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ObjectivesWe aimed to assess the quality of information regarding depression on Chinese websites and popular video platforms.MethodsWe conducted searches on website platforms (Baidu, Bing) and video platforms (Bilibili, Douyin) using search terms “depression”, “depressive disorder”, “depression treatment”, “depressive anxiety”, “depressed patient”, and “depressive symptoms”. We collected the first 50 results with each search term in each platform. Each website and video included in this study was assessed using The DISCERN instrument (DISCERN), Journal of American Medical Association benchmark criteria (JAMA), Hexagonal Radar Schema (HRS), and Global Quality Scores (GQS).ResultsA total of 177 websites, 216 Bilibili videos, and 244 Douyin videos were included. Among all the platforms, websites had the highest median scores on DISCERN and HRS, at 33 and 2 respectively, but were still classified as “poor” and “very poor” according to the classification. Bilibili, Douyin, and websites had median scores of 3, 2, and 2 respectively in JAMA, indicating a moderate level of quality. Bilibili, Douyin, and websites all had a median score of 2 for GQS, and were of poor quality. Only the percentage score for JAMA was more than half of the weighted score, while none of the other scales reached half of the score. The median percentage scores of the websites in DISCERN, HRS, and GQS were higher than those of Bilibili and Douyin (P < 0.001). Compared to other sources, news media on websites and medical organizations on videos demonstrated higher quality (all P values < 0.05).ConclusionsThe findings of the study indicated an overall low quality of online depression information. Collaborative efforts between platforms and professionals are necessary to improve the comprehensiveness and quality of depression-related information available online. In addition, the platform needs to prioritize optimizing the algorithm of recommendations and present real high-quality health information to the audience.

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder posing challenges to patients, caregivers, and society. Accessible and accurate information is crucial for effective AD management. ObjectiveThis study aimed to evaluate the accuracy, comprehensibility, clarity, and usefulness of the Generative Pretrained Transformer’s (GPT) answers concerning the management and caregiving of patients with AD. MethodsIn total, 14 questions related to the prevention, treatment, and care of AD were identified and posed to GPT-3.5 and GPT-4 in Chinese and English, respectively, and 4 respondent neurologists were asked to answer them. We generated 8 sets of responses (total 112) and randomly coded them in answer sheets. Next, 5 evaluator neurologists and 5 family members of patients were asked to rate the 112 responses using separate 5-point Likert scales. We evaluated the quality of the responses using a set of 8 questions rated on a 5-point Likert scale. To gauge comprehensibility and participant satisfaction, we included 3 questions dedicated to each aspect within the same set of 8 questions. ResultsAs of April 10, 2023, the 5 evaluator neurologists and 5 family members of patients with AD rated the 112 responses: GPT-3.5: n=28, 25%, responses; GPT-4: n=28, 25%, responses; respondent neurologists: 56 (50%) responses. The top 5 (4.5%) responses rated by evaluator neurologists had 4 (80%) GPT (GPT-3.5+GPT-4) responses and 1 (20%) respondent neurologist’s response. For the top 5 (4.5%) responses rated by patients’ family members, all but the third response were GPT responses. Based on the evaluation by neurologists, the neurologist-generated responses achieved a mean score of 3.9 (SD 0.7), while the GPT-generated responses scored significantly higher (mean 4.4, SD 0.6; P

Summary: Stapokibart (CM310) is a humanized IL-4Rα monoclonal antibody currently undergoing phase 3 trials for type 2 inflammatory diseases. In contrast to dupilumab, which bound exclusively to human IL-4Rα, stapokibart demonstrated cross-species reactivity to IL-4Rα from human, cynomolgus monkey, and rat. Stapokibart exhibited comparable blocking activity to dupilumab. Epitope mapping revealed that stapokibart bound to distinct sites on IL-4Rα compared to dupilumab. In vitro assays showed that stapokibart was comparable or numerically superior in blocking IL-4Rα-mediated signaling compared to dupilumab. In vivo studies further demonstrated that stapokibart effectively inhibited the progression of type 2 inflammation. Pharmacokinetic studies revealed a circulating half-life of approximately 298–351 h in cynomolgus monkeys and 55–142 h in rats for stapokibart. Toxicity studies indicated a favorable safety profile in cynomolgus monkeys and rats. The preclinical evaluation of stapokibart supports its clinical development.

Summary: Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901’s favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

Summary: Glioblastoma (GBM) is characterized by aggressive growth, invasiveness, and poor prognosis. Elucidating the molecular mechanisms underlying GBM is crucial. This study explores the role of Sm-like protein 14 homolog A (LSM14A) in GBM. Bioinformatics and clinical tissue samples analysis demonstrated that overexpression of LSM14A in GBM correlates with poorer prognosis. CCK8, EdU, colony formation, and transwell assays revealed that LSM14A promotes proliferation, migration, and invasion in GBM in vitro. In vivo mouse xenograft models confirmed the results of the in vitro experiments. The mechanism of LSM14A modulating GBM cell proliferation was investigated using mass spectrometry, co-immunoprecipitation (coIP), protein half-life, and methylated RNA immunoprecipitation (MeRIP) analyses. The findings indicate that during the G1/S phase, LSM14A stabilizes DDX5 in the cytoplasm, regulating CDK4 and P21 levels. Furthermore, METTL1 modulates LSM14A expression via mRNA m7G methylation. Altogether, our work highlights the METTL1-LSM14A-DDX5 pathway as a potential therapeutic target in GBM.

At present, most near-eye display devices adopt flat substrates, which have problems such as limited field of view (FOV) and bulky shape, while the curved structure is expected to expand the FOV with appropriate volume. In this paper, we propose a curved holographic augmented reality (AR) near-eye display system based on holographic optical element (HOE) with the ability to expand the FOV. The system includes a display source and a HOE with curved substrate. We analyze the system by exploiting the diffraction theory between plane and curved surface, and a layered and weighted FOV optimization method using particle swarm optimization algorithm is proposed to realize the optimization of the phase of freeform HOE. Numerical and experimental results show that the proposed curved holographic near-eye display system can realize cylindrical AR display and expand the FOV of the system. It is expected to be applied to the holographic AR near-eye display in the future.

BackgroundBurnout among health care professionals is a significant concern, with detrimental effects on health care service quality and patient outcomes. The use of the electronic health record (EHR) system has been identified as a significant contributor to burnout among health care professionals. ObjectiveThis systematic review and meta-analysis aims to assess the prevalence of burnout among health care professionals associated with the use of the EHR system, thereby providing evidence to improve health information systems and develop strategies to measure and mitigate burnout. MethodsWe conducted a comprehensive search of the PubMed, Embase, and Web of Science databases for English-language peer-reviewed articles published between January 1, 2009, and December 31, 2022. Two independent reviewers applied inclusion and exclusion criteria, and study quality was assessed using the Joanna Briggs Institute checklist and the Newcastle-Ottawa Scale. Meta-analyses were performed using R (version 4.1.3; R Foundation for Statistical Computing), with EndNote X7 (Clarivate) for reference management. ResultsThe review included 32 cross-sectional studies and 5 case-control studies with a total of 66,556 participants, mainly physicians and registered nurses. The pooled prevalence of burnout among health care professionals in cross-sectional studies was 40.4% (95% CI 37.5%-43.2%). Case-control studies indicated a higher likelihood of burnout among health care professionals who spent more time on EHR-related tasks outside work (odds ratio 2.43, 95% CI 2.31-2.57). ConclusionsThe findings highlight the association between the increased use of the EHR system and burnout among health care professionals. Potential solutions include optimizing EHR systems, implementing automated dictation or note-taking, employing scribes to reduce documentation burden, and leveraging artificial intelligence to enhance EHR system efficiency and reduce the risk of burnout. Trial RegistrationPROSPERO International Prospective Register of Systematic Reviews CRD42021281173; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021281173

IntroductionCM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb.MethodsThe binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice.ResultsThere exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly.DiscussionCM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

BackgroundArtificial intelligence models tailored to diagnose cognitive impairment have shown excellent results. However, it is unclear whether large linguistic models can rival specialized models by text alone. ObjectiveIn this study, we explored the performance of ChatGPT for primary screening of mild cognitive impairment (MCI) and standardized the design steps and components of the prompts. MethodsWe gathered a total of 174 participants from the DementiaBank screening and classified 70% of them into the training set and 30% of them into the test set. Only text dialogues were kept. Sentences were cleaned using a macro code, followed by a manual check. The prompt consisted of 5 main parts, including character setting, scoring system setting, indicator setting, output setting, and explanatory information setting. Three dimensions of variables from published studies were included: vocabulary (ie, word frequency and word ratio, phrase frequency and phrase ratio, and lexical complexity), syntax and grammar (ie, syntactic complexity and grammatical components), and semantics (ie, semantic density and semantic coherence). We used R 4.3.0. for the analysis of variables and diagnostic indicators. ResultsThree additional indicators related to the severity of MCI were incorporated into the final prompt for the model. These indicators were effective in discriminating between MCI and cognitively normal participants: tip-of-the-tongue phenomenon (P

Abstract Background Cervical squamous cell carcinoma (SCC) is known to arise through increasingly higher-grade squamous intraepithelial lesions (SILs) or cervical intraepithelial neoplasias (CINs). This study aimed to describe sequential molecular changes and identify biomarkers in cervical malignant transformation. Methods Multidimensional data from five publicly available microarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42 normal, 62 CIN1, 26 CIN2, 47 CIN3, and 177 SCC) to determine the potential diagnostic and prognostic value of identified biomarkers. Results We demonstrated that normal epithelium and SILs presented higher molecular homogeneity than SCC. Genes in the region (e.g., 3q, 12q13) with copy number alteration or HPV integration were more likely to lose or gain expression. The IL-17 signaling pathway was enriched throughout disease progression with downregulation of IL17C and decreased Th17 cells at late stage. Furthermore, we identified AURKA, TOP2A, RFC4, and CEP55 as potential causative genes gradually upregulated during the normal-SILs-SCC transition. For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89). They had equivalent diagnostic performance alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 significantly and independently predicted favorable outcomes in multi-institutional cohorts of SCC patients. Conclusions Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes during cervical carcinogenesis. RFC4 is proposed as a novel surrogate biomarker for determining HSIL and HSIL+, and an independent prognostic biomarker for SCC.

ChatGPT has promising applications in health care, but potential ethical issues need to be addressed proactively to prevent harm. ChatGPT presents potential ethical challenges from legal, humanistic, algorithmic, and informational perspectives. Legal ethics concerns arise from the unclear allocation of responsibility when patient harm occurs and from potential breaches of patient privacy due to data collection. Clear rules and legal boundaries are needed to properly allocate liability and protect users. Humanistic ethics concerns arise from the potential disruption of the physician-patient relationship, humanistic care, and issues of integrity. Overreliance on artificial intelligence (AI) can undermine compassion and erode trust. Transparency and disclosure of AI-generated content are critical to maintaining integrity. Algorithmic ethics raise concerns about algorithmic bias, responsibility, transparency and explainability, as well as validation and evaluation. Information ethics include data bias, validity, and effectiveness. Biased training data can lead to biased output, and overreliance on ChatGPT can reduce patient adherence and encourage self-diagnosis. Ensuring the accuracy, reliability, and validity of ChatGPT-generated content requires rigorous validation and ongoing updates based on clinical practice. To navigate the evolving ethical landscape of AI, AI in health care must adhere to the strictest ethical standards. Through comprehensive ethical guidelines, health care professionals can ensure the responsible use of ChatGPT, promote accurate and reliable information exchange, protect patient privacy, and empower patients to make informed decisions about their health care.

BackgroundDeep learning (DL) prediction models hold great promise in the triage of COVID-19. ObjectiveWe aimed to evaluate the diagnostic test accuracy of DL prediction models for assessing and predicting the severity of COVID-19. MethodsWe searched PubMed, Scopus, LitCovid, Embase, Ovid, and the Cochrane Library for studies published from December 1, 2019, to April 30, 2022. Studies that used DL prediction models to assess or predict COVID-19 severity were included, while those without diagnostic test accuracy analysis or severity dichotomies were excluded. QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2), PROBAST (Prediction Model Risk of Bias Assessment Tool), and funnel plots were used to estimate the bias and applicability. ResultsA total of 12 retrospective studies involving 2006 patients reported the cross-sectionally assessed value of DL on COVID-19 severity. The pooled sensitivity and area under the curve were 0.92 (95% CI 0.89-0.94; I2=0.00%) and 0.95 (95% CI 0.92-0.96), respectively. A total of 13 retrospective studies involving 3951 patients reported the longitudinal predictive value of DL for disease severity. The pooled sensitivity and area under the curve were 0.76 (95% CI 0.74-0.79; I2=0.00%) and 0.80 (95% CI 0.76-0.83), respectively. ConclusionsDL prediction models can help clinicians identify potentially severe cases for early triage. However, high-quality research is lacking. Trial RegistrationPROSPERO CRD42022329252; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD 42022329252

Abstract Background Septic heart failure accounts for high mortality rates globally. With a strong reducing capacity, zero-valent iron nanoparticles (nanoFe) have been applied in many fields. However, the precise roles and mechanisms of nanoFe in septic cardiomyopathy remain unknown. Results NanoFe was prepared via the liquid-phase reduction method and functionalized with the biocompatible polymer sodium carboxymethylcellulose (CMC). We then successfully constructed a mouse model of septic myocardial injury by challenging with cecal ligation and puncture (CLP). Our findings demonstrated that nanoFe has a significant protective effect on CLP-induced septic myocardial injury. This may be achieved by attenuating inflammation and oxidative stress, improving mitochondrial function, regulating endoplasmic reticulum stress, and activating the AMPK pathway. The RNA-seq results supported the role of nanoFe treatment in regulating a transcriptional profile consistent with its role in response to sepsis. Conclusions The results provide a theoretical basis for the application strategy and combination of nanoFe in sepsis and septic myocardial injury. Graphical Abstract

Introduction: Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. Objectives: The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. Methods: ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. Results: PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. Conclusion: In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.

Abstract Cytochrome c oxidase subunit VIc (COX6c) is one of the most important subunits of the terminal enzyme of the respiratory chain in mitochondria. Numerous studies have demonstrated that COX6c plays a critical role in the regulation of oxidative phosphorylation (OXPHOS) and energy production. The release of COX6c from the mitochondria may be a hallmark of the intrinsic apoptosis pathway. Moreover, The changes in COX6c expression are widespread in a variety of diseases and can be chosen as a potential biomarker for diagnosis and treatment. In light of its exclusive effects, we present the elaborate roles that COX6c plays in various diseases. In this review, we first introduced basic knowledge regarding COX6c and its functions in the OXPHOS and apoptosis pathways. Subsequently, we described the regulation of COX6c expression and activity in both positive and negative ways. Furthermore, we summarized the elaborate roles that COX6c plays in various diseases, including cardiovascular disease, kidney disease, brain injury, skeletal muscle injury, and tumors. This review highlights recent advances and provides a comprehensive summary of COX6c in the regulation of OXPHOS in multiple diseases and may be helpful for drug design and the prediction, diagnosis, treatment, and prognosis of diseases.

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

Objective: Acyl-CoA thioesterase 13 (ACOT13) encodes a member of the thioesterase superfamily. It has not been reported in ovarian cancer. This research aimed at evaluating the expression and prognostic value of ACOT13 in ovarian serous cystadenocarcinoma (OSC).Methods: We extracted and analyzed TCGA, GEPIA, THPA, GTEx, miRWalk, and GDSC databases to investigate the potential carcinogenic mechanism of ACOT13 in OSC, including the correlation of ACOT13 with prognosis, immune checkpoint, tumor mutational burden (TMB), and 50% inhibition concentration (IC50) score. The incidence of endpoint events was compared with Kaplan-Meier survival analysis. Independent prognostic factors for OSC were evaluated with univariate and multivariate Cox regression analyses, and a nomogram was established.Results: The expression of ACOT13 was increased in OSC and correlated with tumor stage, with higher expression in stages I and II than in stages III and IV. Besides, it was observed that low expression of ACOT13 is correlated with poor overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) in patients with OSC. There was a positive correlation between ACOT13 expression and immune checkpoint sialic acid-binding Ig-like lectin (SIGLEC) 15 and TMB. Patients with low ACOT13 expression had higher cisplatin IC50 scores.Conclusion: ACOT13 is an independent prognostic factor and a promising clinical target for OSC. In the future, the carcinogenic mechanism and clinical application value of ACOT13 in ovarian cancer need to be further studied.

ChatGPT is receiving increasing attention and has a variety of application scenarios in clinical practice. In clinical decision support, ChatGPT has been used to generate accurate differential diagnosis lists, support clinical decision-making, optimize clinical decision support, and provide insights for cancer screening decisions. In addition, ChatGPT has been used for intelligent question-answering to provide reliable information about diseases and medical queries. In terms of medical documentation, ChatGPT has proven effective in generating patient clinical letters, radiology reports, medical notes, and discharge summaries, improving efficiency and accuracy for health care providers. Future research directions include real-time monitoring and predictive analytics, precision medicine and personalized treatment, the role of ChatGPT in telemedicine and remote health care, and integration with existing health care systems. Overall, ChatGPT is a valuable tool that complements the expertise of health care providers and improves clinical decision-making and patient care. However, ChatGPT is a double-edged sword. We need to carefully consider and study the benefits and potential dangers of ChatGPT. In this viewpoint, we discuss recent advances in ChatGPT research in clinical practice and suggest possible risks and challenges of using ChatGPT in clinical practice. It will help guide and support future artificial intelligence research similar to ChatGPT in health.

Abstract Most sepsis deaths are due to the development of multiple organ failure, in which heart failure is a recognized manifestation of sepsis. To date, the role of liver X receptors α (NR1H3) in sepsis is still uncertain. Here, we hypothesized that NR1H3 mediates multiple essential sepsis‐related signalings to attenuate septic heart failure. Adult male C57BL/6 or Balbc mice and HL‐1 myocardial cell line were performed for in vivo and in vitro experiments, respectively. NR1H3 knockout mice or NR1H3 agonist T0901317 was applied to evaluate the impact of NR1H3 on septic heart failure. We found decreased myocardial expression levels of NR1H3‐related molecules while increased NLRP3 level in septic mice. NR1H3 knockout worsensed cardiac dysfunction and injury in mice subjected to cecal ligation and puncture (CLP), in association with exacerbated NLRP3‐mediated inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis‐related markers. The administration of T0901317 reduced systemic infection and improve cardiac dysfunction in septic mice. Moreover, Co‐IP assays, luciferase reporter assays, and chromatin immunoprecipitation analysis, confirmed that NR1H3 directly repressed NLRP3 activity. Finally, RNA‐seq detection further clarified an overview of the roles of NR1H3 in sepsis. In general, our findings indicate that NR1H3 had a significant protective effect against sepsis and sepsis‐induced heart failure.

The heat shock transcription factors (HSFs) family is widely present in eukaryotes including plants. Recent studies have indicated that HSF is a multifunctional group of genes involved in plant growth and development, as well as response to abiotic stresses. Here we combined the bioinformatic, molecular biology way to dissect the function of Hsf, specifically HsfB4 in wheat under abiotic stresses. In this study, we identified 78 TaHSF genes in wheat (Triticum aestivum) and analyzed their phylogenetic relationship and expression regulation motifs. Next, the expression profiles of TaHSFs and AtHSFs were analyzed in different tissues as well as in response to abiotic stress. Furthermore, to explore the role of HSFB4 in abiotic stress response, we cloned TaHSFB4-2B from the wheat variety, Chinese Spring. Subcellular localization analysis showed that TaHSFB4-2B was localized in the nucleus. In addition, We observed TaHSFB4-2B was highly expressed in the root and stem, its transcription was induced under long-term heat shock, cold, and salinity stress. Additionally, overexpression of TaHSFB4-2B suppressed seed germination and growth in Arabidopsis with salinity and mannitol treatment. It also modulated the expression of stress-responsive genes, including AtHSP17.8, AtHSP17.6A, AtHSP17.6C, CAT2, and SOS1, under both normal and stress conditions. From these finding, we propose that TaHSFB4-2B act as a negative regulator of abiotic stress response in the plant.

BackgroundLung cancer patients with coronavirus disease 2019 (COVID-19) infection experience high mortality rates. The study aims to determine the risk factors for mortality in lung cancer patients with COVID-19 infection.Materials and methodsFollowed the PRISMA reporting guidelines, PubMed, Embase, and Web of Science were systematically searched to February 20, 2023, for studies of lung cancer patients with COVID-19 infection. The main outcome of interest was the risk factor for mortality. We also compared the mortality rate of those patients among different continents. A pooled risk ratio (RR) with 95% CI was presented as the result of this meta-analysis.ResultsMeta-analysis of 33 studies involving 5018 patients showed that pooled mortality rate of lung cancer in COVID-19 patients was 0.31 (95% CI: 0.25-0.36). Subgroup analysis based on the continents showed significant difference of the mortality rate was observed between Asia and the rest of world (χ2 = 98.96, P < 0.01). Older age (SMD: 0.24, 95% CI: 0.09-0.40, P < 0.01), advanced lung cancer (RR: 1.14, 95% CI: 1.04-1.26, P < 0.01), coexisting comorbidities such as hypertension (RR: 1.17, 95% CI: 1.01-1.35, P = 0.04) and cardiovascular disease (RR: 1.40, 95% CI: 1.03-1.91, P = 0.03) were associated with higher risk of mortality rate in those patients.ConclusionsFindings of this meta-analysis confirms an increased risk of mortality in lung cancer patients with COVID-19 infection, whose risk factors for these patients appear to be exacerbated by older age, advanced-stage lung cancer, and comorbidities such as hypertension and cardiovascular disease.

ObjectiveTo evaluate the prognostic value and explore the biological significance of gap junction protein beta 2 (GJB2 or Cx26) in cervical cancer (CC).MethodsWe first compared GJB2 expression between CC and normal tissues using public databases and immunohistochemistry (IHC). Based on The Cancer Genome Atlas data (TCGA cohort, n = 304) and tissue microarray samples (OBC cohort, n = 111), we explored the prognostic value of GJB2 for CC patients using bioinformatics analysis and IHC scoring. To explore the biological significance of GJB2, Gene set enrichment analysis (GSEA) and Gene Ontology (GO) were performed. The impact of GJB2 on the immune microenvironment was analyzed by CIBERSORTx and ESTIMATE algorithms. We finally investigated the relationship between GJB2 and drug sensitivity based on the Genomics of Drug Sensitivity in Cancer (GDSC).ResultsThe expression of GJB2 was significantly increased in CC over normal tissues. Both the TCGA and OBC cohort found that patients with high GJB2 expression had shorter overall survival (OS) time, and high GJB2 expression was the independent risk factor for prognosis (TCGA: HR, 2.566; 95% CI, 1.066–6.180; p = 0.036; OBC: HR, 2.198; 95% CI, 1.019–4.741; p = 0.045). GJB2 was correlated with patient clinical factors such as tumor size and differentiation grade. The p53 signaling pathway and toll-like receptor pathway may be regulated by GJB2. The abundance of various immune cells was significantly different between the low and high GJB2 expression groups. The ImmuneScore was significantly increased in the high GJB2 expression group. In addition, the expression level of GJB2 was positively correlated with the natural log of the half-maximal inhibitory concentration (LN_IC50) value of cisplatin/paclitaxel (Spearman r = 0.238/0.153, p < 0.001).ConclusionGJB2 can serve as a potential prognostic marker of poor survival and a therapeutic target in CC. Moreover, GJB2 may affect the immune microenvironment and is correlated with chemoresistance.

Abstract Background Ovarian cancer is the second fatal malignancy of the female reproductive system. Based on the cancer stem cell (CSC) theory, its poor prognosis of ovarian cancer attributed to tumor recurrence caused by CSCs. A variety of cell surface-specific markers have been employed to identify ovarian cancer stem cells (OCSCs). In this study, we attempted to explore the common feature in ovarian cancer stem cells sorted by multiple approaches. Methods We collected the gene expression profiles of OCSCs were from 5 public cohorts and employed R software and Bioconductor packages to establish differently expressed genes (DEGs) between OCSCs and parental cells. We extracted the integrated DEGs by protein-protein interaction (PPI) network construction and explored potential treatment by the Cellminer database. Results We identified and integrated the DEGs of OCSCs sorted by multiple isolation approaches. Besides, we identified OCSCs share characteristics in the lipid metabolism and extracellular matrix changes. Moreover, we obtained 16 co-expressed core genes, such as FOXQ1, MMP7, AQP5, RBM47, ETV4, NPW, SUSD2, SFRP2, IDO1, ANPEP, CXCR4, SCNN1A, SPP1 and IFI27 (upregulated) and SERPINE1, DUSP1, CD40, and IL6 (downregulated). Through correlation analysis, we screened out ten potential drugs to target the core genes. Conclusion Based on the comprehensive analysis of the genomic datasets with different sorting methods of OCSCs, we figured out the common driving genes to regulating OCSC and obtained ten new potential therapies for eliminating ovarian cancer stem cells. Hence, the findings of our study might have potential clinical significance.

Nitrogen is one of the most important nutrient elements required for plant growth and development, which is also immensely related to the efficient use of nitrogen by crop plants. Therefore, plants evolved sophisticated mechanisms and anion channels to extract inorganic nitrogen (nitrate) from the soil or nutrient solutions, assimilate, and recycle the organic nitrogen. Hence, developing crop plants with a greater capability of using nitrogen efficiently is the fundamental research objective for attaining better agricultural productivity and environmental sustainability. In this context, an in-depth investigation has been conducted into the cassava slow type anion channels (SLAHs) gene family, including genome-wide expression analysis, phylogenetic relationships with other related organisms, chromosome localization, and functional analysis. A potential and nitrogen-responsive gene of cassava (MeSLAH4) was identified and selected for overexpression (OE) analysis in rice, which increased the grain yield and root growth related performance. The morpho-physiological response of OE lines was better under low nitrogen (0.01 mm NH4NO3) conditions compared to the wild type (WT) and OE lines under normal nitrogen (0.5 mm NH4NO3) conditions. The relative expression of the MeSLAH4 gene was higher (about 80-fold) in the OE line than in the wild type. The accumulation and flux assay showed higher accumulation of NO3− and more expansion of root cells and grain dimension of OE lines compared to the wild type plants. The results of this experiment demonstrated that the MeSLAH4 gene may play a vital role in enhancing the efficient use of nitrogen in rice, which could be utilized for high-yielding crop production.

This study is aimed at the special working conditions of seeding on sloping land, combining advanced precision seeding technology and the structure of rotary hole filling corn precision metering device seed rowers at home and abroad, and studying soil entry characteristics, the characteristics of soil particles and the seed transport pattern in the puncture process, in order to improve the seed dispersal qualified index and reduce the coefficient of variation in the process of seeding. The simulation test of the cavity-tying device was carried out using the MBD–DEM coupling method, and it can be seen that the rocker bending angle is 120° when the force is the largest; at this time the rocker and the soil force is the largest, indicating the best effect on soil particle separation and the fastest movement speed. The single-factor test determined that the operating speed of the seed rower ranged from 0.8 to 1.2 m/s, the spring preload force of the seed rower ranged from 5.5 to 25 N, and the operating slope angle of the seed rower ranged from 8° to 16°. The optimal structure and parameter characteristics of the rotary hole filling corn precision metering device were determined with a multi-factor test, and it was proven that the rotary hole filling corn precision metering device has better performance and a higher seed rowing quality, with the qualified index reaching 96.2%. This study can provide a reference for the research of corn precision seeders, enrich the form of corn precision seeders, and effectively improve the level of corn mechanized seeding.

Tyre wear particle emissions have gained significant attention due to their harmful effects on the environment and human health. However, studies on tyre wear particles generated under chassis dynamometer conditions are still scarce. This study measures the instantaneous number concentrations and elemental species of tyre wear particles in different light-duty vehicle test cycles. The results show that the particle number (PN) concentrations of the US06 test cycle are much higher than those of the WLTC test cycle due to the larger and more frequent accelerations and decelerations in the former. High PN concentrations are observed during high driving speeds with rapid accelerations, while PN concentrations are much lower during low driving speed with rapid acceleration. Furthermore, tyre tread temperature is found to be related to the formation of tyre wear particles. The PN concentration in the second and third US06 test cycles are similar, indicating that once the tyre temperature exceeds the critical value, the tyres become heated to a steady state, and the PN concentrations will not be affected by the average temperature of the tyre. A low initial tyre temperature can produce high PN concentrations during the cold start phase of test cycles and prolong the time required for tyres to warm up. In addition, the particles contained a high mass fraction of Zn, which can serve as a tracer of tyre wear particles in non-exhaust particle tests of vehicles.

ABSTRACT: The purpose of the present study was to evaluate the probiotic properties of Bacillus subtilis KC1 as a feed additive in the poultry feed. Effects of the Bacillus subtilis supplementation on growth performance, heat-stress tolerance, resistance to Mycoplasma gallisepticum (MG) and Salmonella Pullorum challenge of broilers were determined. The protective effects of the Bacillus subtilis on liver function and immune response of broilers challenged with Aflatoxin B1 (AFB1) were also scrutinized. The results showed that the Bacillus subtilis supplementation could improve growth performance, increased body weight, relative weight of the immune organ and dressing percentage, and decrease feed conversion ratio. In addition, the Bacillus subtilis supplementation alleviated adverse effects caused by heat stress, MG, and Salmonella Pullorum challenge. Furthermore, the Bacillus subtilis supplementation resulted in improved liver function and enhanced immune response of broilers challenged with AFB1. In conclusion, these results suggested a tremendous potential of Bacillus subtilis KC1 as a feed additive in the poultry feed.

Ischemic stroke is characterized by insufficient blood supply to brain tissue and is associated with increased morbidity and mortality in adults worldwide. Growth arrest-specific protein 6 (GAS6) is a vitamin K-dependent protein and is widely expressed in the central nervous system. The biological functions of GAS6 are mediated by the interaction with TAM (Tyro3, Axl and Mertk) receptors, including cell survival and proliferation, immune regulation and apoptosis. Omentin-1, also known as intelectin-1 (ITLN-1), is a novel adipocytokine that is involved in a variety of biological events, such as insulin resistance, endothelial dysfunction, programmed cell death and metabolic disorders. Our previous study has found that omentin-1 act as a novel regulator of vascular and anti-apoptotic response in cerebral ischemia. However, the specific molecular mechanism of omentin-1’s protective effect on cerebral ischemia-reperfusion injury (IRI) is still unclear. First, the toxicity of recombinant human omentin-1 (rh-omentin) was assessed and a safe concentration was chosen for the next experiments. Then, rh-omentin exerted neuroprotection against hypoxia/reoxygenation (H/R) injury in N2a cells, indicated by increased cell viability, decreased LDH, ROS generation, and cell apoptotic rate. Furthermore, the similar protective effect was observed in omentin-1 overexpression cells constructed by lentivirus transfection. Rh-omentin could also inhibit H/R-induced apoptotic molecules, oxidative stress molecules, and GAS6/Axl signaling molecules which as evidence by increased omentin-1, GAS6, Axl, p-Axl, NQO1, HO-1, Nrf2, Bcl2 and decreased Bax expressions. However, GAS6 siRNA could reverse rh-omentin-induced neuroprotection and the levels of these molecules mentioned above. In conclusion, these findings suggest that omentin-1 treatment exerts neuroprotection against H/R injury partly via activating GAS6/Axl signaling at least. Therefore, these finding may favor omentin-1 a potential neuroprotective drug candidate to alleviate ischemia-reperfusion injury in clinic.

In order to explore the influence of soil force on rotary soil-engaging components during their operation, a kinetic parameter measurement system of rotary soil-engaging components was developed via the sensor strain measurement technique. By taking a single-sided compacting ridge device as an example, the kinetic experiment was carried out on the operation parameters of the compacting device and obtained the variation law of the force of the soil on the pinnae. ADAMS software was used to simulate the operation of the compacting device under different experimental factors (soil moisture content, forward speed of the ridge device, and the rotation speed of the compacting device), and the test data were obtained; the experiment was carried out with the forward speed of the soil tanker and the rotation speed of the compacting device as the experimental factors, and the average of the force of soil on the pinnae and the firmness value of the ridge were the experimental indicators. The results showed that under a moisture content of 27%, the forward speed of the device was 0.8 km∙h−1, the maximum firmness of the ridge was 1233.21 kPa, the minimum firmness of the ridge was 953.85 kPa, and the coefficient of variation of the stability of the firmness value of the ridge was 8.04; the force of the pinnae on the soil increased with an increase in the forward speed of the soil tanker, and the variation range of the force was 2838.1–5695.2 N. It was verified that the design of this operation parameter measurement system for rotary soil-engaging components meets the practical requirements and also provides an important reference for the measurement of the relevant parameters of similar rotary soil-engaging components.

Abstract Background To reveal roles of reactive oxygen species (ROS) status in chemotherapy resistance and to develop a ROS scoring system for prognosis prediction in ovarian cancer. Methods We tested the sensitizing effects of ROS elevating drugs to cisplatin (cDDP) in ovarian cancer both in vitro and in vivo. A ROS scoring system was developed using The Cancer Genome Atlas (TCGA) database of ovarian cancer. The associations between ROS scores and overall survival (OS) were analyzed in TCGA, Tothill dataset, and our in-house dataset (TJ dataset). Results ROS-inducing drugs increased cisplatin-induced ovarian cancer cell injury in vitro and in vivo. ROS scoring system was established using 25 ROS-related genes. Patients were divided into low (scores 0–12) and high (scores 13–25) score groups. Improved patient survival was associated with higher scores (TCGA dataset hazard ratio (HR) = 0.43, P

Background: Previous studies have identified hundreds of constantly changing metabolic genes in cervical cancer, however, their prognostic effect remains to be explored. Methods: In this paper, Cox univariate regression and Lasso regression models were used to identify metabolic genes associated with squamous cervical cancer prognosis, and developed a prognostic risk score. Next, on the basis of the median risk score, cervical squamous cancer patients were divided into two groups: high- and low-risk patients. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were used to evaluate the predictive efficacy of the metabolic gene prognostic risk model. In addition, we analysed the correlation between drug sensitivity, immune cell infiltration, and Gene set variation analysis (GSVA) and the metabolic gene prognostic risk model. Results: The results showed that the prognosis of patients in the high-risk group was worse. The metabolic gene prognostic model was correlated with immune cell infiltration. It is also correlated with sensitivity to common chemotherapeutic drugs. In addition, gene set enrichment analysis results revealed several significantly enriched pathways, which may help to explain the underlying mechanisms of cervical carcinogenesis. Conclusions: The proposed prediction model can be potentially used for prognosis prediction of cervical cancer.

Small nucleolar RNAs (snoRNAs) are a class of highly conserved, stable non-coding RNAs involved in both post-transcriptional modification of RNA and in ribosome biogenesis. Recent research shows that the dysfunction of snoRNAs plays a pivotal role in hepatocellular carcinoma (HCC) and related etiologies, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and non-alcoholic fatty liver disease (NAFLD). Growing evidence suggests that snoRNAs act as oncogenes or tumor suppressors in hepatocellular carcinoma (HCC) through multiple mechanisms. Furthermore, snoRNAs are characterized by their stability in body fluids and their clinical relevance and represent promising tools as diagnostic and prognostic biomarkers. SnoRNAs represent an emerging area of cancer research. In this review, we summarize the classification, biogenesis, activity, and functions of snoRNAs, as well as highlight the mechanism and roles of snoRNAs in HCC and related diseases. Our findings will aid in the understanding of complex processes of tumor occurrence and development, as well as suggest potential diagnostic markers and treatment targets. Furthermore, we discuss several limitations and suggest future research and application directions.

Following publication of the original article [1], the authors reported an error in Fig. 1f.

The Harris Hawks optimization (HHO) is a population-based metaheuristic algorithm; however, it has low diversity and premature convergence in certain problems. This paper proposes an adaptive relative reflection HHO (ARHHO), which increases the diversity of standard HHO, alleviates the problem of stagnation of local optimal solutions, and improves the search accuracy of the algorithm. The main features of the algorithm define nonlinear escape energy and adaptive weights and combine adaptive relative reflection with the HHO algorithm. Furthermore, we prove the computational complexity of the ARHHO algorithm. Finally, the performance of our algorithm is evaluated by comparison with other well-known metaheuristic algorithms on 23 benchmark problems. Experimental results show that our algorithms performs better than the compared algorithms on most of the benchmark functions.

Abstract Background Atrial fibrillation (AF) is one of the common arrhythmia in clinics. Its incidence is high among the elderly. This study aimed to identify a possible connection between ion channel‐related gene polymorphisms and the risk of AF. Methods A total of 381 patients with coronary heart disease were recruited. Based on complete cardiac examination, the patients were divided into two subgroups: 185 patients with AF and 196 patients without AF. An association analysis was performed using 13 genotyped SNPs. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Results In our research, we found that KCNE2 rs8134775 was associated with a decreased AF risk in the allele model (OR = 0.70; 95% CI: 0.50–0.97; p = 0.034). Genetic model analysis shown that the minor allele T of GJA5 rs35594137 was associated with a decreased AF risk under the recessive model (OR = 0.40; 95% CI: 0.19–0.86; p = 0.018) and the minor allele G of KCNJ2 rs8079702 was associated with an increased AF risk in the recessive model (OR = 2.31; 95% CI: 1.20–4.42; p = 0.012). Conclusions Our results suggest that KCNE2, KCNJ2, and GJA5 influence the development of AF.

[This corrects the article DOI: 10.1371/journal.pone.0161779.].

The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.

Human metastasis-associated gene 1 (MTA1) is highly associated with the metastasis of prostate cancer; however, the molecular functions of MTA1 that facilitate metastasis remain unclear. In this study, we demonstrate that the silencing of MTA1 by siRNA treatment results in the upregulation of E-cadherin expression by the phosphorylation of AKT (p-AKT) and decreases the invasiveness of prostate cancer cells. We show that MTA1 is expressed in over 90% of prostate cancer tissues, especially metastatic prostate cancer tissue, comparing to non-expression in normal prostate tissue. RT-PCR analysis and Western blot assay showed that MTA1 expression is significantly higher in highly metastatic prostate cancer PC-3M-1E8 cells (1E8) than in poorly metastatic prostate cancer PC-3M-2B4 cells (2B4). Silencing MTA1 expression by siRNA treatment in 1E8 cells increased the cellular malignant characters, including the cellular adhesive ability, decreased the cellular invasive ability and changed the polarity of cellular cytoskeleton. 1E8 cells over-expressing MTA1 had a reduced expression of E-cadherin, while 1E8 cells treated with MTA1 siRNA had a higher expression of E-cadherin. The expression of phosphorylated AKT (p-AKT) or the inhibition of p-AKT by wortmannin treatment (100 nM) significantly altered the function of MTA1 in the regulation of E-cadherin expression. Alterations in E-cadherin expression changed the role of p-AKT in cellular malignant characters. All of these results demonstrate that MTA1 plays an important role in controlling the malignant transformation of prostate cancer cells through the p-AKT/E-cadherin pathway. This study also provides a new mechanistic role for MTA1 in the regulation of prostate cancer metastasis.

We consider a smooth penalty algorithm to solve nonconvex optimization problem based on a family of smooth functions that approximate the usual exact penalty function. At each iteration in the algorithm we only need to find a stationary point of the smooth penalty function, so the difficulty of computing the global solution can be avoided. Under a generalized Mangasarian-Fromovitz constraint qualification condition (GMFCQ) that is weaker and more comprehensive than the traditional MFCQ, we prove that the sequence generated by this algorithm will enter the feasible solution set of the primal problem after finite times of iteration, and if the sequence of iteration points has an accumulation point, then it must be a Karush-Kuhn-Tucker (KKT) point. Furthermore, we obtain better convergence for convex optimization problem.

We present a smooth augmented Lagrangian algorithm for semiinfinite programming (SIP). For this algorithm, we establish a perturbation theorem under mild conditions. As a corollary of the perturbation theorem, we obtain the global convergence result, that is, any accumulation point of the sequence generated by the algorithm is the solution of SIP. We get this global convergence result without any boundedness condition or coercive condition. Another corollary of the perturbation theorem shows that the perturbation function at zero point is lower semi-continuous if and only if the algorithm forces the sequence of objective function convergence to the optimal value of SIP. Finally, numerical results are given.