abiotic resistance breeding in Chrysanthemum.

Abstract Background Endometriosis frequently results in pain and infertility. While conservative surgery offers some relief, it often falls short of ensuring satisfactory pregnancy outcomes. Adjuvant GnRH-a is administered post-surgery to mitigate recurrence; however, its impact on pregnancy outcomes remains debated. This study endeavors to assess the efficacy of adjuvant GnRH-a in enhancing pregnancy outcomes post-conservative surgery in endometriosis patients. Methods Databases including PubMed, Embase, the Cochrane Library, Medline (Ovid), Web of Science, and Scopus were rigorously searched up to 02 August 2023, without linguistic constraints. Identified articles were screened using strict inclusion and exclusion criteria. Evaluated outcomes encompassed pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, multiple pregnancy rate, mean postoperative pregnancy interval, recurrence rate, and adverse reaction rate. The Cochrane risk of bias tool and the Jadad score evaluated the included studies’ quality. Subgroup and sensitivity analysis were implemented to analyze the pooled results. A meta-analysis model expressed results as standardized mean difference (SMD) and Risk ratio (RR). Results A total of 17 studies about 2485 patients were assimilated. Meta-analysis revealed that post-surgery, the GnRH-a cohort experienced a marginally elevated pregnancy rate (RR = 1.20, 95% CI = 1.02–1.41; P = 0.03) and a reduced mean time to conceive (RR = -1.17, 95% CI = -1.70- -0.64; P

Abstract Background The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. Methods In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. Results We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8+ T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. Conclusions Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.

Abstract Background Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children’s neurodevelopment remains to be assessed. This study aimed to explore the association between first-trimester fetal size and children’s neurodevelopment and to examine whether intrauterine accelerated growth could compensate for the detrimental effects of first-trimester restricted growth on childhood neurodevelopment. Methods The participants were from a birth cohort enrolled from March 2014 to March 2019 in Wuhan, China. A total of 2058 fetuses with crown to rump length (CRL) (a proxy of first-trimester fetal size) measurements in the first trimester and neurodevelopmental assessment at age 2 years were included. We measured the first-trimester CRL and defined three fetal growth patterns based on the growth rate of estimated fetal weight from mid to late pregnancy. The neurodevelopment was assessed using the Bayley Scales of Infant Development of China Revision at 2 years. Results Each unit (a Z score) increase of first-trimester CRL was associated with increased scores in mental developmental index (MDI) (adjusted beta estimate = 1.19, (95% CI: 0.42, 1.95), P = 0.03) and psychomotor developmental index (PDI) (adjusted beta estimate = 1.36, (95% CI: 0.46, 2.26), P

Foal nursing behavior is a crucial indicator of healthy growth. The mare being in a standing posture and the foal being in a suckling posture are important markers for foal suckling behavior. To enable the recognition of a mare’s standing posture and its foal’s suckling posture in stalls, this paper proposes an RT-DETR-Foalnursing model based on RT-DETR. The model employs SACGNet as the backbone to enhance the efficiency of image feature extraction. Furthermore, by incorporating a multiscale multihead attention module and a channel attention module into the Adaptive Instance Feature Integration (AIFI), the model strengthens feature utilization and integration capabilities, thereby improving recognition accuracy. Experimental results demonstrate that the improved RT-DETR achieves a best mAP@50 of 98.5%, increasing by 1.8% compared to the RT-DETR. Additionally, this study achieves real-time statistical analysis of the duration of the foal in the suckling posture, which is one of the important indicators for determining whether the foal is suckling. This has significant implications for the healthy growth of foals.