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Abstract In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1Apo), fluconazole-bound state (Cdr1Flu), and milbemycin oxime-inhibited state (Cdr1Mil). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.

Abstract Background To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. Methods 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. Results After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P

Abstract Background Second victims, defined as healthcare providers enduring emotional and psychological distress after patient safety incidents (PSIs). The potential for positive transformation through these experiences is underexplored but is essential for fostering a culture of error learning and enhancing patient care. Objective To explore the level and determinants of post-traumatic growth (PTG), applying the stress process model. Methods The study was conducted at a tertiary general hospital in Chongqing, China. A descriptive, cross-sectional study design was used. A total of 474 s victims were included. An online survey was conducted in November 2021 to assess various factors related to the second victim experience. These factors included PSIs (considered as stressors), coping styles, perceived threats, and social support (acting as mediators), as well as the outcomes of second victim syndrome (SVS) and PTG. Statistical description, correlation analysis, and structural equation modeling were utilized for the data analysis. A p-value ≤ 0.05 was considered to indicate statistical significance. Results The participants reported moderate distress (SVS = 2.84 ± 0.85) and PTG (2.72 ± 0.85). The total effects on SVS of perceived threat, negative coping, social support, positive coping, and PSIs were 0.387, 0.359, -0.355, -0.220, and 0.115, respectively, accounting for 47% of the variation in SVS. The total effects of social support, positive coping, and PSIs on PTG were 0.355, 0.203, and − 0.053, respectively, accounting for 19% of the variation in PTG. Conclusions The study provides novel insights into the complex interplay between perceived threats, coping styles, and social support in facilitating PTG among second victims. By bolstering social support and promoting adaptive coping strategies, the adverse effects of PSIs can be mitigated, transforming them into opportunities for resilience and growth, and offering a fresh perspective on managing PSIs in healthcare settings.

Abstract Background The built environment, as a critical factor influencing residents' cardiovascular health, has a significant potential impact on the incidence of cardiovascular diseases (CVDs). Methods Taking Xixiangtang District in Nanning City, Guangxi Zhuang Autonomous Region of China as a case study, we utilized the geographic location information of CVD patients, detailed road network data, and urban points of interest (POI) data. Kernel density estimation (KDE) and spatial autocorrelation analysis were specifically employed to identify the spatial distribution patterns, spatial clustering, and spatial correlations of built environment elements and diseases. The GeoDetector method (GDM) was used to assess the impact of environmental factors on diseases, and geographically weighted regression (GWR) analysis was adopted to reveal the spatial heterogeneity effect of environmental factors on CVD risk. Results The results indicate that the built environment elements and CVDs samples exhibit significant clustering characteristics in their spatial distribution, with a positive correlation between the distribution density of environmental elements and the incidence of CVDs (Moran’s I > 0, p

Abstract Background Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient. Case presentation Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as “pathogenic”. c.1415T > G (p.V472G) located in extra-cellular region, was classified as “likely pathogenic”. Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband’s prenatal phenotype. Conclusion The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.

Abstract Background The current understanding to the mechanism of rumen development is limited. We hypothesized that the Hippo signaling pathway controlled the proliferation of rumen epithelium (RE) during postnatal development. In the present study, we firstly tested the changes of the Hippo signaling pathway in the RE during an early growing period from d5 to d25, and then we expanded the time range to the whole preweaning period (d10-38) and one week post weaning (d45). An in vitro experiment was also carried out to verify the function of Hippo signaling pathway during RE cell proliferation. Results In the RE of lambs from d5 to d25, the expression of baculoviral IAP repeat containing (BIRC3/5) was increased, while the expressions of large tumor suppressor kinase 2 (LATS2), TEA domain transcription factor 3 (TEAD3), axin 1 (AXIN1), and MYC proto-oncogene (MYC) were decreased with rumen growth. From d10 to d38, the RE expressions of BIRC3/5 were increased, while the expressions of LATS2 and MYC were decreased, which were similar with the changes in RE from d5 to d25. From d38 to d45, different changes were observed, with the expressions of LATS1/2, MOB kinase activator 1B (MOB1B), and TEAD1 increased, while the expressions of MST1 and BIRC5 decreased. Correlation analysis showed that during the preweaning period, the RE expressions of BIRC3/5 were positively correlated with rumen development variables, while LAST2 was negatively correlated with rumen development variables. The in vitro experiment validated the changes of LATS2 and BIRC3/5 in the proliferating RE cells, which supported their roles in RE proliferation during preweaning period. Conclusions Our results suggest that the LATS2-YAP1-BIRC3/5 axis participates in the RE cell proliferation and promotes rumen growth during the preweaning period.

Abstract Background Continuous renal replacement therapy (CRRT) is a commonly utilized form of renal replacement therapy (RRT) in the intensive care unit (ICU). A specialized CRRT team (SCT, composed of physicians and nurses) engage playing pivotal roles in administering CRRT, but there is paucity of evidence-based research on joint training and management strategies. This study armed to evaluate the knowledge, attitude, and practice (KAP) of ICU staff toward CRRT, and to identify education pathways, needs, and the current status of CRRT implementation. Methods This study was performed from February 6 to March 20, 2023. A self-made structured questionnaire was used for data collection. Descriptive statistics, T-tests, Analysis of variance (ANOVA), multiple linear regression, and Pearson correlation coefficient tests (α = 0.05) were employed. Results A total of 405 ICU staff from 66 hospitals in Central and South China participated in this study, yielding 395 valid questionnaires. The mean knowledge score was 51.46 ± 5.96 (61.8% scored highly). The mean attitude score was 58.71 ± 2.19 (73.9% scored highly). The mean practice score was 18.15 ± 0.98 (85.1% scored highly). Multiple linear regression analysis indicated that gender, age, years of CRRT practice, ICU category, and CRRT specialist panel membership independently affected the knowledge score; Educational level, years of CRRT practice, and CRRT specialist panel membership independently affected the attitude score; Education level and teaching hospital employment independently affected the practice score. The most effective method for ICU staff to undergo training and daily work experience is within the department. Conclusion ICU staff exhibit good knowledge, a positive attitude and appropriately practiced CRRT. Extended CRRT practice time in CRRT, further training in a general ICU or teaching hospital, joining a CRRT specialist panel, and upgraded education can improve CRRT professional level. Considering the convenience of training programs will enhance ICU staff participation. Training should focus on basic CRRT principles, liquid management, and alarm handling.

Abstract Background Exportin 1 (XPO1) is a nuclear export protein that facilitates the transportation of various substances. XPO1 promotes tumor development as a poor prognostic factor in a variety of tumors and is a therapeutic target for screening inhibitors. However, the role of XPO1 in oral squamous cell carcinoma (OSCC) has yet to be determined. Methods The expression patterns of XPO1 mRNA in OSCC were investigated using bioinformatics tools, and the expression levels of XPO1 protein in OSCC specimens were confirmed by immunohistochemical assays. Survival analysis was conducted to evaluate the impact of XPO1 on prognosis. GO and KEGG enrichment analyses were utilized to uncover the signaling pathways mediated by XPO1. Additionally, we examined the association between XPO1 and AKT/MAPK/TGFBR1 and immune infiltration. Results XPO1 mRNA and protein expression levels were significantly enhanced in OSCC and associated with OSCC severity. Enhanced XPO1 expression was indicative of poor survival. Functional analysis showed that XPO1 mediated pathways associated with cell cycle and DNA replication and reduced immune infiltration in OSCC. Additionally, XPO1 mRNA and protein expression levels had significant positive relationships with AKT/MAPK/TGFBR1. Conclusions XPO1, as a marker of poor prognosis in OSCC, can promote OSCC through AKT/MAPK/TGFBR1.

Nanozyme cascade have garnered substantial interest in recent years due to their distinctive properties. However, the conventional stepwise cascade reaction undergoes tedious two-step operation process owing to the incompatibility of reaction conditions. Moreover, most of reported nanozymes exhibit favorable catalytic performance only in acidic medium, which greatly restricts their usage especially in biochemical analysis. To address above challenges, we developed gold nanoparticles/calcium hexacyanoferrate (Ⅲ)/nitrogen-doped graphitic alkyne (AuNPs/CaHF NPs/N-GDY) nanozyme with superior cascade catalytic activity at neutral pH comparable to that of acidic. Specifically, AuNPs/CaHF NPs/N-GDY simultaneously possessed glucose oxidase-like (GOx) and peroxidase-like (HRP) activities, which could induce one-step cascade reaction in the presence of glucose, resulting in 5-fold enhancement in catalytic efficiency compared with conventional two-step cascade reaction. Besides, tripedal DNA walker was equipped with sufficient walking legs to walk on directional and highly controllable stepped track, reducing the possibility of derailment and boosting walking efficiency. As a proof of concept, a novel electrochemical biosensor was constructed for miRNA-21 sensitive detection at physiological pH, and successfully applied in human serum samples as well as practical intracellular analysis, offering great potential in biomedical research and clinical diagnosis.

Resources and the environment are essential for socioeconomic development. A scientific and reasonable evaluation and forewarning of the resource and environmental carrying capacity (RECC) is of great significance for regional sustainable development. Although great progress has made in existing research on RECC, there is still no consensus on the definition, evaluation and forewarning method for RECC. Therefore, this study introduced the novel concepts of pressure, support and adjustment, proposed a theoretical framework of RECC reflecting the interaction between the above three, constructed a new evaluation index system of RECC, evaluated RECC based on the ratio method, identified important influencing factors using obstacle model, and put forward the hierarchical forewarning method of RECC with the threshold of 1. Finally, a case demonstration in regard to Yichang city, with a prominent ecological and economic status as the location of China’s Three Gorges Project, was conducted. The results revealed that: 1) The average pressure, support, and adjustment exhibited overall upward trends. The pressure and adjustment increased from west to east, while the support of central districts was relatively lower. 2) The RECC of Yichang city and counties improved from 2016 to 2021, increasing from west to east, and the differences in the RECC of various counties were remarkable but gradually shrank. 3) The RECC of Yichang city remained at the Non-Alert Level. The number of counties with RECC values at Alert Level II decreased from two to zero, and the number of counties at the Non-Alert Level increased from eight to ten. Xiaoting and Zhijiang, with more RECC values at Alert Level II, should receive more attention. This study is expected to enrich the methodology of RECC evaluation and forewarning, and provide possible implications for economic development and environmental protection planning in Yichang and other cities of the same type.

Abstract Myeloperoxidase (MPO) plays critical role in the pathology of cerebral ischemia–reperfusion (I/R) injury via producing hypochlorous acid (HOCl) and inducing oxidative modification of proteins. High-mobility group box 1 (HMGB1) oxidation, particularly disulfide HMGB1 formation, facilitates the secretion and release of HMGB1 and activates neuroinflammation, aggravating cerebral I/R injury. However, the cellular sources of MPO/HOCl in ischemic brain injury are unclear yet. Whether HOCl could promote HMGB1 secretion and release remains unknown. In the present study, we investigated the roles of microglia-derived MPO/HOCl in mediating HMGB1 translocation and secretion, and aggravating the brain damage and blood-brain barrier (BBB) disruption in cerebral I/R injury. In vitro, under the co-culture conditions with microglia BV cells but not the single culture conditions, oxygen–glucose deprivation/reoxygenation (OGD/R) significantly increased MPO/HOCl expression in PC12 cells. After the cells were exposed to OGD/R, MPO-containing exosomes derived from BV2 cells were released and transferred to PC12 cells, increasing MPO/HOCl in the PC12 cells. The HOCl promoted disulfide HMGB1 translocation and secretion and aggravated OGD/R-induced apoptosis. In vivo, SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus different periods of reperfusion. Increased MPO/HOCl production was observed at the reperfusion stage, accomplished with enlarged infarct volume, aggravated BBB disruption and neurological dysfunctions. Treatment of MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH) and HOCl scavenger taurine reversed those changes. HOCl was colocalized with cytoplasm transferred HMGB1, which was blocked by taurine in rat I/R-injured brain. We finally performed a clinical investigation and found that plasma HOCl concentration was positively correlated with infarct volume and neurological deficit scores in ischemic stroke patients. Taken together, we conclude that ischemia/hypoxia could activate microglia to release MPO-containing exosomes that transfer MPO to adjacent cells for HOCl production; Subsequently, the production of HOCl could mediate the translocation and secretion of disulfide HMGB1 that aggravates cerebral I/R injury. Furthermore, plasma HOCl level could be a novel biomarker for indexing brain damage in ischemic stroke patients.

Abstract Pleckstrin homology domain-containing family M member 2 (PLEKHM2) is an essential adaptor for lysosomal trafficking and its homozygous truncation have been reported to cause early onset dilated cardiomyopathy (DCM). However, the molecular mechanism of PLEKHM2 deficiency in DCM pathogenesis and progression is poorly understood. Here, we generated an in vitro model of PLEKHM2 knockout (KO) induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the potential pathogenic mechanism of PLEKHM2-deficient cardiomyopathy. PLEKHM2-KO hiPSC-CMs developed disease phenotypes with reduced contractility and impaired calcium handling. Subsequent RNA sequencing (RNA-seq) analysis revealed altered expression of genes involved in mitochondrial function, autophagy and apoptosis in PLEKHM2-KO hiPSC-CMs. Further molecular experiments confirmed PLEKHM2 deficiency impaired autophagy and resulted in accumulation of damaged mitochondria, which triggered increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (Δψm). Importantly, the elevated ROS levels caused oxidative stress-induced damage to nearby healthy mitochondria, resulting in extensive Δψm destabilization, and ultimately leading to impaired mitochondrial function and myocardial contractility. Moreover, ROS inhibition attenuated oxidative stress-induced mitochondrial damage, thereby partially rescued PLEKHM2 deficiency-induced disease phenotypes. Remarkably, PLEKHM2-WT overexpression restored autophagic flux and rescued mitochondrial function and myocardial contractility in PLEKHM2-KO hiPSC-CMs. Taken together, these results suggested that impaired mitochondrial clearance and increased ROS levels play important roles in PLEKHM2-deficient cardiomyopathy, and PLEKHM2-WT overexpression can improve mitochondrial function and rescue PLEKHM2-deficient cardiomyopathy.

Abstract Background Immunotherapy is a practical therapeutic approach in breast cancer (BRCA), and the role of FLI1 in immune regulation has gradually been unveiled. However, the specific role of FLI1 in BRCA was conflicted; thus, additional convincing evidence is needed. Methods We explored the upstream regulation of FLI1 expression via summary data-based Mendelian randomization (SMR) analysis and ncRNA network construction centering on FLI1 using BRCA genome-wide association study (GWAS) summary data with expression quantitative trait loci (eQTLs) and DNA methylation quantitative trait loci (mQTLs) from the blood and a series of in silico analyses, respectively. We illuminated the downstream function of FLI1 in immune regulation by integrating a series of analyses of single-cell RNA sequence data (scRNA-seq). Results We verified a causal pathway from FLI1 methylation to FLI1 gene expression to BRCA onset and demonstrated that FLI1 was downregulated in BRCA. FLI1, a transcription factor, served as myeloid and T cells’ communication regulator by targeting immune-related ligands and receptor transcription in BRCA tissues. We constructed a ceRNA network centering on FLI1 that consisted of three LncRNAs (CKMT2-AS1, PSMA3-AS1, and DIO3OS) and a miRNA (hsa-miR-324-5p), and the expression of FLI1 was positively related to a series of immune-related markers, including immune cell infiltration, biomarkers of immune cells, and immune checkpoints. Conclusion Low-methylation-induced or ncRNA-mediated downregulation of FLI1 is associated with poor prognosis, and FLI1 might regulate the tumor immune microenvironment via a cell-type-specific target genes manner in BRCA.

The field of artificial intelligence and neural computing has been rapidly expanding due to the implementation of resistive random-access memory (RRAM) based artificial synaptic. However, the low flexibility of conventional RRAM materials hinders their ability to mimic synaptic behavior accurately. To overcome such limitation, organic-2D composites with high mechanical properties are proposed as the active layer of RRAM. Moreover, we enhance the reliability of the device by ZrO2 insertion layer, resulting in stable synaptic performance. The Ag/PVA:h-BN/ZrO2/ITO devices show stable bipolar resistive switching behavior with an ON/OFF ratio of over 5 × 102, a ∼2 400 cycles endurance and a long retention time (>6 × 103s), which are essential for the development of high-performance RRAMs. We also study the possible synaptic mechanism and dynamic plasticity of the memory device, observing the transition from short-term potentiation (STP) to long-term potentiation (LTP) under the effect of continuous voltage pulses. Moreover, the device exhibits both long-term depression (LTD) and paired-pulse facilitation (PPF) properties, which have significant implications for the design of organic-2D composite material RRAMs that aim to mimic biological synapses, representing promising avenues for the development of advanced neuromorphic computing systems.

Abstract Background Chronic nonhealing wounds remain a considerable challenge in clinical treatment due to excessive inflammation and impeded reepithelialization and angiogenesis. Therefore, the discovery of novel prohealing agents for chronic skin wounds are urgent and important. Amphibian-derived prohealing peptides, especially immunomodulatory peptides, provide a promising strategy for the treatment of chronic skin trauma. However, the mechanism of immunomodulatory peptides accelerating the skin wound healing remains poorly understood. Methods The prohealing ability of peptide Andersonin-W1 (AW1) was assessed by cell scratch, cell proliferation, transwell, and tube formation. Next, full-thickness, deep second-degree burns and diabetic full-thickness skin wounds in mice were performed to detect the therapeutic effects of AW1. Moreover, the tissue regeneration and expression of inflammatory cytokines were evaluated by hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining. Molecular docking, colocalization, and western blotting were used to explore the mechanism of AW1 in promoting wound healing. Results We provide solid evidence to display excellent prohealing effects of AW1, identified as a short antimicrobial peptide in our previous report. At relative low concentration of nM, AW1 promoted the proliferation, migration, and scratch repair of keratinocyte, macrophage proliferation, and tube formation of HUVEC. AW1 also facilitated reepithelialization, granulation regeneration, and angiogenesis, thus significantly boosting the healing of full-thickness, deep second-degree burns and diabetic skin wounds in mice. Mechanistically, in macrophages, AW1 directly bound to Toll-like receptor 4 (TLR4) in the extracellular region and regulated the downstream nuclear factor‐κB (NF-κB) signaling pathway to facilitate the inflammatory factor secretion and suppress excessive inflammation induced by lipopolysaccharide (LPS). Moreover, AW1 regulated macrophage polarization to promote the transition from the inflammatory to the proliferative phase and then facilitated reepithelialization, granulation regeneration, and angiogenesis, thus exhibiting excellent therapeutic effects on diabetic skin wounds. Conclusions AW1 modulates inflammation and the wound healing process by the TLR4/NF-κB molecular axis, thus facilitating reepithelialization, granulation regeneration, and angiogenesis. These findings not only provided a promising multifunctional prohealing drug candidate for chronic nonhealing skin wounds but also highlighted the unique roles of “small” peptides in the elucidation of “big” human disease mechanisms. Graphical Abstract

Abstract During the life-cycle service of the constructed large span bridges, they face various threats every day due to the sophisticated operational environments. To ensure the structural safety, it is necessary to detect potential anomaly. Based on different inspection, monitoring and analysis technique, huge amounts of data that direct or indirect reflect structural characteristics can be obtained, and hence the anomaly detection methods developed. In order to provide a summary of relevant information needed by researchers to realize what is concerned about and how current practices deal with these issues, then further promote the application, this paper reviews understanding of anomaly detection in large span bridges. It starts with an analysis of concerned parameters, including dynamic and static structural parameters of a bridge. The various data sources are then commented. Next, existing anomaly detection methods are reviewed and classified. Finally, this paper concisely provides recent progress and discusses future research trends based on the identified knowledge gaps. We hope that this review will help development in this field.

Abstract Background Some studies have assessed the predictive role of the atherogenic index of plasma (AIP) for macrovascular diseases. This prospective investigation aimed to elucidate whether AIP is associated with diabetic kidney disease (DKD) and diabetic retinopathy (DR) incidence. Methods The data were extracted from 4831 participants, of whom 2943 and 3360 participants with type 2 diabetes (T2D) were included in the DKD and DR follow-up analyses, respectively. Cox regression models were performed to test the relationships of AIP value at baseline with the risk of incident DKD and DR. Group-based trajectory modelling was utilized to discern AIP trajectories during the follow-up period. Subsequently, logistic regressions were applied to ascertain the influence of AIP trajectories on the incidence of DKD and DR. Results During the follow-up period, 709 (24.1%) and 193 (5.7%) participants developed DKD and DR, respectively. The median (interquartile range) follow-up time was 24.2 (26.3) months for DKD and 25.7 (27.0) months for DR. According to the multivariate Cox regression models, baseline AIP was positively and linearly related to the occurrence of DKD, with a hazard ratio of 1.75 (95% confidence interval [CI] 1.36–2.26). Three distinct trajectories of AIP were identified throughout the follow-up time: Low (31.4%), Median (50.2%), and High (18.3%). Compared to participants with the Low AIP trajectory, those with High and Median AIP trajectories presented 117% (95% CI: 1.62–2.91) and 84% (95% CI 1.46–2.32) greater odds of developing DKD, respectively. However, neither baseline levels nor trajectories of AIP were shown to be related to DR after adjusting for confounding factors. Conclusions Baseline levels and trajectories of AIP were independently related to elevated DKD risk, indicating that AIP could be used as a predictor for identifying T2D participants at higher risk of DKD. No association between AIP and DR was detected.

BackgroundInborn errors of metabolism (IEMs) are rare diseases caused by inherited defects in various biochemical pathways that strongly correlate with early neonatal mortality and stunting. Currently, no studies have reported on the incidence of IEMs of multi-ethnic groups in Huaihua, China.MethodsA total of 206,977 neonates with self-reported ethnicity who underwent IEM screening at Huaihua from 2015 to 2021 were selected for observation. Among them, 69 suspected IEM-positive neonates were referred for urine gas chromatography-mass spectrometry analysis, biochemical detection, next-generation sequencing, and Sanger sequencing.ResultsSixty-nine newborns were diagnosed with IEMs, with an overall incidence of 1:3,000. The two most common disorders were 2-methylbutyryl glycinuria (1:7,137) and phenylalanine hydroxylase deficiency (1:22,997). Moreover, the incidence of IEMs in the minority ethnic group (Miao, Dong, Tujia and Yao) (1:1,852) was markedly higher than in the Han ethnic group (1:4,741). Some ethnic features variants were identified; NM_001609.4:c.1165A>G in the ACADSB gene for Miao and Dong ethnic groups, NM_014251.2:c.852_855del in the SLC25A13 gene for Miao ethnic groups.ConclusionThis study revealed the IEM incidence within the minority ethnic groups is markedly higher than among the Han nationality and the gene variant spectrum is dramatically different in Huaihua, China. Hence, It serves as a theoretical reference for the screening and diagnosing of neonatal IEMs of multi-ethnic groups in the Huaihua area, and across China.

Background The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well‐tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin‐induced heart failure. Methods and Results Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin‐induced cardiotoxicity. Conclusions Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

ABSTRACTZur (zinc uptake regulator) is a significant member of the Fur (ferric uptake regulator) superfamily, which is widely distributed in bacteria. Zur plays crucial roles in zinc homeostasis and influences cell development and environmental adaptation in various species. Yersinia pseudotuberculosis is a Gram-negative enteric that pathogen usually serves as a model organism in pathogenicity studies. The regulatory effects of Zur on the zinc transporter ZnuABC and the protein secretion system T6SS have been documented in Y. pseudotuberculosis. In this study, a comparative transcriptomics analysis between a ∆zur mutant and the wild-type (WT) strain of Y. pseudotuberculosis was conducted using RNA-seq. This analysis revealed global regulation by Zur across multiple functional categories, including membrane transport, cell motility, and molecular and energy metabolism. Additionally, Zur mediates the homeostasis not only of zinc but also ferric and magnesium in vivo. There was a notable decrease in 35 flagellar biosynthesis and assembly-related genes, leading to reduced swimming motility in the ∆zur mutant strain. Furthermore, Zur upregulated multiple simple sugar and oligopeptide transport system genes by directly binding to their promoters. The absence of Zur inhibited biofilm formation as well as reduced resistance to chloramphenicol and acidic stress. This study illustrates the comprehensive regulatory functions of Zur, emphasizing its importance in stress resistance and pathogenicity in Y. pseudotuberculosis.IMPORTANCEBacteria encounter diverse stresses in the environment and possess essential regulators to modulate the expression of genes in responding to the stresses for better fitness and survival. Zur (zinc uptake regulator) plays a vital role in zinc homeostasis. Studies of Zur from multiple species reviewed that it influences cell development, stress resistance, and virulence of bacteria. Y. pseudotuberculosis is an enteric pathogen that serves a model organism in the study of pathogenicity, virulence factors, and mechanism of environmental adaptation. In this study, transcriptomics analysis of Zur’s regulons was conducted in Y. pseudotuberculosis. The functions of Zur as a global regulator in metal homeostasis, motility, nutrient acquisition, glycan metabolism, and nucleotide metabolism, in turn, increasing the biofilm formation, stress resistance, and virulence were reviewed. The importance of Zur in environmental adaptation and pathogenicity of Y. pseudotuberculosis was emphasized.

Summary: Pancreatic cancer (PC) is a lethal disease and associated with metabolism dysregulation. Nogo-B is related to multiple metabolic related diseases and types of cancers. However, the role of Nogo-B in PC remains unknown. In vitro, we showed that cell viability and migration was largely reduced in Nogo-B knockout or knockdown cells, while enhanced by Nogo-B overexpression. Consistently, orthotopic tumor and metastasis was reduced in global Nogo knockout mice. Furthermore, we indicated that glucose enhanced cell proliferation was associated to the elevation expression of Nogo-B and nuclear factor κB (NF-κB). While, NF-κB, glucose transporter type 1 (GLUT1) and sterol regulatory element-binding protein 1 (SREBP1) expression was reduced in Nogo-B deficiency cells. In addition, we showed that GLUT1 and SREBP1 was downstream target of NF-κB. Therefore, we demonstrated that Nogo deficiency inhibited PC progression is regulated by the NF-κB/GLUT1 and SREBP1 pathways, and suggested that Nogo-B may be a target for PC therapy.

Cyanobacteria, which have a photoautotrophic lifestyle, are threatened by ultraviolet solar rays and the reactive oxygen species generated during photosynthesis. They can adapt to environmental conditions primarily because of their DNA damage response and repair mechanisms, notably an efficient homologous recombination repair system. However, research on double-strand break (DSB) repair pathways, including the Holliday junction (HJ) resolution process, in Synechocystis sp. PCC6803 is limited. Here, we report that SynRuvC from cyanobacteria Synechocystis sp. PCC6803 has classical HJ resolution activity. We investigated the structural specificity, sequence preference, and biochemical properties of SynRuvC. SynRuvC strongly preferred Mn2+ as a cofactor, and its cleavage site predominantly resides within the 5′-TG↓(G/A)-3′ sequence. Interestingly, novel flap endonuclease and replication fork intermediate cleavage activities of SynRuvC were also determined, which distinguish it from other reported RuvCs. To explore the effect of SynRuvC on cell viability, we constructed a knockdown mutant and an overexpression strain of Synechocystis sp. PCC6803 (synruvCKD and synruvCOE) and assessed their survival under a variety of conditions. Knockdown of synruvC increased the sensitivity of cells to MMS, HU, and H2O2. The findings suggest that a novel RuvC family HJ resolvase SynRuvC is important in a variety of DNA repair processes and stress resistance in Synechocystis sp. PCC6803.

Abstract A mathematical morphological filter-based de-noising method is developed in this study for bridge cable force monitoring data. Structure elements, one of the most important parameters in the mathematical morphology, dominate de-noising effects. The de-noising effects subject to single structure element and multi-structure element filters are discussed based on the simulation signals. The results indicate that the de-noising effects by using the spherical structure element are better than using the straight line or rhombic structure element. Moreover, the multi-structure element filter outperforms the single one. Through simulation analysis, the de-noising performance of the low-pass filter, wavelet filter and morphological filter is compared. The results show that the performance of the wavelet and morphological filters is better than that of the low-pass filter. For low signal-to-noise signals, the performance of the wavelet filter is superior. With the increase of signal-to-noise ratio, the morphological filters show more advantages. Taking the cable force monitoring data of the 3rd Nanjing Yangtze River Bridge as an example, the de-noising performance of the wavelet and morphological filters is discussed. The results show that both the wavelet filters and morphological filters have satisfactory de-noising effects. The mathematical morphology method can provide an optional and effective de-nosing choice, which enriches the means of de-noising for bridge monitoring data.

Water content is a key factor influencing the seed cryopreservation, but its effecting mechanism is not fully understood. In order to explore the effect and way of water content on the viability of seed cryopreservation on viability, Malus × robusta seeds with different water contents were obtained by silica gel. The seed viability, sugar content and related enzyme indexes before and after cryopreservation were measured and correlation analysis were done. The results were as follows: (1) After 15 days of cryopreservation, the viability of seeds with different water contents was different, and the viability of seeds showed a trend of increasing and then decreasing as the water content of seeds decreased, and the seeds with 9.02% water content had the highest germination rate, at 53.33%. But after 120 days of cryopreservation, the viability of seeds increased as the water content decreased, and the seeds with 6.40% water content got the highest germination rate, at 27.78%. This indicates that the water content of Malus × robusta seeds has a significant effect on the viability after cryopreservation. It is affected by the storage time in liquid nitrogen, and the optimum water content decreases as the storage time extended in liquid nitrogen. (2) Correlation analysis showed that there was a significant negative correlation between water content and viability (r=-0.82). There was significant negative correlation with fructose and sucrose content, acid invertase, fructokinase, while seed germination rate was significantly positive correlation with these indexes, suggesting that water content affects the contents of sucrose and fructose through effecting the activity of acid converting enzymes, which in turn affects sucrose metabolism to respond to low temperature and dehydration stress, ultimately leading to differences in viability. The seed viability was also affected by fructose metabolism through fructose kinase. Besides, alginate was one of the important regulatory substances of Malus × robusta seed in response to water and low temperature stresses. In summary, water content has a significant effect on the viability of Malus × robusta seeds cryopreservation through the combined effects of sucrose and fructose metabolism. This study provides a theoretical reference to further explore the cryopreservation mechanism of seed.

Abstract Background Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias. Methods Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues. Results The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively. Conclusion Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

Abstract Transcription factors (TFs) and long noncoding RNAs (lncRNAs) contribute to gastric cancer (GC). However, the roles of TFs and lncRNAs in the invasion and metastasis of GC remain largely unknown. Here, we observed that the transcription factor VAX2 is significantly upregulated in GC cells and tissues and acts as an oncogene. Moreover, high VAX2 expression is associated with the advancement of tumors in GC. In terms of functionality, the enforced expression of VAX2 promotes the proliferation and metastasis of GC cells. Mechanistically, VAX2 specifically interacts with the LINC01189 promoter and represses LINC01189 transcription. Furthermore, LINC01189 exhibits significant downregulation in GC and functions as a suppressor gene. Functionally, it inhibits migratory and invasive abilities in GC cells. In the context of GC metastasis, VAX2 plays a role in modulating it by trans-repressing the expression of LINC01189. Additionally, LINC01189 binds to hnRNPF to enhance hnRNPF degradation through ubiquitination. The cooperation between LINC01189 and hnRNPF regulates GC cell invasion and migration. In addition, both VAX2 and hnRNPF are highly expressed, while LINC01189 is expressed in at low levels in GC tissues compared to normal gastric tissues. Our study suggests that VAX2 expression facilitates, while LINC01189 expression suppresses, metastasis and that the VAX2-LINC01189-hnRNPF axis plays a contributory role in GC development.

Abstract Various miRNAs have been shown to participate in the tumor progression and development of colorectal cancer (CRC). However, the role of miR-3913-5p in CRC are yet to be clearly defined. In the present study, we determine that miR-3913-5p is downregulated in CRC cell lines and CRC tissues. Exogenous miR-3913-5p expression weakens the CRC cells growth, migration and invasion. Mechanistically, miR-3913-5p directly targets the 3’UTR of CREB5. Overexpression of CREB5 reverses the suppression of CRC cells proliferation, migration and invasion induced by miR-3913-5p. Furthermore, ATF2 negatively regulates the transcription of miR-3913-5p by binding to its promoter. CREB5 can cooperate with ATF2. CREB5 is required for ATF2 in regulating miR-3913-5p. Finally, inverse correlations can be found between the expressions of miR-3913-5p and CREB5 or ATF2 in CRC tissues. Thus, a plausible mechanism of ATF2/miR-3913-5p/CREB5 axis regulating CRC progression is elucidated. Our findings suggest that miR-3913-5p functions as a tumor suppressor in CRC. ATF2/miR-3913-5p/CREB5 axis might be a potential therapeutic target against CRC progression.

Polyhalogenated carbazoles (PHCZs) are a class of nitrogen-containing heterocyclic compounds that are widely distributed throughout the marine environment and sediment. These compounds share structural and toxicity similarities with dioxins. However, our understanding of the toxicological effects of PHCZs on marine organisms and their underlying molecular mechanisms remains limited. In this study, we employed the marine model organism Mugilogobius chulae as the experimental subject and selected 2,7-dibromocarbazole (2,7-DBCZ), a compound known for its high toxicity and detection frequency, to conduct both an acute toxicity test and transcriptome analysis on M. chulae embryos. Our findings revealed that the 96 h median lethal concentration (LC50) of 2,7-DBCZ for M. chulae embryos was 174 μg/L, with a median effective concentration (EC50) resulting in pericardial edema deformity of 88.82 μg/L. Transcriptome analysis revealed significant impacts on various systems in M. chulae embryos following exposure to 2,7-DBCZ, including the sensory, cardiovascular, immune, and endocrine systems. Furthermore, this compound perturbed signaling pathways such as phototransduction, protein folding and processing, amino acid metabolism, lipid transport, and exogenous compound metabolism. Notably, transcript abundance of the CYP1A gene associated with the activation of the AhR signaling pathway, similar to dioxin-like compounds, was 18.18 times higher than that in the control group. This observation suggests that M. chulae embryos mount a stress response when exposed to PHCZs. In summary, this study contributes to our understanding of the toxicological implications of PHCZ in marine fish and offers a theoretical foundation for risk assessment and regulatory frameworks for PHCZs in the marine environment.

Assessing healthy cities is a crucial strategy for realizing the concept of “health in all policies”. However, most current quantitative assessment methods for healthy cities are predominantly city-level and often overlook intra-urban evaluations. Building on the concept of geographic spatial case-based reasoning (CBR), we present an innovative healthy city spatial case-based reasoning (HCSCBR) model. This model comprehensively integrates spatial relationships and attribute characteristics that impact urban health. We conducted experiments using a detailed multi-source dataset of health environment determinants for middle-layer super output areas (MSOAs) in Birmingham, England. The results demonstrate that our method surpasses traditional data mining techniques in classification performance, offering greater accuracy and efficiency than conventional CBR models. The flexibility of this method permits its application not only in intra-city health evaluations but also in extending to inter-city assessments. Our research concludes that the HCSCBR model significantly improves the precision and reliability of healthy city assessments by incorporating spatial relationships. Additionally, the model’s adaptability and efficiency render it a valuable tool for urban planners and public health researchers. Future research will focus on integrating the temporal dimension to further enhance and refine the healthy city evaluation model, thereby increasing its dynamism and predictive accuracy.

The objective of the study is to investigate the mechanism by which summer pruning enhances the growth of pepper plants, as indicated by growth and fruit appearance indicators, photosynthetic rate and gas exchange parameters, rapid light response and induction kinetics curves and the related chlorophyll fluorescence parameters. The results indicated that the leaf growth rate, the individual pepper fruit weight, and the fruit longitudinal and cross diameters of the pruned group were significantly higher than those of the control. The stomatal conductance (Gs), intercellular CO2 concentration (Ci) and transpiration rate (Tr) of the pruned group were significantly higher than those of the control. The initial slope of the rapid light response curve, which represents light energy utilisation efficiency (α), the maximum electron transfer rate (Jmax) and saturated light intensity (PARsat) were all higher in the summer pruning group than in the control group. The F0 of the pruned group decreased by 16.83%, Fv/F0 increased by 23.69%, PIabs increased by 58.33%, and DIo/RC decreased by 22.09% compared to the control group. In summary, summer pruning significantly improves the leaf growth rate and fruit appearance quality of pepper, effectively promotes the photosynthesis of functional leaves, and reduces the degree of stress under adverse environmental conditions.

Abstract Background Pulmonary tuberculosis (PTB) is a common infectious disease caused by mycobacterium tuberculosis (MTB) and the present study aims to explore the associations of genetic variants within tyrosine kinases 2 (TYK2) with PTB incidence. Methods A population‐based case control study including 168 smear‐positive PTB cases and 251 controls was conducted. Five single nucleotide polymorphisms (SNPs) including rs280520, rs91755, rs2304256, rs12720270, rs280519 located within TYK2 gene were selected and MassARRAY® MALDI‐TOF system was employed for genotyping. SPSS 19.0 was adopted for statistical analysis, non‐conditional logistic regression was conducted. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to estimate their contributions to PTB incidence. Results In the overall study population, rs91755 TT and rs280519 AA genotypes were found to be associated with reduced PTB risk (OR = 0.34, 95% CI: 0.16–0.72; OR = 0.38, 95% CI: 0.18–0.79, respectively). After stratification for sex, we found that among the male population, rs91755TG/TT, rs12720270AG/GG and rs280519AG/AA genotypes were associated with reduced PTB risk (OR = 0.41, 95% CI: 0.21–0.80; OR = 0.44, 95% CI: 0.21–0.94; OR = 0.42, 95% CI: 0.21–0.82, respectively). After stratification for age, we found that among those aged

Pulmonary fibrosis is the result of dysfunctional repair after lung tissue injury, characterized by fibroblast proliferation and massive extracellular matrix aggregation. Once fibrotic lesions develop, effective treatment is difficult, with few drugs currently available. Here, we identified a short cyclic decapeptide RL-RF10 derived from frog skin secretions as a potential novel lead molecule for the amelioration of pulmonary fibrosis. In vivo experiments indicated that RL-RF10 treatment ameliorated lung histopathological damage and fibrogenesis after paraquat (PQ) induction in a concentration-dependent manner. On day 7, bronchoalveolar lavage fluid assays performed on mice showed that RL-RF10 exerted anti-inflammatory effects by decreasing the expression of inflammation-related factors, including transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α, in lung tissue. In addition, RL-RF10 down-regulated the levels of collagen I, collagen III, and vimentin, while increasing the expression of E-cadherin to inhibit epithelial-mesenchymal transition. Further research demonstrated that the SMAD2/3 signaling pathway, which is strongly linked to TGF-β1, played a critical function in enhancing the pulmonary fibrosis relief achieved by RL-RF10. Both in vivo and in vitro assays showed that RL-RF10 treatment led to a significant reduction in the phosphorylation levels of SMAD2 and SMAD3 following PQ induction. Overall, we investigated the protective effects and underlying mechanisms of the RL-RF10 peptide against pulmonary fibrosis and demonstrated its potential as a novel therapeutic drug candidate for the treatment of pulmonary fibrotic diseases.

BackgroundHigh-quality medication compliance is critical for the cure of pulmonary tuberculosis (PTB); however, the implementation of directly observed treatment (DOT) under direct interview still faces huge difficulties. Assessment of the effect of digital tool during community management has not been performed in eastern China.MethodsAll drug-sensitive PTB cases notified in Yiwu city from June to December 2020 were divided into the routine group and digital tool group based on patients’ willingness. The variables influencing the on-time completion level of home visits, medication adherence and treatment outcomes were estimated.ResultsA total of 599 eligible patients were enrolled, with 268 participating in the routine group and 331 using a digital tool. Most participants were men (n = 357, 59.6%), and nearly all were new cases (n = 563, 94.0%). Participants’ mean age was 44.22 ± 20.32 years. There were significant differences in age, diagnostic type, and source of patients between the two groups. During the study period, the digital tool group had a higher on-time completion rate of home visits (91.5% vs. 82.5%) and medication adherence rate (94.3% vs. 89.6%) than the routine group, whereas there was no significant difference in the treatment success rate between the two groups (91.2% vs. 86.8%). Multivariate logistic regression analysis demonstrated that the digital tool group showed a more positive function in the on-time completion status of home visits, with an adjusted odds ratio of 0.41 (95% confidence interval: 0.25–0.70).ConclusionDigital tools can be employed to improve the on-time completion rate of home visits in Yiwu city. Further large-scale studies that use digital tools for community management are warranted.

Pectic oligosaccharides have been proposed as a novel prebiotic to prevent obesity and associated with metabolic disorders by regulating gut microbiota, but their various probiotic functions in the gut depended on their complex and heterogeneous sugar composition. This study aimed to obtain specific oligogalacturonic acids (POAS) from pectin and investigate the effects of POAS on high-fat diet-induced obesity in mice. The results showed that POAS improved body weight gain, serum lipids and hepatic steatosis in obese mice. POAS notably enhanced intestinal barrier function, reduced inflammatory response and regulated the expression of key genes in lipid synthesis and metabolism. Besides, POAS also promoted short-chain fatty acids (SCFAs) production. Furthermore, POAS alleviated the gut microbiota dysbiosis caused by HFD with significantly increasing beneficial gut microbiota such as Akkermansia and Lactobacillus. Spearman's correlation analysis indicated that these bacteria were strongly correlated with obesity-related parameters. We conclude that POAS is a potential prebiotic to treat obesity and related complications.

Introduction: Jichuan decoction (JCD) is a well-known traditional Chinese medicinal formula that moistens the intestines and is widely used for the treatment of constipation in China. However, its effects and mechanisms in alleviating slow transit constipation (STC) in vivo remain unclear. We attempted to demonstrate the effect of JCD, with and without essential oil (VO), on intestinal transit and its underlying molecular mechanisms in rats with loperamide-induced STC. Materials and methods: Water consumption, body weight, fecal water content, time to first melena excretion, and intestinal transit ratio of the animals were measured. 5-Hydroxytryptamine (5-HT), substance P (SP), vasoactive intestinal peptide (VIP), and interleukin-6 (IL-6) levels in the sera of rats were evaluated using ELISA. Hematoxylin and eosin and Periodic Acid–Schiff staining were used to determine intestinal tissue histology, while quantitative real-time PCR, western blotting, and immunohistochemical analysis were used to assess the relative expression levels of cAMP/PKA/AQPs pathway- and inflammation-related proteins. 16 S rDNA sequence analysis of rat feces was used to determine the diversity and abundance of the intestinal flora. Results: The JCD groups showed reduced time to first melena excretion and expression of VIP and IL-6. The JCD groups, specifically JCD + VO groups, showed increased fecal water content, intestinal transit rate, and SP expression. Further, these groups showed improved histological characteristics of the colon, with no significant change in the index of immune organs or morphological characteristics of other organs. In addition, a significant decrease in the activation of the cAMP/PKA/AQPs signaling pathway in the colon tissue was observed in these groups, specifically the JCD + VO groups. Moreover, treatment with JCD, with or without VO, downregulated the expression of inflammatory factors and enriched the diversity of intestinal flora as evidenced by polymorphism analysis and the contents of Bacteroides, Lactobacillus, and Erysipelas, with the JCD + VO groups showing better therapeutic outcomes. Conclusion: JCD improved loperamide-induced STC, and co-administration with VO exhibited better activity than sole JCD therapy. JCD may improve STC by inhibiting the cAMP/PKA/AQPs signaling pathway and maintaining inflammatory/intestinal flora homeostasis.

Wuzi Yanzong Wan (WZYZW) is a classic formula for tonifying the kidneys in Traditional chinese medicine (TCM) and is widely used clinically in diseases of the reproductive system, immune system and nervous system. Therefore, the quality control and prediction quality markers (Q-markers) of WZYZW is of positive significance.In this study, We first established the fingerprints, calibrated 28 common peaks, identified 12 common peaks of gallic acid, geniposidic acid, chlorogenic acid, ellagic acid, rutin, hyperoside, verbascoside, astragalin, kaempferol, schisandrol A, schisandrol B and schisandrin B, and the similarity was greater than 0.9 of 10 batches.Then, withing network pharmacology, we screened 41 core targets such as PIK3CA, AKT1, PIK3CB, potential pathways such as pathways in cancer and PI3K-Akt signalling pathway of 12 components. The results showed that they were tightly connected to predicated targets and pathways. Finally, by using the hyperoside as internal reference standard, a Quantitative analysis of multi-components (QAMS) for WZYZW was established to determine the contents of WZYZW. The percent difference(%) showed that there was no significant difference between the quantitative results of external standard method (ESM) and QAMS method. Contents of the 11 components above were 0.0091 ∼ 0.0185 %, 0.1019 ∼ 0.1361 %, 0.0518 ∼ 0.0718 %, 0.0130 ∼ 0.0320 %, 0.0084 ∼ 0.0190 %, 0.0621 ∼ 0.1192 %, 0.0127 ∼ 0.0419 %, 0.0006 ∼ 0.0089 %, 0.0212 ∼ 0.0261 %, 0.0061 ∼ 0.0400 %, 0.0084 ∼ 0.0103 %, respectively. Overall, the method developed was applied to the quality evaluation and Q-markers research of WZYZW as well as provided guiding significance for the Q-marker research of TCM.

Abstract Background Influenza is a common illness for its high rates of morbidity and transmission. The implementation of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic to manage its dissemination could affect the transmission of influenza. Methods A retrospective analysis, between 2018 and 2023, was conducted to examine the incidence of influenza virus types A and B among patients in sentinel cities located in North or South China as well as in Wuhan City. For validations, data on the total count of influenza patients from 2018 to 2023 were collected at the Central Hospital of Wuhan, which is not included in the sentinel hospital network. Time series methods were utilized to examine seasonal patterns and to forecast future influenza trends. Results Northern and southern cities in China had earlier outbreaks during the NPIs period by about 8 weeks compared to the 2018–2019. The implementation of NPIs significantly reduced the influenza-like illness (ILI) rate and infection durations. Influenza B Victoria and H3N2 were the first circulating strains detected after the relaxation of NPIs, followed by H1N1 across mainland China. The SARIMA model predicted synchronized H1N1 outbreak cycles in North and South China, with H3N2 expected to occur in the summer in southern cities and in the winter in northern cities over the next 3 years. The ILI burden is expected to rise in both North and South China over the next 3 years, with higher ILI% levels in southern cities throughout the year, especially in winter, and in northern cities mainly during winter. In Wuhan City and the Central Hospital of Wuhan, influenza levels are projected to peak in the winter of 2024, with 2 smaller peaks expected during the summer of 2023. Conclusions In this study, we report the impact of NPIs on future influenza trends in mainland China. We recommend that local governments encourage vaccination during the transition period between summer and winter to mitigate economic losses and mortality associated with influenza.

SiGe is recognised as an excellent thermoelectric material with superior mechanical properties and thermal stability in regions with high temperatures. This study explores a novel strategy for co-regulating thermoelectric transport parameters to achieve high thermoelectric properties of p-type SiGe in the mid-temperature region by incorporating nano-TaC into SiGe combined ball milling with spark plasma sintering. By optimizing the amount of TaC in the SiGe matrix, the power factors were significantly increased due to the modulation doping effect based on the work function matching of SiGe with TaC. Simultaneously, the ensemble effect of the nanostructure leads to a significant decrease in thermal conductivity. Thus, a high ZT of 1.06 was accomplished at 873 K, which is 64 % higher than that of typical radioisotope thermoelectric generator. Our research offers a novel strategy for expanding and enhancing the thermoelectric properties of SiGe materials in the medium temperature range.

Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the role of BBR on POI is still unknown. In this study, we investigated the role of BBR on ovarian function decline by establishing a POI mouse model using cyclophosphamide (CTX) and busulfan (BU). Our results showed that POI was attenuated by BBR, which was evidenced by enhanced body weight and ovarian weight, improved morphology of ovary, increased the number of healthy follicles, decreased the production of atretic follicles and restored serum hormone levels, including estradiol, anti-Müllerian hormone and follicle-stimulating hormone. In addition, we showed that germ cell function markers, mouse vasa homologue (MVH) and octamer-binding transcription factor 4 (OCT4) were enhanced by BBR, at both protein and mRNA levels. Furthermore, our results revealed that BBR inhibited inflammation and oxidative stress by reducing nuclear factor kappa B (NF-κB) and enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Taken together, we demonstrate that BBR can effectively improve ovarian function in POI mice, which is mainly mediated by reducing oxidative stress and inflammatory response. Our study also provides new strategy for POI treatment.

It is common sense that a phase interface (or grain boundary) could be used to scatter phonons in thermoelectric (TE) materials, resulting in low thermal conductivity (κ). However, a large number of impurity phases are always so harmful to the transport of carriers that poor TE performance is obtained. Here, we demonstrate that numerous superior multiphase (AgCuTe, Ag2Te, copper telluride (Cu2Te and Cu2−xTe), and nickel telluride (NiTe)) interfaces with simultaneous strong phonon scattering and weak electron scattering could be realized in AgCuTe-based TE materials. Owing to the similar chemical bonds in these phases, the depletion region at phase interfaces, which acts as carrier scattering centers, could be ignored. Therefore, the power factor (PF) is obviously enhanced from ~609 to ~832 μW·m−1·K−2, and κ is simultaneously decreased from ~0.52 to ~0.43 W·m−1·K−1 at 636 K. Finally, a peak figure of merit (zT) of ~1.23 at 636 K and an average zT (zTavg) of ~1.12 in the temperature range of 523–623 K are achieved, which are one of the best values among the AgCuTe-based TE materials. This study could provide new guidance to enhance the performance by designing superior multiphase interfaces in the TE materials.

Abstract Background Body fat composition is believed to be associated with the progression, medical response, and prognosis of inflammatory bowel disease (IBD). Hence, we conducted this study to explore if fat metrics were associated with the disease activity of severe IBD and the response to intravenous corticosteroids (IVCS). Methods We included 69 patients with ulcerative colitis (UC) and 72 patients with Crohn's disease (CD) who had previously received IVCS during hospitalization. We quantified individual fat distribution using abdominal computed tomography slices. The correlations between fat parameters and disease activity were available with Spearman correlation analysis. The prediction model was developed using independent risk factors derived from multivariable logistic regression analysis. Model discrimination was evaluated leveraging the receiver operating characteristic curve. 1000 bootstrap resamples internally validated the model's prediction performance. Results Notable differences in age, nutritional status, serum cytomegalovirus replication, stool condition, and extraintestinal involvement between UC and CD patients were observed. UC subjects who responded to IVCS had higher subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), and mesorectal adipose tissue index (MATI) than non-responders. IVCS-responding CD individuals had lower VATI and mesenteric fat index (MFI) than non-responders. CD patients with a prolonged disease duration had a decreased SATI and an elevated MFI. VATI and MATI were reduced as UC clinically progressed, while more prominent clinical activity in CD correlated with increased VATI, MATI, and MFI. A high SATI indicated that patients with UC were more prone to be IVCS responders. For patients with CD, levels of VATI and MFI were negatively associated with effective IVCS treatment. The established models showed a discriminative accuracy of 0.834 [95% confidence interval (CI) 0.740–0.928] in the UC cohort and 0.871 (95% CI 0.793–0.949) in the CD cohort. Repeated samples supported the reliability of the developed models (AUCUC = 0.836, 95% CI 0.735–0.919; AUCCD = 0.876, 95% CI 0.785–0.946). Conclusion Human fat indexes represent novel imaging biomarkers for identifying IBD patients who respond to IVCS, thus building accelerated therapy regimens and avoiding the adverse effects of ineffective IVCS.

Abstract Background Glycemic variability plays an important role in the development of cardiovascular disease (CVD). This study aims to determine whether long-term visit-to-visit glycemic variability is associated with aortic stiffness progression in participants with type 2 diabetes (T2D). Methods Prospective data were obtained from 2115 T2D participants in the National Metabolic Management Center (MMC) from June 2017 to December 2022. Two brachial-ankle pulse wave velocity (ba-PWV) measurements were performed to assess aortic stiffness over a mean follow-up period of 2.6 years. A multivariate latent class growth mixed model was applied to identify trajectories of blood glucose. Logistic regression models were used to determine the odds ratio (OR) for aortic stiffness associated with glycemic variability evaluated by the coefficient of variation (CV), variability independent of the mean (VIM), average real variability (ARV), and successive variation (SV) of blood glucose. Results Four distinct trajectories of glycated hemoglobin (HbA1c) or fasting blood glucose (FBG) were identified. In the U-shape class of HbA1c and FBG, the adjusted ORs were 2.17 and 1.21 for having increased/persistently high ba-PWV, respectively. Additionally, HbA1c variability (CV, VIM, SV) was significantly associated with aortic stiffness progression, with ORs ranging from 1.20 to 1.24. Cross-tabulation analysis indicated that the third tertile of the HbA1c mean and VIM conferred a 78% (95% confidence interval [CI] 1.23–2.58) higher odds of aortic stiffness progression. Sensitivity analysis demonstrated that the SD of HbA1c and the highest HbA1c variability score (HVS) were significantly associated with the adverse outcomes independent of the mean of HbA1c during the follow-up. Conclusions Long-term visit-to-visit HbA1c variability was independently associated with aortic stiffness progression, suggesting that HbA1c variability was a strong predictor of subclinical atherosclerosis in T2D participants.

Objectives: To address gaps in health services for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB), a treatment cascade model was used to evaluate patient retention and attrition at each successive step required to achieve a successful treatment outcome. Methods: From 2015–2018, a four-step treatment cascade model was established in patients with confirmed MDR/RR-TB in southeast China. Step 1: diagnosis of MDR/RR-TB, step 2: Initiation of treatment, step 3: still under treatment at 6 month and step 4: cure or completion of MDR/RR-TB treatment, with each successive step including a gap that shows attrition of patients between steps. The retention and attrition of each step were graphed. Multi-variate logistic regression was carried out to further identify potential factors associated with the attrition. Results: In the treatment cascade consisting of 1752 MDR/RR-TB patients, the overall patient attrition rate was 55.8% (978/1752), with 28.0% (491/1752), 19.9% (251/1261), and 23.4% (236/1010) of patients attrition in the first, second, and third gap. Factors associated with MDR/RR-TB patients not initiating treatment included age ≥60 years (OR:2.875), and time for diagnosis ≥30 days (OR: 2.653). Patients who were diagnosed with MDR/RR-TB through rapid molecular test (OR: 0.517) and non-migrant residents of Zhejiang Province (OR: 0.273) both exhibited a lower likelihood of attrition during the treatment initiation phase. Meanwhile, old age (OR: 2.190) and non-resident migrants to the province were factors associated with not completing ≥ 6 months of treatment. Old age (OR: 3.883), retreatment (OR: 1.440), and time to diagnosis ≥30 days (OR: 1.626) were factors contributing to poor treatment outcomes. Conclusion: Several programmatic gaps were identified in the MDR/RR-TB treatment cascade. Future policies should provide more comprehensive support for vulnerable populations to improve the care quality at each step.

Abstract Atopic dermatitis is defined as an intensely systemic inflammation among skin diseases. Exosomes derived from adipose-derived stem cells may be a novel cell-free therapeutic strategy for atopic dermatitis treatment. This study aims to elucidate the possible underlying mechanism of adipose-derived stem cells-exosomes harboring microRNA-147a in atopic dermatitis pathogenesis. BALB/c mice treated with Dermatophagoides farinae extract/2,4-dinitrochlorobenzene were defined as a mouse model of atopic dermatitis, either with inflamed HaCaT cells and HUVECs exposed with TNF-α/IFN-γ stimulation were applied for a cell model of atopic dermatitis. The concentrations of IL-1β and TNF-α in the supernatants were examined by ELISA. Cell viability and migration were assessed by MTT and Transwell assay. The apoptosis was examined using flow cytometry and TUNEL staining. The tube formation assay was employed to analyzed angiogenesis. The molecular regulations among miR-147a, MEF2A, TSLP and VEGFA were confirmed using luciferase reporter assay, either with ChIP. microRNA-147a was markedly downregulated in the serum and skin samples of atopic dermatitis mice, of which overexpression remarkably promoted HaCaT cell proliferation, meanwhile inhibiting inflammatory response and cell apoptosis. microRNA-147a in adipose-derived stem cells was subsequently overexpressed, and exosomes (Exos-miR-147a mimics) were collected. Functionally, exos-microRNA-147a mimics attenuated TNF-α/IFN-γ-induced HaCaT cell inflammatory response and apoptosis, and suppressed HUVECs angiogenesis. Encouraging, molecular interaction experiments revealed that exosomal microRNA-147a suppressed TNF-α/IFN-γ-induced HUVECs angiogenesis by targeting VEGFA, and exosomal microRNA-147a repressed HaCaT cells inflammatory injury through the MEF2A-TSLP axis. Mechanistically, exosomal microRNA-147a repressed pathological angiogenesis and inflammatory injury during atopic dermatitis progression by targeting VEGFA and MEF2A-TSLP axis. microRNA-147a-overexpressing adipose-derived stem cells-derived exosomes suppressed pathological angiogenesis and inflammatory injury in atopic dermatitis by targeting VEGFA and MEF2A-TSLP axis.

Abstract Long non-coding RNAs (lncRNAs) have been functionally characterised in various diseases. LncRNA PAX-interacting protein 1-antisense RNA 1 (PAXIP1-AS1) has reportedly been associated with cancer development. However, its role in gastric cancer (GC) remains poorly understood. Here, we showed that PAXIP1-AS1 was transcriptionally repressed by homeobox D9 (HOXD9) and was significantly downregulated in GC tissues and cells. Decreased expression of PAXIP1-AS1 was positively correlated with tumour progression, while PAXIP1-AS1 overexpression inhibited cell growth and metastasis both in vitro and in vivo. PAXIP1-AS1 overexpression significantly attenuated HOXD9-enhanced epithelial-to-mesenchymal transition (EMT), invasion and metastasis in GC cells. Poly(A)-binding protein cytoplasmic 1 (PABPC1), an RNA-binding protein, was found to enhance the stability of PAK1 mRNA, leading to EMT progress and GC metastasis. PAXIP1-AS1 was found to directly bind to and destabilise PABPC1, thereby regulating EMT and metastasis of GC cells. In summary, PAXIP1-AS1 suppressed metastasis, and the HOXD9/PAXIP1-AS1/PABPC1/PAK1 signalling axis may be involved in the progression of GC.

Abstract Background Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs. Methods ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages. Discussion This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB. Trial registration The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

Pseudoachondroplasia (PSACH) is a rare, dominant genetic disorder affecting bone and cartilage development, characterized by short-limb short stature, brachydactyly, loose joints, joint stiffness, and pain. The disorder is caused by mutations in the COMP gene, which encodes a protein that plays a role in the formation of collagen fibers. In this study, we present the clinical and genetic characteristics of PSACH in two Chinese families. Whole-exome sequencing (WES) analysis revealed two novel missense variants in the COMP gene: NM_000095.3: c.1319G>T (p.G440V, maternal) and NM_000095.3: c.1304A>T (p.D435V, paternal-mosaic). Strikingly, both the G440V and D435V mutations were located in the same T3 repeat motif and exhibited the potential to form hydrogen bonds with each other. Upon further analysis using Missense3D and PyMOL, we ascertained that these mutations showed the propensity to disrupt the protein structure of COMP, thus hampering its functioning. Our findings expand the existing knowledge of the genetic etiology underlying PSACH. The identification of new variants in the COMP gene can broaden the range of mutations linked with the condition. This information can contribute to the diagnosis and genetic counseling of patients with PSACH.