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Abstract Background The fall armyworm (FAW, Spodoptera frugiperda) threatens maize production worldwide, and benzoxazinoids (Bxs) are known as the main secondary metabolites produced by maize to defend against FAW. However, we do not yet know whether and in what ways certain endophytes in the digestive system of FAW can metabolize Bxs, thus enhancing the fitness of FAW when feeding on maize. Results Using Bxs as the sole carbon and nitrogen source, we isolated Pantoea dispersa from the guts of FAW. P. dispersa can colonize maize roots and leaves as indicated by GFP-labeling and further successfully established itself as an endophyte in the Malpighian tubules and the gut of FAW after FAW feeding activities. Once established, it can be vertically transmitted through FAW eggs, suggesting the potential that FAW can convert maize-derived endophytes into symbiotic bacteria for intergenerational transmission. The prevalence of P. dispersa in FAW guts and maize leaves was also confirmed over large geographic regions, indicating its evolutionary adaptation in fields. Bxs determination in the gut and frass of FAW combined with bioassays performance on maize bx2 mutants revealed that the colonization of P. dispersa can promote FAW growth by metabolizing Bxs rather than other metabolites. Additionally, genome and transcriptome analyses identified plasmid-borne genes, rather than chromosomes of this species, were crucial for Bxs metabolism. This was further validated through in vitro prokaryotic expression assays by expressing two candidate genes form the plasmid. Conclusions FAW can convert maize endophytes into its own probiotics to detoxify Bxs and thus enhance caterpillar growth. This represents a novel strategy for lepidopteran pests—transforming allies of the host into its own—thereby shedding light on the rapid spread of FAW and enhancing our understanding of ecological and evolutionary mechanisms underlying the pest-microbe–plant interactions. Video Abstract

Abstract Structure-based machine learning algorithms have been utilized to predict the properties of protein-protein interaction (PPI) complexes, such as binding affinity, which is critical for understanding biological mechanisms and disease treatments. While most existing algorithms represent PPI complex graph structures at the atom-scale or residue-scale, these representations can be computationally expensive or may not sufficiently integrate finer chemical-plausible interaction details for improving predictions. Here, we introduce MCGLPPI, a geometric representation learning framework that combines graph neural networks (GNNs) with MARTINI molecular coarse-grained (CG) models to predict PPI overall properties accurately and efficiently. Extensive experiments on three types of downstream PPI property prediction tasks demonstrate that at the CG-scale, MCGLPPI achieves competitive performance compared with the counterparts at the atom- and residue-scale, but with only a third of computational resource consumption. Furthermore, CG-scale pre-training on protein domain-domain interaction structures enhances its predictive capabilities for PPI tasks. MCGLPPI offers an effective and efficient solution for PPI overall property predictions, serving as a promising tool for the large-scale analysis of biomolecular interactions.

Abstract Objective This study aims to analyze the differences in mechanical stability of OTA/AO 31A1.3 intertrochanteric fractures under various reduction conditions. Methods Twenty standard synbone artificial femur test bones were selected for the OTA/AO 31A1.3 intertrochanteric fracture model. The models were divided into five groups according to their reduction state: positive support, neutral support, negative support, varus fixation, and valgus fixation, with four specimens in each group. All models were fixed using PFNA intramedullary fixation and subjected to static axial compression tests. The subsidence displacement of the proximal femur under different loads and the axial stiffness of the model were measured to verify the mechanical stability of the OTA/AO 31A1.3 intertrochanteric fracture under different reduction conditions. Results After the static axial compression test, the proximal femoral subsidence displacement in the positive support and neutral support groups was lower than that in the negative support, valgus fixation, and varus fixation groups (p

Abstract Background and aims Human papillomavirus (HPV) infection is widespread. The regional differences in infection rates and dominant HPV types are a significant aspect of the virus’s epidemiological characteristics. In China, these differences are further influenced by the country’s diverse ethnic composition, as well as varying economic and cultural conditions across regions. Additionally, factors such as population migration contribute to the exacerbation of these regional disparities in HPV infection rates. Methods We conducted an analysis of the current prevalence of HPV among 108,863 patients in Chongqing from 2017 to 2022, along with an investigation into the interaction between HPV and vaginal microbiota. Additionally, we explored the relationship between HPV clearance time and disease outcomes. Results Our findings revealed an overall HPV positive rate of 30.14% (32,813/108,863) in Chongqing, China. The top five HPV positive rates were as follows: HPV52 (7.78%), HPV16 (5.85%), HPV58 (4.41%), HPV53 (3.17%), and HPV39 (2.47%). The age-related trend of HPV infection exhibited a bimodal curve. Importantly, the positive rate of high-risk HPV (BV: 24.74%, AV: 24.38%, VVC: 18.19%, TV: 22.81%) was significantly higher than those in the control group (all P

Abstract SASH1 (SAM and SH3 domain containing 1) has been increasingly reported as a tumor suppressor gene. However, there is limited research on the role of SASH1 in breast cancer. This manuscript aims to investigate the mechanism of SASH1 in the occurrence, development, and prognosis of breast cancer. Firstly, we obtained RNA-sequencing data of the tumors from the Genomic Data Commons data portal website, along with the corresponding clinical information of patients. Pan-cancer analysis was performed to analyze the expression of SASH1 across all tumors. Univariate Cox regression analysis was used to assess the correlation between SASH1 expression and the prognosis of breast cancer patients. Then, immunohistochemistry was utilized to evaluate the expression levels of SASH1, p-Akt, p-PI3K, and p-mTOR in breast cancer tissue. Finally, a cell assay was employed to analyze the impact of SASH1 on the proliferation and invasion of breast cancer cells (MDA-MB-231). The results revealed that SASH1 expression is decreased in BRCA, LUSC, LUAD, CESC, ESCA, and COAD. Meta-analysis also found that SASH1 is downregulated in most tumor tissues, and the expression level of SASH1 in breast cancer was significantly lower than that in the control group (OR = 0.14, 95% CI = 0.08–0.25; P

Background: Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone. Methods: Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research). Results: Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis. Conclusion: During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.The translational potential of this article is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.

Abstract Background Advances in emergency and critical care have improved outcomes, but gaps in communication and decision-making persist, especially in the emergency department (ED), prompting the development of a checklist to aid in serious illness conversations (SIC) in China. Methods This was a single-centre prospective interventional study on the quality improvement of SIC for life-sustaining treatment (LST). The study recruited patients consecutively for both its observational baseline and interventional stages until its conclusion. Eligible participants were adults over 18 years old admitted to the Emergency Intensive Care Unit (EICU) of a tertiary teaching hospital, possessing full decisional capacity or having a legal proxy. Exclusions were made for pregnant women, patients deceased upon arrival, those who refused participation, and individuals with incomplete data for analysis. First, a two-round Delphi process was organized to identify major elements and generate a standard process through a checklist. Subsequently, the efficacy of SIC in adult patients admitted to the EICU was compared using the Decisional Conflict Scale (DCS) score before (baseline group) and after (intervention group) implementing the checklist. Results The study participants presented with the most common comorbidities, such as diabetes, myocardial infarction, cerebrovascular disease, moderate-to-severe renal disease, congestive heart failure, and chronic pulmonary disease. The median Charlson Index did not differ between the baseline and intervention cohorts. The median length of hospital stay was 11.0 days, and 82.9% of patients survived until hospital discharge. The total DCS score was lower in the intervention group than in the baseline group. Three subscales, including the informed, values clarity, and support subscales, demonstrated significant differences between the intervention and baseline groups. Fewer intervention group patients agreed with and changed their minds about cardiopulmonary resuscitation (CPR) compared to the baseline group. Conclusion The use of a SIC checklist in the EICU reduced the DCS score by increasing medical information disclosure, patient value awareness, and decision-making support.

Abstract In the realm of multiferroicity in 2D magnets, whether magnetic and polar skyrmions can coexist within a single topological entity has emerged as an important question. Here, we study Janus 2D magnets CrInX 3 (X=Se, Te) for a comprehensive investigation of the magnetic ground state, magnetic excited state, and corresponding ferroelectric polarization by first-principles electronic structure calculations and Monte Carlo simulations. Specifically, we have thoroughly elucidated the magnetic exchange mechanisms, and have fully exemplified the magnetic field dependence of the magnon spectrum. More importantly, our study reveals a previously unrecognized, remarkably large spin-spiral-induced ferroelectric polarization (up to 194.9 μC/m2) in both compounds. We propose an approach to identify polar skyrmions within magnetic skyrmions, based on the observed direct correlation between spin texture and polarization density. Elucidating this correlation not only deepens our understanding of magnetic skyrmions but also paves the way for innovative research in the realm of multiferroic skyrmions.

Abstract The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23–induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23–stimulated IL-17A production was observed. In an IL-23–induced rat skin inflammation model, JNJ-77242113 inhibited IL-23–induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23–stimulated IFNγ production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23–driven immune-mediated diseases.

Introduction Neurosurgery is a risk factor for postoperative delirium. Dexmedetomidine has a potential effect on reducing postoperative delirium. We aim to test the primary hypothesis that perioperative administration of dexmedetomidine reduces the incidence of postoperative delirium in patients undergoing neurosurgical resections of temporal glioma.Methods This is a single-centre, randomised, blinded and parallel-group controlled trial. A total of 366 patients will be randomised to either dexmedetomidine group (n=183) or placebo group (n=183). Subjects assigned to dexmedetomidine group will be given a continuous infusion at 0.4 µg/kg/h after anaesthesia induction until dural closure and then immediately receive an infusion of dexmedetomidine at 0.08 µg/kg/h by intravenous analgesia pump during the first 48 hours postoperatively. Patients in the placebo group will be given comparable volumes of normal saline, and intravenous analgesia pumps contain equal amounts of sufentanil and antiemetics, but no dexmedetomidine. The primary outcome is the incidence of postoperative delirium, which will be assessed with the Confusion Assessment Method two times per day during the first five postoperative days.Ethics and dissemination The protocol (V.1.1) has been approved by the medical ethics committee of Beijing Tiantan Hospital, Capital Medical University (KY2023-186-02). The findings of this study will be disseminated through presentations at scientific conferences and publication in peer-reviewed journals.Trial registration number NCT06164314.

Abstract The effectiveness of Toll‐like 9 agonists (CpG) as an adjuvant for tumor immunotherapy is restricted due to their insufficient ability to activate anti‐tumor immunity. To address that, the common nutrient metal ions are explored (Mn2+, Cu2+, Ca2+, Mg2+, Zn2+, Fe3+, and Al3+), identifying Mn2+ as a key enhancer of CpG to mediate immune activation by augmenting the STING‐NF‐κB pathway. Mn2+ and CpG are then self‐assembled with epigallocatechin gallate (EGCG) into a nanoadjuvant MPN/CpG. Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma‐bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2‐type tumor‐associated macrophages (TAMs) to an M1‐type and boosting intra‐tumoral infiltration of CD8+/CD4+ T lymphocytes and DCs. Furthermore, compared to free CpG, MPN/CpG exhibits heightened accumulation in lymph nodes, enhancing CpG uptake and DC activation, consequently inducing significant antigen‐specific cytotoxic CD8+ T cell immune response and humoral immunity. In a prophylactic tumor‐bearing mouse model, MPN/CpG vaccination with OVA antigen significantly delays B16‐OVA melanoma growth and extends mouse survival. These findings underscore the potential of MPN/CpG as a multifunctional adjuvant platform to drive powerful innate and adaptive immunity and regulate TME against tumors.

BackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the relationship between the newly identified Dynein Axonemal Heavy Chain 3 (DNAH3) mutation and oligonasthenospermia in humans has not yet been established.MethodsWhole exome sequencing, pathogenicity analysis, and species conservation analysis of mutation sites were conducted on two patients from different unrelated families with DNAH3 mutations. We identified representative mutation sites and predicted the protein structure following these mutations. The sperm characteristics of the two patients with DNAH3 mutations were verified using Papanicolaou staining, scanning electron microscopy, and transmission electron microscopy. Additionally, mRNA and protein levels were assessed through RT-qPCR and Western blotting.ResultsThe biallelic mutations in the first progenitor included a heterozygous deletion and insertion, c.6535_6536 delinsAC (to infect mutation (p.Asp2179Thr), and stop codon premutation, c.3249G > A (p.Trp1083Ter). In Family II, the patient (P2) harbored a DNAH3 heterozygous missense mutation, c. 10439G> A(p.Arg3480Gln), along with a stop codon premutation, (c.10260G > A; p.Trp3420Ter). Patients with premature termination of transcription or translation due to DNAH3 mutations exhibit OAT phenotypes, including fibrous sheath dysplasia and multiple tail malformations. We identified the representative sites after mutation, predicted the protein structure, and assessed changes in the protein levels of DNAH3 and related genes following mutations. Notably,a significant reduction in DNAH3 protein expression was validated in these patients. We may explore in the future how DNAH3 affects sperm motility and quality through regulatory mechanisms involving protein structural changes.ConclusionNovel biallelic mutations in DNAH3, especially those resulting in a premature stop codon, may alter protein expression, structure, and active site, leading to spermatogenic failure and potentially inducing OAT. The discovery of new mutations in DNAH3 may be the key to the diagnosis and treatment of OAT.

As the COVID-19 pandemic persists, the increasing evidences suggest that the patients with COVID-19 may face the risks of the neurological complications and sequelae. To address this issue, we conducted a comprehensive study aimed at exploring the relationship between COVID-19 and various neurological disorders, with a particular focus on the shared dysregulated genes and the potential therapeutic targets. We selected six neurological disorders for investigation, including Alzheimer’s disease, epilepsy, stroke, Parkinson’s disease, and the sleep disorders. Through the bioinformatics analysis of the association between these disorders and COVID-19, we aimed to uncover the common molecular mechanisms and the potential treatment pathways. In this study, we utilized the publicly available RNA-Seq and microarray datasets, and employed tools such as Limma and DESeq2 for the differential gene analysis. Through the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we explored the common biological features and pathways. Additionally, we focused on analyzing the regulatory roles of miRNA and transcription factors on the shared differentially expressed genes, and predicted the potential drugs interacting with these genes. These analyses contribute to a better understanding of the relationship between COVID-19 and the neurological disorders, and provide a theoretical basis for the future treatment strategies. Through this research, we aim to offer the deeper insights to the scientific community and present the new perspectives for the clinical practice in addressing the challenges of the neurological complications and sequelae faced by the COVID-19 patients.

ObjectiveHematological indicators in the early stage of PD-1 inhibitor treatment may show superior predictive ability of the occurrence of immune related adverse event (irAE) compared to the pre-treatment indicators, as the immune response is modulated during the PD-1 inhibitor treatment. The objective of this study was to investigate the predictive capabilities of biomarkers in the early treatment stage for immune related thyroid dysfunction (irTD), and explore the potential predictive cytokines.MethodsMedical records and blood test results of cancer patients treated with PD-1 inhibitor at a certain medical institution were collected. Logistic regression analysis was utilized to identify the predictive factors of irTD, ROC curves were plotted and the area under the curves (AUC) was calculated. Serum samples were collected before and during early treatment phase, cytokine detection was performed to explore potential predictive cytokines.ResultsA total of 264 patients were enrolled, 58 developed irTD (21.97%), including 31 patients with thyrotoxicosis and 27 with hypothyroidism. There were no significant differences in demographic characteristics, tumor types and PD-1 inhibitors between patients with and without irTD. Multivariate logistic analysis showed that anti-thyroglobulin antibody (TgAb) (OR=2.831, 95%CI: 1.077-7.443, P=0.035) and anti-thyroperoxidase antibody (TPOAb) (OR=9.565, 95%CI: 3.399-26.921, P=0.000) in the early treatment phase were independent predictive factors for irTD, the AUC of early-stage biomarkers was larger than that of pre-treatment (0.655 vs 0.571); low level of TSH at the early stage (OR=0.162, 95%CI: 0.077-0.341, P=0.000) was significantly correlated with thyrotoxicosis; female (OR=3.889, 95%CI: 1.457-10.380, P=0.007) and positive TPOAb (OR=8.678, 95%CI: 2.656-28.357, P=0.000) at the early stage were significantly correlated with hypothyroidism. The AUCs of early-stage biomarkers were larger than that of pre-treatment both in thyrotoxicosis (0.812 vs 0.637) and hypothyroidism patients (0.728 vs 0.710). The increase of IL-16 (adjusted P=0.004), IL-12p70 (adjusted P=0.014), IL-17 (adjusted P=0.014), CCL-15 (adjusted P=0.014) and IL-1a (adjusted P=0.021) in the early treatment phase were positively correlated with irTD.ConclusionsBiomarkers at the early stage of PD-1 inhibitor treatment could predict irTD, and demonstrated stronger predictive ability compared to pre-treatment biomarkers. IL-16, IL-12p70, IL-17, CCL-15 and IL-1a could serve as potential predictive biomarkers for irTD.

To solve the problem of complex and difficult to quantify factors affecting investment returns and risks in clean energy power grids, this study comprehensively applies the interpretive structural model and Monte Carlo model to the analysis of investment risk-returns in clean energy power grid projects. The interpretive structural model is utilized to analyze project investment returns, while the Monte Carlo model is used to analyze project investment risks. The project investment risk is based on the factor analysis of project investment returns, and key risk factors are identified through 1000 simulations, and the impact of these risks on project returns is quantified. By combining the two, the investability of the project is analyzed. The results showed that grid electricity prices, kilowatt hour subsidies, technology learning rates, total annual sunshine hours, and system power generation efficiency were key factors driving investment returns. The average expected value of investment return was about 20%, and the probability of investment return below 6% was close to 0. The overall project is worth investing in. From this, it can be seen that the research designed investment risk-return analysis methods for clean energy grid projects can effectively distinguish the main factors affecting investment returns and risks, and pre simulate the risk situation of returns. This study can provide reference for investor decision-making.

Abstract Background: Acid-sensing ion channel 1a (ASIC1a) plays a critical role in physiological and pathological processes. To further elucidate the biological functions of ASICs and their relationships with disease occurrence and development, it is advantageous to investigate and develop additional regulatory factors for ASICs. Methods: In this study, cation exchange chromatography was used to separate seven chromatographic components from Naja naja atra venom. Capillary electrophoresis was employed to detect that Ⅶ peak component containing a main protein Ⅶ-2, which could bind to ASIC1a. The analgesic effects of Ⅶ-2 protein were determined using hot plate methods, and ASIC1a expression in spinal cord tissue from rats with inflammatory pain was detected using western blot. Results: The purified Ⅶ-2 protein named Naja naja atra venom-Ⅶ-2 (NNAV-Ⅶ-2) was obtained by Sephadex G-50 gel filtration, which exhibited a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of 6.7 kD. Remarkably, the NNAV-Ⅶ-2 protein demonstrated a significant analgesic effect and downregulated ASIC1a expression in the spinal cord tissue of rats with inflammatory pain. Conclusions: The analgesic mechanism of the NNAV-Ⅶ-2 protein may be associated with its binding to ASIC1a, consequently downregulating ASIC1a expression in neural tissues.

ABSTRACT: This study aimed to investigate how various selenium sources affect the intestinal health of broiler chickens. A total of 384, one-day-old Arbor Acres broilers were weighed and randomly allocated to four treatment groups. The control diet was a basal diet added with: 0.2 mg/kg Sodium Selenite (SS-control), 0.2 mg/kg Selenium nano-particles (Nano-Se), 0.2 mg/kg Selenomethionine (SeMet), and 0.2 mg/kg Selenocysteine (Sec) as the treatments. The results indicated that Nano-Se and SeMet were effective in enhancing the villus height (VH) and the villus height/crypt depth ratio (VH/CD) in the jejunum compared to (SS) (P < 0.05). The inclusion of Nano-Se into the diets increased the mRNA levels of zonula occluden-1 (ZO-1), ZO-2, Occludin, Claudin-1, and Claudin-3 compared to the SS diet (P < 0.05). The SeMet increased the levels of ZO-1 and Claudin-3 compared to the SS (P < 0.05). Moreover, SeMet upregulated the marker genes of intestinal enteroendocrine cells, stem cells, and epithelial cells compared to the SS diet (P < 0.05). However, supplementation of Nano-Se reduced the mRNA levels of interleukin 1β (IL-1β), and IL-8 and the concentration of reactive oxygen species (ROS) in the jejunum compared to the SS (P < 0.05). The Nano-Se and SeMet also increased the protein levels of CAT and SOD compared to the SS and Sec diet (P < 0.05). The number of the goblet cells and Mucin-2 (Muc2) levels were the highest in the Nano-Se group (P < 0.05). The protein expression levels of goblet cell differentiation regulator (v-myc avian myelocytomatosis viral oncogene homolog, c-Myc) were highest in the Nano-Se compared to the SS diet (P < 0.05). The Nano-Se decreased the mRNA and protein levels of NLRP3 signaling pathway-related genes compared to the SS diet (P < 0.05). In conclusion, our study demonstrated that Nano-Se and SeMet are better at improving the intestinal health of 21-day-old broilers. Additionally, Nano-Se demonstrated superior antioxidant and anti-inflammatory effects, promoting the development of intestinal goblet cells by modifying the NLRP3 signaling pathway.

Abstract Background Case-based learning (CBL) methods have gained prominence in medical education, proving especially effective for preclinical training in undergraduate medical education. Tetralogy of Fallot (TOF) is a congenital heart disease characterized by four malformations, presenting a challenge in medical education due to the complexity of its anatomical pathology. Three-dimensional printing (3DP), generating physical replicas from data, offers a valuable tool for illustrating intricate anatomical structures and spatial relationships in the classroom. This study explores the integration of 3DP with CBL teaching for clinical medical undergraduates. Methods Sixty senior clinical medical undergraduates were randomly assigned to the CBL group and the CBL-3DP group. Computed tomography imaging data from a typical TOF case were exported, processed, and utilized to create four TOF models with a color 3D printer. The CBL group employed CBL teaching methods, while the CBL-3DP group combined CBL with 3D-printed models. Post-class exams and questionnaires assessed the teaching effectiveness of both groups. Results The CBL-3DP group exhibited improved performance in post-class examinations, particularly in pathological anatomy and TOF imaging data analysis (P

Background/Aims: A large number of differentially expressed molecules exist in hepatocellular carcinoma (HCC), and the mechanism by which they upregulate or downregulate expression is still unclear. The purpose of this study is to explore the possible mechanism of differential expression of apoptotic chromatin condensation inducer 1 (Acin1) in HCC. Materials and Methods: A mouse HCC model was constructed, and the expression of Acin1 in HCC was analyzed by whole transcriptome sequencing, bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction, and differentially expressed Acin1-related genes were screened to construct a protein–protein interaction and competing endogenous RNA (ceRNA) network. The microRNA (miRNAs) targeting Acin1 were further predicted using online databases and finally compared with sequencing data. Results: The expression of Acin1 was significantly up-regulated in HCC compared to the paracancerous and healthy control groups (P < .001). The top 10 upregulated genes closely related to Acin1 (Slc3a2, Wiz, Srrm2, Akt1, Hnrnpu, Sap18b, Pabpn1, Ddx39b, Eif4a3, and Rnps1) were mainly involved in pathways such as messenger RNA (mRNA) surveillance, RNA transport, spliceosome, Janus kinase/ signal transducers and activators of transcription signaling, apoptosis, and ubiquitin-mediated proteolysis. The ceRNA network identified several molecules (2 long noncoding RNAs, 50 miRNAs, and 49 mRNAs) interacting with Acin1, among which miR-674-5p was highly expressed in all sample tissues, and higher than that of other differentially expressed miRNAs, and significantly downregulated in HCC. Multiple online databases such as miRWalk also predicted that miR-674-5p targets Acin1. This shows that miR-674-5p may be an important molecule for targeting Acin1. Conclusion: Acin1 is overexpressed in HCC, and the overexpressed Acin1 is most likely regulated by miR-674-5p and other ceRNA molecules

Abstract Rapeseed is a critical cash crop globally, and understanding its distribution can assist in refined agricultural management, ensuring a sustainable vegetable oil supply, and informing government decisions. China is the leading consumer and third-largest producer of rapeseed. However, there is a lack of widely available, long-term, and large-scale remotely sensed maps on rapeseed cultivation in China. Here this study utilizes multi-source data such as satellite images, GLDAS environmental variables, land cover maps, and terrain data to create the China annual rapeseed maps at 30 m spatial resolution from 2000 to 2022 (CARM30). Our product was validated using independent samples and showed average F1 scores of 0.869 and 0.971 for winter and spring rapeseed. The CARM30 has high spatial consistency with existing 10 m and 20 m rapeseed maps. Additionally, the CARM30-derived rapeseed planted area was significantly correlated with agricultural statistics (R2 = 0.65–0.86; p

Selenomethionine (SeMet) is a beneficial organic source of selenium that is extensively used as a food additive owing to its antioxidant and anti-inflammatory properties. Due to the sensitivity of the kidneys to noxious stimuli, they are more susceptible to various injuries. To investigate the protective mechanisms of SeMet supplementation against kidney injury, we established an in vivo experimental model using laying hens treated with SeMet (0.5 mg/kg diet) and/or lipopolysaccharide (LPS) (0.2 mg/kg. BW) and an in vitro model of chicken embryo primary kidney (CEK) cells treated with SeMet (0.075 mM) and with/ without LPS (60 μg/mL). SeMet treatment alleviated the LPS-induced kidney insufficiency and mitochondrial damage. Furthermore, it reduced the expression of TLR4, RIPK3, MLKL, DRP1, NLRP3, and IL-1β in the kidneys of laying hens. RIPK3 is known to induced necroptosis and inflammation by activating of the downstream factors DRP1 and MLKL. To investigate the mechanism whereby SeMet alleviates LPS-induced necroptosis in the kidney, we pretreated CEK cells with TLR4, RIPK3, and DRP1 inhibitors. The results demonstrated that RIPK3 inhibition resulted in a significantly increased in the mitochondrial membrane potential and downregulation of DRP1. Upon the inhibition of DRP1 expression, MLKL, NLRP3, and IL-1β expression also decreased. In summary, SeMet regulates the TLR4/RIPK3/DRP1 signaling pathway to restore the LPS-induced imbalances in mitochondrial dynamics, thereby alleviating necroptosis and inflammation in the kidneys of laying hen. Selenium also increases the expression of selenoproteins. This study provides valuable information for the development of new therapeutic strategies using SeMet to alleviate kidney injury.

Inspired by the tip feathers of soaring birds, the device of tip sails was designed and installed on the wing to achieve drag reduction. The influences of design parameters including cant angles, toe angles and twist angles on aerodynamic characteristics of tip sails were investigated through 77 cases of 11 configurations at 7 different angles of attack. According to the results grouped, the optimal cant angles [Formula: see text] were determined. By adjusting the toe angles, drag reduction can be improved under different flight conditions. The decreasing twist angles can inhibit flow separation on sail surface. The optimal toe angles [Formula: see text] and twist angles [Formula: see text] resulted in the weakest flow separation. Ensuring that the twist angle of each sail is [Formula: see text] less than that of the corresponding toe angle can effectively inhibit flow separation on the sail surface. The tip sails can also split and weaken the wingtip vortex. In addition, in the validation of the numerical method, we also investigate the influence of numerical schemes and turbulence models on the results of wingtip vortex flow. In the cases with unstructured meshes, the third-order finite volume scheme had higher computational efficiency than the traditional second-order finite volume scheme in obtaining grid independent solutions, and the turbulence model with rotation correction can improve the calculation accuracy of the wingtip vortex flow. The results of this paper provide a valuable reference for the design of tip sails.

ABSTRACTHeartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease. Moreover, little is known about HRTV-host interactions, viral replication mechanisms, pathogenesis and virulence, further hampering the development of vaccines and antiviral interventions. Here, we aimed to provide a brief review of HRTV epidemiology, molecular biology, pathogenesis and virulence on the basis of published article data to better understand this virus and provide clues for further study.

This study is intended to explore the effect of hypoxia-inducible factor-1α (HIF-1α) activation on lipid accumulation in the diabetic kidney. A type 1 diabetic rat model was established by STZ intraperitoneal injection. Cobalt chloride (CoCl2) and YC-1 were used as the HIF-1α activator and antagonist, respectively. CoCl2 treatment significantly increased HIF-1α expression, accelerated lipid deposition, and accelerated tubular injury in diabetic kidneys. In vitro, CoCl2 effectively stabilized HIF-1α and increased its transportation from the cytoplasm to the nucleus, which was accompanied by significantly increased lipid accumulation in HK-2 cells. Furthermore, results obtained in vivo showed that HIF-1α protein expression in the renal tubules of diabetic rats was significantly downregulated by YC-1 treatment. Meanwhile, lipid accumulation in the tubules of the DM + YC-1 group was markedly decreased in comparison to the DM + DMSO group. Accordingly, PAS staining revealed that the pathological injury caused to the tubular epithelial cells was alleviated by YC-1 treatment. Furthermore, the blood glucose level, urine albumin creatinine ratio, and NAG creatinine ratio in the DM + YC-1 group were significantly decreased compared to the DM + DMSO group. Moreover, the protein expression levels of transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) in diabetic kidneys were decreased by YC-1 treatment. Our findings demonstrate that the activation of HIF-1α contributed to interstitial injury in a rat model of diabetic nephropathy and that the underlying mechanism involved the induction of lipid accumulation.

Background Acute kidney injury (AKI) is recognized as a common complication following cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Characterized by prolonged renal function impairment, acute kidney disease (AKD) is associated with a higher risk of chronic kidney disease (CKD) and mortality.Methods From January 2018 to December 2021, 158 patients undergoing CRS-HIPEC were retrospectively reviewed. Patients were separated into non-AKI, AKI, and AKD cohorts. Laboratory parameters and perioperative features were gathered to evaluate risk factors for both HIPEC-induced AKI and AKD, with the 90-day prognosis of AKD patients.Results AKI developed in 21.5% of patients undergoing CRS-HIPEC, while 13.3% progressed to AKD. The multivariate analysis identified that ascites, GRAN%, estimated glomerular filtration rate (eGFR), and intraoperative (IO) hypotension duration were associated with the development of HIPEC-induced AKI. Higher uric acid, lessened eGFR, and prolonged IO hypotension duration were more predominant in patients proceeding with AKD. The AKD cohort presented a higher risk of 30 days of in-hospital mortality (14.3%) and CKD progression (42.8%).Conclusions Our study reveals a high incidence of AKI and AKI-to-AKD transition. Early identification of risk factors for HIPEC-induced AKD would assist clinicians in taking measures to mitigate the incidence.

ABSTRACTPersistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers susceptibility and progression, recently attracting considerable attention. This study aimed to determine the infection status and relationship between high-risk HPV (HR-HPV) and lower genital tract infectious pathogens in cervical cancer and its precursors. From a retrospective and a prospective cohort analysis, Escherichia coli (E. coli) dominated the pathogens isolated from cervical discharges, and an isolation rate uptrend has been shown recently. HPV16 and E. coli’s coinfection rate gradually increased with the severity of cervical intraepithelial neoplasia. The adhesion and invasion abilities of the isolated E. coli to HPV16-positive SiHa cells were evaluated in vitro. The TCGA database and cervical tissues samples analysis showed that IL-10 was upregulated in cervical cancer. IL-10 expression levels increased in tissue samples with the severity of cervical cancer and its precursors with HPV16 and E. coli coinfection. Although no significant changes in IL-10 production were observed in the co-culture supernatant, we hypothesized that Treg immune cells in the tumour microenvironment might be responsible for the local IL-10 upregulation, according to our data showing Foxp3 upregulation and an upward trend with the cervical intraepithelial neoplasia grading to cancer and tumours with E. coli and HPV16 coinfection. Our data provide insights into the possible role of E. coli in cervical cancer progression and suggest that the application of HPV and E. coli screening programs may be an effective strategy to relieve the burden of cervical cancer and its precursor lesions.

BackgroundThe human epidermal growth factor receptor 2 gene (HER2) has been identified as a potential therapeutic target in lung adenocarcinoma (LUAD). Non-invasive positron emission tomography (PET) imaging provides a reliable strategy for in vivo determination of HER2 expression through whole-body detection of abnormalities. The PET tracer 68Ga-NOTA-MAL-Cys-MZHER2:342 has shown promising results for HER2-positive breast and gastric cancers. This study aims to evaluate the performance of 68Ga-NOTA-MAL-Cys-MZHER2:342in vitro and in vivo models and in clinical patients with HER2-positive LUAD.MethodsNOTA-MAL-Cys-MZHER2:342 was synthesized and labeled with 68Ga. Cell uptake, cell binding ability, and stability studies of 68Ga-NOTA-MAL-Cys-MZHER2:342 were assessed both in the Calu-3 lung cancer (LC) cell line and normal mice. In vivo assessment in tumor-bearing mice was conducted using microPET imaging and biodistribution experiments. Additionally, preliminary PET/CT imaging analysis was performed on HER2-positive LC patients.Results68Ga-NOTA-MAL-Cys-MZHER2:342 was prepared with a radiochemical purity (RCP) exceeding 95%. The tracer demonstrated high cell uptake in HER2-overexpressing Calu-3 cells, with an IC50 of 158.9, an adequate 1.73 nM. Good stability was exhibited both in vitro and in vivo. MicroPET imaging of Calu-3-bearing mice revealed high tumor uptake and notable tumor-to-background ratios. Positive outcomes were also observed in two HER2-positive LUAD patients.Conclusion68Ga-NOTA-MAL-Cys-MZHER2:342 demonstrated satisfactory stability, sensitivity, and specificity. These findings suggest that 68Ga-NOTA-MAL-Cys-MZHER2:342 PET/CT imaging provides a novel tool for non-invasive visual assessment of HER2 expression in LUAD patients.

Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense Tropical Race 4 (Foc TR4), poses a significant threat to banana production globally, thereby necessitating effective biocontrol methods to manage this devastating disease. This study investigates the potential of Bacillus siamensis strain JSZ06, isolated from smooth vetch, as a biocontrol agent against Foc TR4. To this end, we conducted a series of in vitro and in vivo experiments to evaluate the antifungal activity of strain JSZ06 and its crude extracts. Additionally, genomic analyses were performed to identify antibiotic synthesis genes, while metabolomic profiling was conducted to characterize bioactive compounds. The results demonstrated that strain JSZ06 exhibited strong inhibitory activity against Foc TR4, significantly reducing mycelial growth and spore germination. Moreover, scanning and transmission electron microscopy revealed substantial ultrastructural damage to Foc TR4 mycelia treated with JSZ06 extracts. Genomic analysis identified several antibiotic synthesis genes, and metabolomic profiling revealed numerous antifungal metabolites. Furthermore, in pot trials, the application of JSZ06 fermentation broth significantly enhanced banana plant growth and reduced disease severity, achieving biocontrol efficiencies of 76.71% and 79.25% for leaves and pseudostems, respectively. In conclusion, Bacillus siamensis JSZ06 is a promising biocontrol agent against Fusarium wilt in bananas, with its dual action of direct antifungal activity and plant growth promotion underscoring its potential for integrated disease management strategies.

Abstract Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

Abstract Background Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients. Methods A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation. Results A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5–58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906–8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176–2.384), arthralgia (OR = 3.197, 95% CI 1.986–5.148), eye bulging pain (OR = 3.482, 95% CI 1.349–8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310–2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145–2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%). Conclusions More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers.

Autonomous driving is a prominent research area, with the primary challenge being the precise perception and interpretation of the surrounding environment. To address issues such as low resolution, dense occlusion, and small targets in complex road scenes, we propose an improved road target detection algorithm, SNCE-YOLO, based on YOLOv5. Firstly, to avoid the loss of feature information during training for low-resolution and small targets, the Space-to-Depth Convolution(SPD-Conv) is introduced to replace the original convolutional layer for retaining global feature information. Secondly, to address the issue of confusing complex backgrounds with detection targets when features are extracted too early and deeply, the Normalization-based Attention Module (NAM) is incorporated into the backbone network without increasing the computational effort, focusing on the channel and spatial information of interest. Thirdly, to enhance the capture and fusion of multi-level feature information, we optimized the neck network’s feature fusion module by implementing the C2f structure. Finally, to reduce the bias in the regression of the occluded target positions, we introduced the EIOU loss function to better define the relationship between the predicted and real frames. The SNCE-YOLO algorithm achieves a mean Average Precision (mAP@0.5) of 91.9% on the KITTI dataset, which represents a 2.6% improvement over the baseline model. Additionally, with a detection speed of 95.24 frames per second (FPS), it meets the requirements for real-time target detection in complex road scenes. Comparisons are also made with other mainstream target detection algorithms to verify the effectiveness of SNCE-YOLO.

Abstract Background Standardized training for pain, agitation-sedation, and delirium (PAD) management is urgently needed for Chinese intensivists’ continuing education. Since 2020, because of the COVID-19 pandemic, the Chinese Analgesia and Sedation Education and Research (CASER) group has used an online blended teaching mode based on a small private online course (SPOC) and case-based learning (CBL). This study evaluated whether an online blended teaching mode has similar effects on PAD management training when an offline mode cannot be used. Materials and methods Since 2020, the CASER group has provided offline training and online SPOC&CBL training three times each, targeting intensivists and ICU nurses in China. All participants were divided into an offline group and SPOC&CBL group. A final examination was offered in each training session to assess the students' mastery of professional knowledge. Teachers’ and students’ perceptions regarding the online SPOC&CBL mode were evaluated through questionnaires. Results Of all participants (n = 117), 106 completed all examinations and questionnaires. Most participants were aged 31–40 years (53, 50.0%), had an academic degree (60, 56.6%), and worked in a tertiary hospital (100, 94.34%). We assessed the learning effect on participants from two aspects: theory and clinical practice. There was no significant difference between the SPOC&CBL and offline groups in terms of theoretical, case analysis, and total scores (p > 0.05). In terms of the participants’ perceptions regarding the SPOC&CBL mode, 91.5% considered the online mode to be a useful and accessible alternative to improve knowledge and skills. A total of 95.7% of the participants believed that they could interact well with group members, and 87.2% believed that they had a good degree of participation. Of these participants, 76.6% believed that they had received valuable learning resources. All instructors believed that the SPOC&CBL mode was more flexible than the offline mode in terms of teaching time and location, and they were all willing to carry out training with the SPOC&CBL mode. Conclusion Compared to the offline mode, the SPOC&CBL mode can also enhance participants’ knowledge and skills and meets their expectations. Therefore, an online mode can be considered a potential method in PAD management education in China.

Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.

Abstract Background Neuropsychiatric involvement in systemic lupus erythematosus (SLE) is a common clinical manifestation. In SLE patients, cerebral function is a more sensitive predictor of central nervous system damage, and abnormalities in cerebral function may be apparent before substantial neuropsychiatric symptoms occur. The 5-hydroxynyptamine(5-HT) system has the ability to interact with the majority of the neurochemical systems in the central nervous system (CNS), influencing brain function. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) is an essential element of the 5-HT system gene polymorphism and is directly related to the control of 5-hydroxytryptamine transporter (5-HTT)gene expression. The relationship between 5-HTTLPR and functional brain measurements in SLE patients requires more investigation because it is one of the most attractive imaging genetics targets for shedding light on the pathophysiology of neuropsychiatric lupus. Methods Resting-state functional magnetic resonance imaging (rs-fMRI) images were collected from 51 SLE patients without obvious neuropsychiatric manifestations and 44 healthy volunteers. Regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), and fractional amplitude of low-frequency fluctuations (fALFF) were selected as indicators for evaluating brain function. In accordance with the Anatomical Automatic Labeling template, the gray matter was divided into 116 regions. The mean ReHo value, mean ALFF value, and mean fALFF value of each brain region were extracted. 5-HTTLPR genotypes of all research objects were tested by polymerase chain reaction and agarose gel electrophoresis. Two-way analysis of covariance was used to investigate whether there is an interaction effect between SLE disease status and 5-HTTLPR genotype on resting-state brain function. Results In SLE patients with S/S homozygosity, there were notably lower mean ReHo, mean ALFF, and mean fALFF values observed in the right parietal, inferior angular gyrus, and the right paracentral lobule compared to healthy controls. However, this distinction was not evident among carriers of the L allele. Within the S/S genotype, SLE patients exhibited decreased mean ReHo in the left posterior cingulate gyrus, reduced mean fALFF in the left caudate nucleus, and diminished mean ALFF in the left temporal pole: superior temporal gyrus, in contrast to the HC group. Conversely, no such differences were discerned among carriers of the L allele. Notably, among L allele carriers, SLE patients displayed a higher mean ReHo value in the right hippocampus compared to the HC group, while demonstrating a lower mean ALFF value in the left medial and paracingulate gyrus in contrast to the HC group. Conversely, these differences were not apparent among S/S homozygotes. Conclusions Brain function in the right parietal and inferior angular gyrus and the right paracentral lobule is affected by the interaction effect of SLE disease status and 5-HTTLPR genotype.

In this work, we examine an adaptive and event-triggered distributed controller for nonlinear multi-agent systems (MASs). Second, we present a fuzzy adaptive event-triggered distributed control approach using a Lyapunov-based filter and the backstepping recursion technique. Next, the controller and adaptive rule presented guarantee that all tracking errors between the leader and the follower converge in a limited area close to the origin. According to the Lyapunov stability theory, this demonstrates that all other signals inside the closed loop are assured to be semi-globally, uniformly and finally constrained. Finally, simulation tests are conducted to illustrate the effectiveness of the control mechanism.

Abstract Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI—induced by contrast media, ischemia–reperfusion injury, cisplatin, and folic acid—to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1–UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

Abstract Probing the surface of proteins to predict the binding site and binding affinity for a given small molecule is a critical but challenging task in drug discovery. Blind docking addresses this issue by performing docking on binding regions randomly sampled from the entire protein surface. However, compared with local docking, blind docking is less accurate and reliable because the docking space is too largetly sampled. Cavity detection-guided blind docking methods improved the accuracy by using cavity detection (also known as binding site detection) tools to guide the docking procedure. However, it is worth noting that the performance of these methods heavily relies on the quality of the cavity detection tool. This constraint, namely the dependence on a single cavity detection tool, significantly impacts the overall performance of cavity detection-guided methods. To overcome this limitation, we proposed Consensus Blind Dock (CoBDock), a novel blind, parallel docking method that uses machine learning algorithms to integrate docking and cavity detection results to improve not only binding site identification but also pose prediction accuracy. Our experiments on several datasets, including PDBBind 2020, ADS, MTi, DUD-E, and CASF-2016, showed that CoBDock has better binding site and binding mode performance than other state-of-the-art cavity detector tools and blind docking methods.

Abstract Sepsis is a life-threatening syndrome resulting from immune system dysfunction that is caused by infection. It is of great importance to analyze the immune characteristics of sepsis, identify the key immune system related genes, and construct diagnostic models for sepsis. In this study, the sepsis transcriptome and expression profiling data were merged into an integrated dataset containing 277 sepsis samples and 117 non-sepsis control samples. Single-sample gene set enrichment analysis (ssGSEA) was used to assess the immune cell infiltration. Two sepsis immune subtypes were identified based on the 22 differential immune cells between the sepsis and the healthy control groups. Weighted gene co-expression network analysis (WCGNA) was used to identify the key module genes. Then, 36 differentially expressed immune-related genes were identified, based on which a robust diagnostic model was constructed with 11 diagnostic genes. The expression of 11 diagnostic genes was finally assessed in the training and validation datasets respectively. In this study, we provide comprehensive insight into the immune features of sepsis and establish a robust diagnostic model for sepsis. These findings may provide new strategies for the early diagnosis of sepsis in the future.

Abstract Clustering ensemble (CE), renowned for its robust and potent consensus capability, has garnered significant attention from scholars in recent years and has achieved numerous noteworthy breakthroughs. Nevertheless, three key issues persist: (1) the majority of CE selection strategies rely on preset parameters or empirical knowledge as a premise, lacking adaptive selectivity; (2) the construction of co-association matrix is excessively one-sided; (3) the CE method lacks a more macro perspective to reconcile the conflicts among different consensus results. To address these aforementioned problems, a dual-level clustering ensemble algorithm with three consensus strategies is proposed. Firstly, a backward clustering ensemble selection framework is devised, and its built-in selection strategy can adaptively eliminate redundant members. Then, at the base clustering consensus level, taking into account the interplay between actual spatial location information and the co-occurrence frequency, two modified relation matrices are reconstructed, resulting in the development of two consensus methods with different modes. Additionally, at the CE consensus level with a broader perspective, an adjustable Dempster–Shafer evidence theory is developed as the third consensus method in present algorithm to dynamically fuse multiple ensemble results. Experimental results demonstrate that compared to seven other state-of-the-art and typical CE algorithms, the proposed algorithm exhibits exceptional consensus ability and robustness.

Abstract Focal and systemic infections are serious threats to human health. Preclinical models enable the development of new drugs and therapeutic regimens. In vivo, animal bioluminescence (BL) imaging has been used with bacterial reporter strains to evaluate antimicrobial treatment effects. However, high‐sensitivity bioluminescent systems are required because of the limited tissue penetration and low brightness of the BL signals of existing approaches. Here, we report that NanoLuc (Nluc) showed better performance than LuxCDABE in bacteria. However, the retention rate of plasmid constructs in bacteria was low. To construct stable Staphylococcus aureus reporter strains, a partner protein enolase (Eno) was identified by screening of S. aureus strain USA300 for fusion expression of Nluc‐based luciferases, including Nluc, Teluc, and Antares2. Different substrates, such as hydrofurimazine (HFZ), furimazine (FUR), and diphenylterazine (DTZ), were used to optimize a stable reporter strain/substrate pair for BL imaging. S. aureus USA300/Eno‐Antares2/HFZ produced the highest number of photons of orange‐red light in vitro and enabled sensitive BL tracking of S. aureus in vivo, with sensitivities of approximately 10 CFU from mouse skin and 750 CFU from mouse kidneys. USA300/Eno‐Antares2/HFZ was a powerful combination based on the longitudinal evaluation of the therapeutic efficacy of antibiotics. The optimized S. aureus Eno‐Antares2/HFZ pair provides a technological advancement for the in vivo evaluation of antimicrobial treatment.

Long non-coding RNAs (lncRNAs) are emerging as important players in gene regulation and cardiovascular diseases. However, the roles of lncRNAs in atherosclerosis are poorly understood. In the present study, we found that the levels of NIPA1-SO were decreased while those of NIPA1 were increased in human atherosclerotic plaques. Furthermore, NIPA1-SO negatively regulated NIPA1 expression in human umbilical vein endothelial cells (HUVECs). Mechanistically, NIPA1-SO interacted with the transcription factor FUBP1 and the NIPA1 gene. The effect of NIPA1-SO on NIPA1 protein levels was reversed by the knockdown of FUBP1. NIPA1-SO overexpression increased, whilst NIPA1-SO knockdown decreased BMPR2 levels; these effects were enhanced by the knockdown of NIPA1. The overexpression of NIPA1-SO reduced while NIPA1-SO knockdown increased monocyte adhesion to HUVECs; these effects were diminished by the knockdown of BMPR2. The lentivirus-mediated-overexpression of NIPA1-SO or gene-targeted knockout of NIPA1 in low-density lipoprotein receptor-deficient mice reduced monocyte-endothelium adhesion and atherosclerotic lesion formation. Collectively, these findings revealed a novel anti-atherosclerotic role for the lncRNA NIPA1-SO and highlighted its inhibitory effects on vascular inflammation and intracellular cholesterol accumulation by binding to FUBP1 and consequently repressing NIPA1 expression.

The problem of machining complex surfaces with non-ball-end cutters by strip-width-maximization machining is formulated as a kind of surface fitting problem in which the tool surface envelope feature line approximates the design surface under the movement transform. The theory of surface envelope−approximation is proposed as a general method for optimizing tool movement in single-contact strip-width-maximization machining of sculptured surfaces with non-ball-end cutters. Based on the surface moving frame, the velocity equations and transformation matrices for the tool motion relative to the workpiece, described by the motion-invariant parameters of the tool surface and design surface, are derived. A functional extremum model for optimizing the tool position ensures continuous and symmetrical motion relative to the workpiece to achieve the highest machining efficiency and accuracy. Finally, a Matlab-based simulation example verifies the machining efficiency and accuracy of the envelope approximation theory.

On 28 September 2022, the European Commission released its long-awaited proposal for an Artificial Intelligence Liability Directive (AILD). In contrast to the high expectations on providing a harmonised liability framework for the damage caused by AI systems, the proposed AILD only proposes minimum harmonised procedural rules to facilitate evidence disclosure and alleviate the burden of proof undertaken by claimants. This article provides a comprehensive analysis of the proposed AILD and points out the problems when implementing the proposed rules. This article argues that the AILD may never reach its full potential as its name indicates. The fragmentation among Member States regarding the substantive matters may preclude the AILD from moving a step further for harmonising substantial issues. While a comprehensive risk regulation (the EU AI Act) must be followed by an effective remedy mechanism, the proposed AILD will not fill this gap in the short run.

Abstract As emerging alternatives to natural enzymes, nanoscale materials featuring enzyme‐like catalytic behaviors (nanozymes) exhibit some attractive merits including robust activity, low cost, and easy‐to‐regulate performance. These merits have enabled them to be intensively used in the biomedical field in recent years. To remedy the lack of catalytic selectivity in most nanozymes, deoxyribonucleic acid (DNA) chains with specific recognition functions are utilized to integrate with nanozymes to produce various nanozyme–DNA combinations via adsorption/desorption. In the formed combinations, the DNA component provides the molecular/ionic recognition role, and the nanozyme part offers response with catalytically amplified signals, enabling them to detect analytes and biomarkers selectively and sensitively. To highlight this interesting topic, here we made a critical review of the interactions between nanozymes and DNA and their applications in biosensing and disease diagnosis. First, strategies for the conjugation of DNA chains onto nanozyme surface were introduced briefly. Then, the interactions between DNA and nanozymes were summarized in detail, where flexible modulations of nanozyme activity by DNA adsorption/desorption as well as various factors were analyzed, and potential impacts caused by nanozymes on the recognition characteristics of DNA chains were pointed out. After that, typical applications of DNA‐mediated nanozyme modulation in toxic ion sensing, health risk factor monitoring, and biomedical diagnosis were introduced. In the end, prospects of the combination of nanozymes and DNA chains were presented, and future challenges of the emerging field were also discussed, to attract more interest and effort to advance this promising area.

Dilated cardiomyopathy (DCM) is a primary cause of heart failure (HF), with the incidence of HF increasing consistently in recent years. DCM pathogenesis involves a combination of inherited predisposition and environmental factors. Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with endogenous hormone action and are capable of targeting various organs, including the heart. However, the impact of these disruptors on heart disease through their effects on genes remains underexplored. In this study, we aimed to explore key DCM-related genes using machine learning (ML) and the construction of a predictive model. Using the Gene Expression Omnibus (GEO) database, we screened differentially expressed genes (DEGs) and performed enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to DCM. Through ML techniques combining maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) logistic regression, we identified key genes for predicting DCM (IL1RL1, SEZ6L, SFRP4, COL22A1, RNASE2, HB). Based on these key genes, 79 EDCs with the potential to affect DCM were identified, among which 4 (3,4-dichloroaniline, fenitrothion, pyrene, and isoproturon) have not been previously associated with DCM. These findings establish a novel relationship between the EDCs mediated by key genes and the development of DCM.

The programmed cell death 1 (PD-1) immune checkpoint of co-inhibitory signaling plays crucial roles in controlling the magnitude and duration of T cell activation to limit tissue damage and maintain self-tolerance. Cancer cells hijack the co-inhibitory pathway and escape immune surveillance by overexpressing the PD-1 ligand PD-L1. Immune checkpoint inhibitors, such as PD-1 blocking antibody have been approved for tumor immunotherapy. However, not all patients can benefit from PD-1 monotherapy. Combination immunotherapy based on PD-1 axis blockade substantially improves clinical anti-tumor efficacy. In this review, we briefly summarize the current progress on the mechanisms of PD-1-mediated inhibition of T cell activation and strategies for cancer combination immunotherapy.

Fusarium wilt of banana caused by Fusarium oxysporum f. sp. cubense, Tropical Race 4 (TR4) is a soil-borne disease, and it is devastating. At present, the biological control using antagonistic microorganisms to mitigate TR4 is one of the best strategies as a safe and green way. Yunnan has abundant and diverse microbial resources. Using the dual-culture method, the antagonistic endophytic fungi against TR4 were isolated and screened from the root nodule of Dolichos lablab. The effect of the highest antagonistic activity strain on the morphology of the TR4 mycelium was observed using the scanning electron microscope. According to morphological characteristics and sequence analysis, the strain was identified. The biocontrol effect and plant growth promotion were investigated by greenhouse pot experiment. Using the confocal laser scanning microscope and the real-time fluorescence quantitative PCR, the dynamics of TR4 infestation and the TR4 content in banana plant roots and corms would also be detected. In this study, 18 native endophytic fungi were isolated from a root nodule sample of Dolichos lablab in the mulch for banana fields in Yuxi, Yunnan Province, China. The YNF2217 strain showed a high antagonistic activity against TR4 in plate confrontation experiments, and the inhibition rate of YNF2217 is 77.63%. After TR4 culture with YNF2217 for 7 days in plate confrontation experiments, the morphology of the TR4 mycelium appeared deformed and swollen when observed under a scanning electron microscope. According to morphological characteristics and sequence analysis, the strain YNF2217 was identified as Pochonia chlamydosporia. In the greenhouse pot experiment, the biocontrol effect of YNF2217 fermentation solution on TR4 was 70.97% and 96.87% on banana plant leaves and corms, respectively. Furthermore, YNF2217 significantly promoted the growth of banana plants, such as plant height, leaf length, leaf width, leaf number, pseudostem girth, and both the aboveground and underground fresh weight. Observations of TR4 infestation dynamics in banana roots and corms, along with real-time fluorescence quantitative PCR, verified that YNF2217 inoculation could significantly reduce the TR4 content. Therefore, YNF2217 as P. chlamydosporia, which was found first time in China and reported here, is expected to be an important new fungal resource for the green control of Fusarium wilt of banana in the future.

Abstract Background Elderly patients with breast cancer often have more unmet needs after receiving common treatments such as surgery and chemotherapy. Type D personality has been related to supportive care needs in the general population. However, its association with supportive care needs in elderly breast cancer patients has not been prospectively explored. This study aimed to address this gap. Objectives The aim was to understand the impact of Type D personality on the supportive care needs of elderly breast cancer patients at diagnosis, 2 weeks postoperatively, 3 months postoperatively, and 6 months postoperatively and to analyse the impact of Type D personality on the changing trajectory of supportive care needs after controlling for confounding factors such as demographics, symptom distress and social support. Methods A total of 122 elderly patients (≥ 65 years) with breast cancer in Ruijin Hospital, Shanghai, China, were included from September 2021 until August 2022. Supportive care needs were measured by the Supportive Care Needs Survey Short Form and tracked at diagnosis, 2 weeks postoperatively, 3 months postoperatively, and 6 months postoperatively. To investigate changes in the supportive care needs of elderly breast cancer patients and the effect of Type D personality on these needs, a linear mixed model was applied. Results A total of 122 elderly patients participated. There was an overall decreasing trend in supportive care needs, with Type D personality patients having significantly higher levels of supportive care needs than the non-Type D personality patients at all stages. Through linear mixed models, it was found that the Type D personality group had a lower overall downward trend than the non-Type D personality group, with need levels remaining consistently higher. This difference persisted after controlling for demographic information, symptom burden, social support. Conclusions Elderly breast cancer patients with Type D personality had higher levels of supportive care needs and a slower rate of decline that was maintained over a longer period than those with non-Type D personality.

Abstract Objective The present study aimed to investigate the association of triglyceride-glucose (TyG) index and neutrophil-to-lymphocyte ratio (NLR) with coronary artery disease (CAD), and evaluate the cumulative value of TyG index and NLR in identifying CAD, as well as the severity of CAD. Methods This retrospective study enrolled 2867 patients who underwent coronary angiography (CAG) for the first time between January 2013 and June 2022 in Zhongnan Hospital of Wuhan University. There were 2109 patients with CAD and 758 patients without CAD. The CAD patients were divided into two groups based on the median of Gensini score (mild stenosis CAD group: Gensini score