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We present the Manatee variational autoencoder model to predict transcription factor (TF) perturbation-induced transcriptomes. We demonstrate that the Manatee in silico perturbation analysis recapitulates target transcriptomic phenotypes in diverse cellular lineage transitions. We further propose the Manatee in silico screening analysis for prioritizing TF combinations targeting desired transcriptomic phenotypes.

Abstract Lung carcinoma, predominantly manifested as non-small cell lung cancer (NSCLC), significantly contributes to oncological mortality, underscoring an imperative for novel therapeutic paradigms. Amidst this context, the present investigation delineates the synergistic potentiation of doxorubicin (DOX)—a canonical chemotherapeutic—by Ursodeoxycholic acid (UDCA), a compound with a historical pedigree in hepatobiliary medicine, now repositioned within oncological pharmacotherapy due to its dichotomous cellular modulation—affording cytoprotection to non-malignant epithelia whilst eliciting apoptotic cascades in neoplastic counterparts. This study, through a rigorous methodological framework, elucidates UDCA’s capacity to inhibit NSCLC cellular proliferation and induce apoptosis, thereby significantly amplifying DOX’s chemotherapeutic efficacy. Notably, the co-administration of UDCA and DOX was observed to attenuate DOX-induced autophagy via the modulation of the TGF-β/MAPK signaling axis, a pathway pivotal in mediating cellular survival and autophagic mechanisms. Such findings not only underscore the therapeutic potential of UDCA as a chemosensitizer but also illuminate the molecular underpinnings of its modulatory effects, thereby contributing to the corpus of knowledge necessary to surmount chemoresistance in NSCLC. The implications of this research are twofold: firstly, it offers a compelling evidence base for the clinical reevaluation of UDCA in combinatory chemotherapeutic regimens; secondly, it posits a novel mechanistic insight into the modulation of chemotherapeutic efficacy and resistance. Collectively, these insights advocate for the expedited clinical translation of UDCA-DOX synergy, potentially heralding a paradigm shift in the management of NSCLC, thereby addressing a critical lacuna in contemporary oncological therapy.

Abstract Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

Abstract Cytochrome c oxidase (complex IV) is the terminal enzyme in the mitochondrial respiratory chain. As a rare neurometabolic disorder caused by mutations in the human complex IV assembly factor SURF1, Leigh Syndrome (LS) is associated with complex IV deficiency. In this study, we comprehensively characterized Schizosaccharomyces pombe Shy1, the homolog of human SURF1. Bioinformatics analysis revealed that Shy1 contains a conserved SURF1 domain that links to the biogenesis of complex IV and shares high structural similarity with its homologs in Saccharomyces cerevisiae and humans. Our study showed that Shy1 is required for the expression of mtDNA-encoded genes and physically interacts with structural subunits and assembly factors of complex IV. Interestingly, Rip1, the subunit of ubiquinone-cytochrome c oxidoreductase or cytochrome bc 1 complex (complex III), can also co-immunoprecipitate with Shy1, suggesting Shy1 may be involved in the assembly of the mitochondrial respiratory chain supercomplexes. This conclusion is further corroborated by our BN-PAGE analysis. Unlike its homologs, deletion of shy1 does not critically disrupt respiratory chain assembly, indicating the presence of the compensatory mechanism(s) within S. pombe that ensure mitochondrial functionality. Collectively, our investigation elucidates that Shy1 plays a pivotal role in the sustainability of the regular function of mitochondria by participating in the assembly of complex IV in S. pombe.

Abstract Purpose The relationship between exposure doses of 2.5-micrometer Particulate Matter (PM2.5), Inhalable particles (PM10), Sulfur Dioxide (SO2), Nitrogen Dioxide (NO2) and Ozone (O3) in the first trimester and spontaneous abortion of pregnant women was evaluated by global average method and nearest monitoring station method, respectively. Method Retrospective analysis of the clinical data of pregnant women with spontaneous abortion and full-term pregnant women in the Department of Obstetrics and Gynecology of two third-class hospitals in a valley city in Northwest China. According to the age factor, the eligible pregnant women were matched at a ratio of 1 : 4. The global average method and the nearest monitoring station method were used to evaluate the exposure of pollutants. The rank-sum test and conditional logistic regression were used to analyze the correlation between air pollutants and spontaneous abortion. Results Although the global average method and the nearest monitoring station method are slightly different in the assessment of exposure dose, they do not affect the correlation evaluation with spontaneous abortion. The exposure of pregnant women to PM2.5(OR1 = 1.156, OR2 = 1.036), SO2 (OR1 = 1.432, OR2 = 1.429) and NO2 (OR1 = 1.121, OR2 = 1.159) in the first trimester is related to the occurrence of spontaneous abortion.(OR1: the global average method, OR2: the nearest monitoring station method) Conclusion The exposure of PM2.5, SO2 and NO2 in the first trimester in valley cities is associated with the occurrence of spontaneous abortion in pregnant women.

Abstract Angiogenesis following cerebral ischemia is crucial for restoring blood supply to the ischemic region. Extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) offer potential therapeutic benefits in the treatment of cerebral ischemia. Houshiheisan (HSHS) has been shown to improve clinical outcomes in ischemic stroke patients, reduce cerebral ischemic damage in rats, and protect endothelial cells. However, the potential effects of HSHS-modified EPC-derived EVs (EVsHSHS) for cerebral ischemia remain unexplored. This study investigated the impact of EVsHSHS on angiogenesis using rats with permanent middle cerebral artery occlusion (pMCAO) and brain microvascular endothelial cells (BMECs) subjected to oxygen-glucose deprivation (OGD). Results demonstrated that EVsHSHS promoted the proliferation, migration, and tube formation of BMECs in vitro. In vivo, high doses of EVsHSHS exhibited better performance than equivalent doses of unmodified EPC-derived EVs in reducing cerebral infarction volume, improving cortical blood perfusion, decreasing neurological deficit scores, and increasing cortical microvessel density at day 7 post-modeling. The pro-angiogenic effects of EVsHSHS following cerebral ischemia were associated with the regulation of miR-126 and the PIK3R2/PI3K/AKT pathway.

Abstract Pollen coat proteins (PCPs) are cysteine-rich small-molecule proteins, which exhibit high levels of polymorphism and are expressed in gametocytes. Previous investigations have revealed that PCP genes are involved in pollen wall synthesis, pollen-stigma recognition, and pollen development and germination. However, gene expression and function of PCP family in pollen development is not well understood in Wucai (Brassica campestris L.). In this study, genome-wide identification and expression analysis of the BcPCP gene family members were conducted, including their physical and chemical properties, chromosome localization, phylogenetic relationships, gene structure, and tertiary structure. A total of 20 BcPCP genes were identified and classified into three subfamilies showing high homology to Arabidopsis thaliana. Expression pattern analysis indicated that the BcPCP gene family exhibits higher expression levels in reproductive organs, suggesting their potential involvement in the reproductive development. Notably, BraA02g002400.3 C, potentially associated with male sterility, was identified through multiple transcriptomic and proteomic datasets. Subsequently, sequence analysis revealed its homology with the Arabidopsis GRP20 gene, and thus it was named BcGRP20. Functional analysis of this gene showed that overexpression of BcGRP20 gene in the Arabidopsis grp20 mutant could restore anther fertility. Overall, our findings indicate that BcGRP20 plays a critical role in pollen development and may be the causative gene for male sterility in Wucai. This study provides candidate genes for further functional identification of BcPCP genes in Wucai, which are crucial for anther development.

Abstract Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.

Abstract Post-stroke depression (PSD) affects millions of patients who suffer cerebral stroke. However, the molecular mechanisms and pathophysiology are poorly understood. Previous studies have shown that exosomes have been proven to be involved in neuropsychiatric disorders such as stroke and post-stroke depression in neurotransmitter release, neuronal remodeling, and neuron angiogenesis. Here we extracted and purified hippocampal exosomes from stroke mouse model to investigate mechanisms of hippocampal exocytosis in PSD assessed by using behavioral tests and biochemical methods. Aiming at the effect of hippocampal exosomes from stroke on the development of PSD, behavioral test was compared including sugar water preference experiment, open fields, forced swimming test, to explore it in depth. Further, the expression of depression-related protein (proBDNF and p75NTR) and synapse-associated proteins (Synaptotagmin and PSD95) was evaluated by Western blotting, RT-qPCR or immunofluorescence staining. Density of dendritic protrusions of neurons was assessed by Golgi staining to measure changes in spine density after the treatment of hippocampal exosomes from stroke. Our results revealed that injection of exosomes from stroke models significantly aggravated depressive-like behaviors, increase of depression-related protein (proBDNF and p75NTR) expression and deficiency of synapse-associated proteins (Synaptotagmin and PSD95) expression, and the decreased number of spin density. Our findings together suggest that hippocampal exosomes from stroke cause exacerbation of depressive-like behavior in mice, possibly resulting from the regulation of neurogenesis by its depression-associated proteins (proBDNF and p75NTR). Therefore, hippocampal exosomes from stroke are promising targets for the diagnosis and treatment of PSD.

Abstract This study aimed to confirm the hypothesis that continuous ACB (CACB) combined with a popliteal plexus block (PPB) can improve posterior knee pain, reduce nalbuphine consumption, and shorten the length of hospital stay. Patients who underwent TKA were allocated to the CACB + sham block (SHAM) or CACB + PPB groups. The primary outcome was the maximum pain score originating from the posterior knee within 4 h after TKA. Secondary outcomes included the maximum pain score originating from the posterior and anterior knees within 72 h after TKA, range of motion on postoperative day (POD) 1–3, postoperative nalbuphine consumption within 72 h of surgery, length of hospital stay, and complications. The maximum pain score of the posterior knee was lower in the CACB + PPB group than in the CACB + SHAM group within 0–12 h after surgery. Nalbuphine consumption within 24 h after surgery was lower in the CACB + PPB group than in the CACB + SHAM group. The range of motion was better in the CACB + PPB group than in the CACB + SHAM group on POD1 and 2. The length of hospital stay was shorter in the CACB + PPB group than in the CACB + SHAM group. The incidence of clinical significant nausea and vomiting was lower in the CACB + PPB group than in the CACB + SHAM group. This study found that PPB combined with CACB could relieve pain in the posterior knee within at least 12 h after TKA, reduce nalbuphine consumption within 24 h after TKA, improve the range of motion on POD1 and 2, and shorten the length of hospital stay for patients who underwent TKA.

Abstract The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1 −/− mice in the Apc fl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1’s impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.

Abstract Chromosome microarray analysis (CMA) and whole exome sequencing (WES) are increasingly utilized in prenatal diagnosis of abnormal ultrasound findings, but studies on correlation between pathogenic copy number variations (pCNVs) and single-gene mutations in fetuses with nuchal translucency (NT) thickening/cystic hygroma (CH), and pregnancy outcomes, are rare. This study aimed to investigate clinical value of CMA and WES for NT thickening/CH in fetuses, explore genetic correlation between fetal NT thickening and CH, and analyze pregnancy outcomes. We retrospectively selected 215 pregnant women diagnosed with fetal NT thickening (NT > 95th)/CH who underwent invasive prenatal diagnosis at our hospital from January 2020 to June 2022. With negative chromosomal karyotype analysis (KA) and CMA results, patients voluntarily underwent WES. Patients were grouped by NT thickening/CH, and application value of KA, CMA, and WES examined. Ultrasound findings, pregnancy outcomes, and fetal growth post-birth were followed during mid/late pregnancy and post-delivery. Abnormalities in chromosomal number were detected in 28 of 215 samples, with a detection rate of 13.0%, and pCNVs were detected in 12 cases, with a detection rate of 5.6%. The most common abnormality in fetuses from both groups suggested by CMA was 22q11.21 microdeletion-microduplication syndrome. 35 patients with negative KA and CMA results underwent WES, and single gene variants were detected in 12 fetuses, with an abnormality rate of 34.3%. The incidence of adverse pregnancy outcomes was 28.2% in the NT thickening group and 82.9% in the CH group (P

Abstract Abnormal growth of blood vessels (choroidal neovascularization) can lead to age-related macular degeneration (AMD) and eventually cause vision loss due to detachment of the retinal pigmented epithelium. This indicates that choroidal neovascularization is important for the treatment of AMD. The circadian clock in the mammalian retina is responsible for controlling various functions of the retina, enabling it to adjust to changes in light and darkness. Recent studies have revealed a potential connection between the circadian clock and eye diseases, although a cause-and-effect relationship has not been definitively established. C57BL/6J male mice (aged 6 weeks) were randomly divided into two groups (Control group: 9:00–21:00 light period (300 lx); Jet lag group: 8-hour phase advance once every 4 days). A laser-induced CNV model was created after 2 weeks of feeding in a controlled or jet-lagged environment. Then, full transcriptome sequencing was performed. The pathways regulated by differentially expressed mRNAs were identified by GO analysis and GSEA. Further protein networks were constructed with the STRING database and Cytoscape software. WGCNA was used to further explore the co-expression modules of these differential genes and the correlation between these differential genes and phenotypes. ceRNA networks were constructed with miRanda and TargetScan. The pathways associated with the overlapping differentially expressed mRNAs in the ceRNA network were identified, and the hub genes were validated by qPCR. A total of 661 important DEGs, 31 differentially expressed miRNAs, 106 differentially expressed lncRNAs and 87 differentially expressed circRNAs were identified. GO and GSEA showed that the upregulated DEGs were mainly involved in reproductive structure development and reproductive system development. The STRING database and Cytoscape were used to determine the protein interaction relationships of these DEGs. WGCNA divided the expression of these genes into several modules and screened the hub genes of each module separately. Furthermore, a ceRNA network was constructed. GO analysis and GSEA showed that these target DEmRNAs mainly function in wound healing, cell spreading, epiboly involved in wound healing, epiboly, and morphogenesis of an epithelial sheet. Finally, ten key genes were identified, and their expression patterns were confirmed by real-time qPCR. In this study, we investigated the regulatory mechanism of ceRNAs in choroidal neovascularization according to different light-dark cycles in the eyeball.

Abstract This study aimed to evaluate the safety profile and beneficial effects of Heyndrickxia coagulans strain BC99 (BC99) for potential use in functional foods and pharmaceuticals. We began with whole genome sequencing of BC99, followed by a comprehensive safety assessment comprising genome analysis, hemolysis, cytotoxicity, antibiotic susceptibility tests, and cell adhesion and tolerance studies, along with acute and subacute oral toxicity studies in animal models. BC99 was isolated from a well-characterized collection originating from the feces of a healthy infant. Our results indicated no hemolytic activity on Columbia blood agar plates and broad antibiotic sensitivity, including to gentamicin, ampicillin, chloramphenicol, ciprofloxacin, and others. Cytotoxicity testing confirmed no adverse effects on HT-29 cells and significant adhesive properties to intestinal epithelial cells. Tolerance tests demonstrated over 90% viability of BC99 under simulated gastrointestinal conditions. In vivo studies in mice and rats confirmed the absence of adverse effects following oral administration. Collectively, these findings support BC99’s robust tolerance to gastrointestinal environments, strong adhesion capabilities, and a broad spectrum of antibiotic resistance, underlining its potential as a safe and effective agent for gut microbiota modulation and host health enhancement.

Abstract Sulfadoxine-pyrimethamine (SP) is a key drug recommended by the World Health Organization for the chemoprevention of malaria. However, the strategy is affected by the parasite resistance to SP. This study evaluated Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, associated with SP resistance, from 508 P. falciparum isolates imported from West African countries to Henan Province, China, during 2012–2022. High mutant prevalence of the genes Pfdhfr (94.7%) and Pfdhps (96.8%) was observed. The mutants Pfdhfr N51I, C59R, S108N, and Pfdhps A437G were at high frequency in all countries analyzed. The overall prevalence of the mutant Pfdhps K540E was low (3.4%), but with a high frequency in Liberia (24.3%). The frequency of mutants Pfdhps I431V, A581G, and A613S was 11.7%, 9.8%, and 16.2%, respectively, all of which had the highest mutant prevalence in Nigeria. The mutant Pfdhps A581G and A613S were identified in the absence of K540E. The partially resistant haplotype (I51R59N108 - G437) was the most common (72.6%), and the fully resistant haplotype (I51R59N108 - G437E540) had a low prevalence of 3.4% and mainly occurred in Liberia. No super resistant haplotype was identified. The mutant Pfdhps I431V and the octuple mutant haplotype I51R59N108 - V431A436G437G581S613 deserve more attention. In areas of high SP resistance, the intervention still reduces low birthweight and maternal anaemia. SP should continue to be used in areas of high SP resistance until more effective alternatives for malaria chemoprevention are found. It is important to continuously monitor the molecular markers associated with SP resistance to better implement intermittent preventive treatment policies in pregnancy (IPTp) and infants (IPTi).

Abstract Disulfidptosis is a novel programmed cell death mode that has been reported to play a role in oncogenesis. Increasing evidences suggest that the long non-coding RNAs (lncRNAs) play crucial roles in the initiation and progression of bladder cancer (BLCA). However, the role and prognostic value of disulfidptosis-related lncRNAs in BLCA remain unknown.The aim of this study was to construct and validate a disulfidptosis-related lncRNA risk model for predicting the prognosis of BLCA patients. A risk model consisting of 5 disulfidptosis-related lncRNAs was developed to predict the prognosis of BLCA patients. The overall survival (OS) of BLCA patients in the high-risk group was significantly shorter than that in the low-risk group (P

Abstract The pharmacokinetics of vancomycin exhibit significant inter-individual variability, particularly among elderly patients. This study aims to develop a predictive model that integrates machine learning with population pharmacokinetics (popPK) to facilitate personalized medication management for this demographic. A retrospective analysis incorporating 33 features, including popPK parameters such as clearance and volume of distribution. A combination of multiple algorithms and Shapley Additive Explanations was utilized for feature selection to identify the most influential factors affecting drug concentrations. The performance of each algorithm with popPK parameters was superior to that without popPK parameters. Our final ensemble model, composed of support vector regression, light gradient boosting machine, and categorical boosting in a 6:3:1 ratio, included 16 optimized features. This model demonstrated superior predictive accuracy compared to models utilizing all features, with testing group metrics including an R2 of 0.656, mean absolute error of 3.458, mean square error of 28.103, absolute accuracy within ± 5 mg/L of 81.82%, and relative accuracy within ± 30% of 76.62%. This study presents a rapid and cost-effective predictive model for estimating vancomycin plasma concentrations in elderly patients. The model offers a valuable tool for clinicians to accurately determine effective plasma concentration ranges and tailor individualized dosing regimens, thereby enhancing therapeutic outcomes and safety.

Abstract This is a prospective case-control study investigated the factors influencing ultra-early visual acuity and quality after Small Incision Lenticule Extraction (SMILE) surgery, with a specific focus on the morphology and distribution of “black clefts” observed in posterior lenticule laser scanning images. A total of 174 patients who underwent SMILE surgery were included, and their preoperative ocular clinical parameters, visual quality indicators, and posterior lenticule laser scanning images were analyzed. The morphological features of black clefts were calculated using image processing techniques. Univariate and multivariate logistic analyses were conducted to identify factors impacting ultra-early visual acuity recovery, while correlation analysis was used to explore the association between black cleft morphology and postoperative visual quality. The results showed that although patients experienced significant visual acuity improvement one day after surgery, 26% had poor early recovery. Postoperative visual quality parameters were significantly lower, while the Object Scatter Index (OSI) was higher compared to preoperative values. Patients with poor visual recovery had a higher number of irregular black clefts in their laser scanning images. Logistic regression analysis revealed that intraoperative morphological parameters of black clefts were independent factors influencing early postoperative visual acuity recovery. Additionally, correlation analysis demonstrated a negative correlation between black cleft morphology and postoperative visual quality parameters, and a positive correlation with OSI. In conclusion, the morphology and distribution of black clefts during SMILE surgery significantly affect ultra-early postoperative visual acuity and quality, with increased variability in black cleft area leading to higher OSI, thereby impacting visual quality recovery.

Abstract Acne is a prevalent inflammatory disease in dermatology, and its pathogenesis may be associated with inflammation, immunity, and other mechanisms. It commonly manifests in young individuals and frequently imposes a heavy economic, physical, and psychological burden on patients. Gut microbes and blood metabolites, as significant immune and inflammatory regulators in the body, have been hypothesized to form the “neurocutaneous axis.” Nonetheless, the precise causal relationships among the gut microbes, circulating blood metabolites, and acne development have yet to be elucidated. This study employed bidirectional two-sample Mendelian randomization (MR) to probe the causal impacts of 412 distinct gut microbes and 249 blood metabolites on acne. Single nucleotide polymorphisms (SNPs), which are closely associated with gut microbes and blood metabolites, were utilized as instrumental variables. This approach was taken to discern whether these elements serve as pathogenic or protective factors in relation to acne. Furthermore, a mediation analysis encompassing gut microbes, blood metabolites, and acne was conducted to explore potential correlations between gut microbes and blood metabolites, as well as their cumulative effects on acne. This was done to substantiate the notion of causality. Bidirectional two-sample MR analysis revealed 8 gut bacteria, 6 bacterial metabolic abundance pathways determined by birdshot, and 8 blood metabolites significantly associated with acne. The mediation MR analysis revealed 2 potential causal relationships, namely, Bifidobacterium-DHA-Acne and Bifidobacterium-Degree of Unsaturation-Acne. This study identified gut microbes and blood metabolites that are causally associated with acne. A potential causal relationship between gut microbes and blood metabolites was obtained via mediation analysis. These insights pave the way for the identification of new targets and the formulation of innovative approaches for the prevention and treatment of acne.

Abstract Conveyor belt deviation is a commmon and severe type of fault in belt conveyor systems, often resulting in significant economic losses and potential environment pollution. Traditional detection methods have obvious limitations in fault localization precision and analysis accuracy, unable to meet the demands of efficient and real-time fault detection in complex industrial scenarios. To address these issues, this paper proposes an improved detection algorithm based on YOLOv8, aiming to achieve efficient and accurate detection during the operation of the belt. Firstly, an Enhanced Squeeze-and-Excitation (ESE) module is incorporated into C2f to boost feature extraction for rollers and belts. Secondly, the construction of the BiFPN_DoubleAttention module in the neck network enhances bidirectional feature fusion and attention mechanism, thereby improving multi-scale object localization accuracy under complex environments. Then, a Multi-Head Self-Attention (MHSA) mechanism is introduced in the head network, better capturing positional features of small roller targets and belt areas in various environments, thus enhancing detection performance. Finally, extensive experiments are conducted on a self-built dataset, achieving an accuracy of 98.1%, mAP0.5 of 99.0%, and a detection speed of 46 frames per second (FPS). This method effectively handles variations and disturbances in the conveyor belt transportation environment, meeting real-time diagnostic needs for belt misalignment in the industry.

Abstract In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Abstract Asthma and cognitive dysfunction represent significant public health challenges. Our study aimed to investigate the relationship between asthma and cognitive dysfunction in adults aged ≥ 60 years, and explore the role of systemic immune inflammation index (SII) in asthma - cognitive dysfunction link. The retrospective cross-sectional study included 2,579 participants aged ≥ 60 years from the 2011–2014 National Health and Nutrition Examination Survey (NHANES) cycles. Asthma diagnosis was confirmed using the MCQ010 questionnaire, cognitive function assessed through the Digit Symbol Substitution Test (DSST). SII was calculated using the formula: (platelet count × neutrophil count)/lymphocyte count. Controlling for demographic variables including sex, age, race and/ethnicity, poverty-to-income ratio (PIR) and education level, a negative association was found between asthma and DSST scores (β = -1.75, 95% CI: -3.38, -0.120, P = 0.037). This association persisted even after further adjustments for body mass index (BMI) and diabetes (β = -1.72, 95% CI: -3.38, -0.057, P = 0.043). Moreover, subgroup analysis showed no significant association of sex, age, race/ethnicity, BMI or diabetes with the relationship between asthma and cognitive function. Mediation analysis indicated SII was a mediator of asthma-induced cognitive impairment, a notable Average Causal Mediated Effect (ACME) (P = 0.004) between SII and cognitive dysfunction. Our investigation indicated that elderly asthma (aged ≥ 60 years) was predisposed to cognitive dysfunction, independent of sex, age, race/ethnicity, BMI and diabetes. Furthermore, mediation analysis suggested that asthma might contribute to cognitive dysfunction through the involvement of SII.

Abstract The efficacy of diversion ileostomy followed by radical surgery for locally advanced upper-half rectal cancer remains uncertain. This study seeks to compare the effectiveness of treatment with and without diversion ileostomy in preventing anastomotic leakage (AL) and to identify a subset who may benefit from diversion ileostomy after AL occurs in Chinese patients with stage II and III upper-half rectal cancer. A retrospective study enrolled a total of 809 patients with locally advanced upper-half rectal cancer between 2017 and 2021, with 27.6% (n = 223) treated with diversion ileostomy and 72.4% (n = 586) treated without diversion ileostomy. The Diversion(+) group (n = 172) and Diversion(−) group (n = 172) were compared for perioperative outcomes through 1:1 propensity score matching (PSM). The selection of variables for multivariable logistic regression was determined through bivariate logistic regression analysis. Additionally, optimal cutoff values for risk factors were identified using ROC curve analysis. Within the entire cohort, patients in the Diversion(+) group exhibited a lower distance from the anal verge (DAV) and higher rates of chemoradiotherapy (CRT), diabetes, cN2 stage, mrCRM positivity, EMVI positivity, and CEA elevation compared to those in the Diversion(−) group. Following PSM, a satisfactory balance of baseline variables was achieved between the two groups. There were no statistically significant differences in AL rates (7.0% vs. 5.8%, p = 0.659) or AL grade distribution (Grade A: 0.6% vs. 0%, Grade B: 5.2% vs. 4.1%, Grade C: 1.2% vs. 1.7%, p = 0.691) between the two groups. However, the Diversion(+) group demonstrated a higher incidence of postoperative complications (30.8% vs. 17.4%, p = 0.004), Clavien‒Dindo III–IV complications (2.9% vs. 2.3%, p = 0.013), particularly wound infections (8.1% vs. 1.2%, p = 0.002), and early postoperative inflammatory small bowel obstruction (EPISBO) (8.7% vs. 1.2%, p = 0.001) compared to the Diversion(−) group. Results from multivariate logistic regression analysis revealed that male gender (OR = 2.354, p = 0.014) was the only independent risk factor associated with AL, while the presence of diversion ileostomy (with vs. without, OR = 1.144, p = 0.686) did not show significant associations. In patients with AL, the onset of the AL was observed to occur later in the Diversion(+) group compared to the Diversion(−) group (7.0 ± 3.3 vs. 3.4 ± 1.4 days, p

Abstract Thyroid hormone (TH) plays a crucial role in regulating glucose metabolism. However, the potential impact of the FT3/FT4 ratio, which reflects peripheral sensitivity to thyroid hormones, on glycemic variability in patients with type 2 diabetes (T2DM), has not been previously reported. To investigate the correlation between the FT3/FT4 ratio and glycemic variability in individuals with T2DM. In this retrospective analysis, a total of 468 inpatients with T2DM underwent continuous glucose monitoring (CGM) systems for a period of 6–14 days. Baseline clinical characteristics, laboratory tests, and CGM parameters were documented to investigate the correlation between FT3/FT4 ratio and CGM parameters. The levels of HBA, MG, SD, CV, LAGE, MODD and TAR2Scale were all higher in FT3/FT4Q1 compared with FT3/FT4Q2, FT3/FT4Q3 and FT3/FT4Q4 (all P

Abstract This study aimed to develop and validate a nomogram using clinical variables to guide personalized treatment strategies for adenoid cystic carcinoma of the head and neck (ACCHN). Data from 1069 patients with ACCHN diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were used to construct the nomogram. External validation was performed using an independent cohort of 70 patients from Fujian Cancer Hospital. Multivariate Cox regression analysis was conducted using IBM SPSS version 26.0 and R Software version 4.2.3. The concordance index (C-index) and receiver operating characteristic (ROC) curves were used to assess the predictive accuracy of the nomogram. Age, tumor site, surgery, N stage, M stage, and TNM stage were identified as independent prognostic factors through univariate and multivariate Cox analyses. The nomogram demonstrated superior predictive performance compared to the TNM staging system, effectively stratifying patients into high-risk and low-risk groups. This nomogram offers a valuable tool for predicting overall survival in patients with ACCHN and tailoring individualized treatment approaches.

Abstract Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.

Abstract With an aging population seeking infertility treatment, diminished ovarian reserve (DOR) is a prevalent indication for assisted reproductive technology (ART). This study aims to investigate the relationship between sleep parameters and DOR among women attending an infertility clinic. Methods We consecutively enrolled women attending an infertility clinic from July 2020 to June 2021. Participants completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale(ESS), and STOP-Bang Questionnaire to assess self-reported sleep quality. DOR-related indices including antral follicle count, anti-Müllerian hormone(AMH), follicle-stimulating hormone (FSH) were evaluated. A total of 979 women were enrolled, with 148 classified into the DOR group and 831 in the non-DOR group. The DOR group was notably older compared to the non-DOR group. Analysis showed that the DOR group exhibited significantly shorter sleep onset latency (p = 0.001) and shorter total sleep duration (p = 0.014) compared to the non-DOR group. Logistic regression analysis identified age, PSQI-sleep latency, and PSQI score as independent factors associated with an increased risk of DOR(all p

Abstract To evaluate the levels of YKL40, IL-6(interleukin-6), IL-8(interleukin-8), IL-10(interleukin-10), TNF-α (tumor necrosis factor-α) in OSAS (obstructive sleep apnea syndrome)children and explore the mechanism of YKL40 promoting inflammatory factors overexpression in tonsils. qPCR and ELISA were used to identify the expression of YKL40, IL-6, IL-8, IL-10, and TNF-α in the tonsils of OSAS children. Primary tonsil lymphocytes (PTLCs) were cultured and recombinant human YKL40(rhYKL40)was used to stimulate PTLCs in different concentrations and at different time points. The activation of NF-κB in PTLCs was screened by western blotting. Relative mRNA of YKL40, IL-6, IL-8, TNF-α was over expressed in OSAS-derived tonsil tissue and the levels of YKL40, IL-6, IL-8, and TNF-α was increased in OSAS-derived protein supernatant of tonsil tissue.The relative mRNA expression of IL-6, IL-8 and TNF-α increased under the treatment of YKL40 (100 ng/mmol for 24 h). The phosphorylation of p65 in NF-κB pathway was stimulated in the process. The levels of YKL40, IL-6, IL-8, and TNF-α increases in OSAS children, and YKL40 promotes the overexpression of IL-6, IL-8 and TNF-α in PTLCs via NF-κB pathway. The result implements that inflammation may play an important role in the pathogenesis of OSAS in children.

Abstract This study aimed to construct a high-performance prediction and diagnosis model for type 2 diabetic retinopathy (DR) and identify key correlates of DR. This study utilized a cross-sectional dataset of 3,000 patients from the People’s Liberation Army General Hospital in 2021. Logistic regression was used as the baseline model to compare the prediction performance of the machine learning model and the related factors. The recursive feature elimination cross-validation (RFECV) algorithm was used to select features. Four machine learning models, support vector machine (SVM), decision tree (DT), random forest (RF), and gradient boost decision tree (GBDT), were developed to predict DR. The models were optimized using grid search to determine hyperparameters, and the model with superior performance was selected. Shapley-additive explanations (SHAP) were used to analyze the important correlation factors of DR. Among the four machine learning models, the optimal model was GBDT, with predicted accuracy, precision, recall, F1-measure, and AUC values of 0.7883, 0.8299, 0.7539, 0.7901, and 0.8672, respectively. Six key correlates of DR were identified, including rapid micronutrient protein/creatinine measurement, 24-h micronutrient protein, fasting C-peptide, glycosylated hemoglobin, blood urea, and creatinine. The logistic model had 27 risk factors, with an AUC value of 0.8341. A superior prediction model was constructed that identified easily explainable key factors. The number of correlation factors was significantly lower compared to traditional statistical methods, leading to a more accurate prediction performance than the latter.

Abstract Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.

Abstract During the operation of load cell, heat is generated by the strain gauge and the electronics on the PCB board, which leads to temperature gradients within the sensor itself. These temperature gradients are unstable at different ambient temperatures. Compensation inaccuracies can also occur when compensating for sensor measurements at different temperatures This paper proposes a method to change the position of temperature compensation resistors to address errors caused by the temperature field effect of the strain gauge sensor itself. Without affecting the sensor’s strain measurement, the correctness of the proposed method is demonstrated through steady-state thermal simulation results in ANSYS and experimental results, effectively addressing errors caused by unstable temperature gradients during the operation of strain gauge sensors.

Abstract With the aging process of the global population and the development of medical technology, the cases of postoperative cognitive dysfunction (POCD) are also increasing. Due to the complexity of the pathogenesis, urgent treatment has been sought. Neuroinflammation induced by the accumulation of lipid droplets (LDs) in microglia has been closely watched in recent years and is also considered to be an important cause of nerve damage. Our study found that derived from Withania somnifera, Withaferin A (WA) could reduce the accumulation of LDs in the hippocampus of POCD mice, inhibit the expression of inflammatory factor interleukin-1β (IL-1β), and improve the cognitive ability of mice. Further in vitro experimental studies showed that WA increased the autophagy level of microglia, promoted the degradation of LDs, and reduced the production of inflammatory factors. In this regard, our comprehensive research endeavor holds the potential to furnish novel insights into therapeutic strategies aimed at addressing POCD and its associated neural impairments.

Abstract A nomogram to estimate the risk of linezolid-induced thrombocytopenia in patients with renal impairment is not available. The aim of the study is to develop a nomogram for predicting linezolid-induced thrombocytopenia in patients with renal impairment and to investigate the incremental value of PNU-142300 concentration beyond clinical factors and linezolid trough concentration (Cmin) for risk prediction. Logistic regression was used to identify independent risk factors for linezolid-induced thrombocytopenia in patients with renal impairment and nomograms were established. The performance of the nomograms was assessed in terms of area under the receiver operating characteristic curve (AUROC), net reclassification improvement (NRI), integrated discrimination improvement (IDI) , decision curve analysis (DCA) and calibration. Internal validation and external validation of the nomograms were also performed. Four nomograms were created: nomogram A including total bilirubin, creatinine clearance and concomitant mannitol use; nomogram B containing linezolid Cmin additionally; nomogram C containing total bilirubin, concomitant mannitol use, linezolid Cmin, and PNU142300 concentration; nomogram D including total bilirubin, concomitant mannitol use, and PNU142300 concentration. Nomogram C improved the prediction performance than nomogram A (AUROC 0.881 vs. 0.749; NRI 0.290; IDI 0.226) and nomogram B (AUROC 0.881 vs. 0.812; NRI 0.152; IDI 0.130) in the training cohort. DCA analysis showed that nomogram C yielded a greater net benefit. Compared with nomogram A and nomogram B, nomogram C also showed superior discriminatory efficacy, good calibration and clinical usefulness in the external validation cohort. The nomogram containing PNU-142300 concentration and linezolid Cmin had better predictive capability than that containing linezolid Cmin for predicting linezolid-induced thrombocytopenia in patients with renal impairment.

Abstract This study investigated the role of mitochondrial dynamics in postoperative cognitive dysfunction (POCD) and assessed the therapeutic potential of mitochondrial modulation, particularly through the inhibition of dynamin-related protein 1 (DRP1) with Mdivi-1. Our findings indicated that DRP1 inhibition substantially mitigated neuroinflammation mediated by microglial cells, contributing to improved cognitive function in POCD models. The administration of Mdivi-1 led to a notable decrease in mitochondrial fission, reduced reactive oxygen species (ROS) production, and stabilization of mitochondrial membrane potential, all of which correlate with diminished neuroinflammation, as evidenced by lower NOD-like receptor family pyrin domain containing 3 (NLRP3)/ interleukin-1β (IL-1β) expression in microglial cells. Importantly, Mdivi-1 treatment was also found to enhance synaptic plasticity, increasing synaptic spine density in the hippocampal region of POCD mice. This improvement in mitochondrial health and synaptic integrity was paralleled by enhanced cognitive performance, as demonstrated in Y-maze tests. These results underscored the critical role of mitochondrial dynamics in the pathophysiology of POCD and suggested that targeting mitochondrial dysfunction, specifically through DRP1 inhibition, could be an effective approach for POCD treatment.

Abstract Overall response rates in advanced Non-Small Cell Lung Cancer (NSCLC) remains low. Thus, novel molecular targets, tailored drugs and/or drug combinations are needed. Casein Kinase-2 (CK2) is a constitutively active and frequently over-expressed enzyme which fosters tumor survival, proliferation and metastasis. By using a clinical-grade and Cell Penetrating Peptide-based inhibitor coined as CIGB-300, we explore the anti-neoplastic effects caused by interruption of CK2 signaling in lung cancer cells lacking EGFR, ALK and ROS mutations. CIGB-300 penetrated and impaired viability and proliferation of Lung Adenocarcinoma (LUAD) (A549, NCI-H522) and Lung Squamous Carcinoma (LUSC) (NCI-H226 and SK-MES-1) cells in a dose-response manner. The differential activity could not be explained by overall peptide uptake or its subcellular distribution, as evidenced by flow cytometry and confocal microscopy. Upon internalization, CIGB-300 interacted with CK2 catalytic subunits (ɑ1/ɑ2) and CK2 substrates, thus impairing phosphorylation of enzyme substrates (CDC37s13, NPM1s125) and downstream proteins (RPS6s325/326). CK2 inhibition induced an early Reactive Oxygen Species (ROS) and mitochondrial membrane depolarization, which predates lung cancer cell death. Finally, intravenous injection of CIGB-300 in a cell line-based xenograft corroborated CIGB-300’s anti-tumor effects and suggested concurrent in situ reductions of CSNK2ɑ subunit and downstream RPS6s235/236 phosphorylation. Overall, CIGB-300 therapeutic hypothesis and antineoplastic effects demonstrated herein, further support the evaluation of this clinical-grade CK2 inhibitor in advanced NSCLC with limited therapeutic options.