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Abstract Background Renal cold ischemia-reperfusion injury (CIRI), a pathological process during kidney transplantation, may result in delayed graft function and negatively impact graft survival and function. There is a lack of an accurate and non-invasive tool for evaluating the degree of CIRI. Multi-parametric MRI has been widely used to detect and evaluate kidney injury. The machine learning algorithms introduced the opportunity to combine biomarkers from different MRI metrics into a single classifier. Objective To evaluate the performance of multi-parametric magnetic resonance imaging for grading renal injury in a rat model of renal cold ischemia-reperfusion injury using a machine learning approach. Methods Eighty male SD rats were selected to establish a renal cold ischemia -reperfusion model, and all performed multiparametric MRI scans (DWI, IVIM, DKI, BOLD, T1mapping and ASL), followed by pathological analysis. A total of 25 parameters of renal cortex and medulla were analyzed as features. The pathology scores were divided into 3 groups using K-means clustering method. Lasso regression was applied for the initial selecting of features. The optimal features and the best techniques for pathological grading were obtained. Multiple classifiers were used to construct models to evaluate the predictive value for pathology grading. Results All rats were categorized into mild, moderate, and severe injury group according the pathologic scores. The 8 features that correlated better with the pathologic classification were medullary and cortical Dp, cortical T2*, cortical Fp, medullary T2*, ∆T1, cortical RBF, medullary T1. The accuracy(0.83, 0.850, 0.81, respectively) and AUC (0.95, 0.93, 0.90, respectively) for pathologic classification of the logistic regression, SVM, and RF are significantly higher than other classifiers. For the logistic model and combining logistic, RF and SVM model of different techniques for pathology grading, the stable and perform are both well. Based on logistic regression, IVIM has the highest AUC (0.93) for pathological grading, followed by BOLD(0.90). Conclusion The multi-parametric MRI-based machine learning model could be valuable for noninvasive assessment of the degree of renal injury.

Abstract Erectile dysfunction (ED) is the most prevalent consequences in men with diabetes mellitus (DM). Recent studies demonstrates that neutrophil extracellular traps (NETs) play important roles in DM and its complications. Nevertheless, whether NETs are involved in ED remains unknown. This work intended to explore the role and mechanisms of NETs in ED in the context of DM. Here, we observed that NET generation and pyroptosis were promoted in DM rats with ED compared with controls. Mechanistically, NETs facilitated NLRP3 inflammasome activation and subsequently triggered pyroptosis under high glucose stress, ultimately leading to ED. Intriguingly, DNase I (a NET degrading agent) alleviated ED and corpus cavernosum injury in DM rats. Overall, NETs might induce ED in DM by promoting NLRP3-mediated pyroptosis in the corpus cavernosum.

Abstract Background Despite abundant evidence on the epidemiological risk factors of metabolic diseases related to hyperuricemia, there is still insufficient evidence regarding the nonlinear relationship between triglyceride-glucose (TyG) index and hyperuricemia. Thus, the purpose of this research is to clarify the nonlinear connection between TyG and hyperuricemia. Methods From 2011 to 2018, a cross-sectional study was carried out using data from the National Health and Nutrition Examination Survey (NHANES). This study had 8572 participants in all. TyG was computed as Ln [triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The outcome variable was hyperuricemia. The association between TyG and hyperuricemia was examined using weighted multiple logistic regression, subgroup analysis, generalized additive models, smooth fitting curves, and two-piecewise linear regression models. Results In the regression model adjusting for all confounding variables, the OR (95% CI) for the association between TyG and hyperuricemia was 2.34 (1.70, 3.21). There is a nonlinear and reverse U-shaped association between TyG and hyperuricemia, with a inflection point of 9.69. The OR (95% CI) before the inflection point was 2.64 (2.12, 3.28), and after the inflection point was 0.32 (0.11, 0.98). The interaction in gender, BMI, hypertension, and diabetes analysis was statistically significant. Conclusion Additional prospective studies are required to corroborate the current findings, which indicate a strong positive connection between TyG and hyperuricemia among adults in the United States.

Graptemys ouachitensis (CAGLE, 1953) belongs to the Graptemys genus, the Emydidae family, and the Testudines order. This study involved sequencing the complete mitochondrial genome (mitogenome) of G. ouachitensis using next-generation sequencing, and analyzing the essential characteristics, and phylogenetic relationship. The results revealed that the G. ouachitensis mitogenome was 16,674 bp in length (A: 34.1%, C: 26.0%, G: 13.0%, T: 26.9%) and included 22 tRNAs, 13 protein-coding genes, two ribosomal RNA genes, and a non-coding control region (GenBank accession: NC071766). The genome composition of G. ouachitensis presented a slight A + T bias (61.0%) and exhibited a positive AT skew (0.118) and a negative GC skew (–0.333). A phylogenetic analysis based on the complete mitogenome indicated that the G. ouachitensis was more closely associated with Malaclemys terrapin than the other eight known Emydidae species. Thus, our findings present a novel mitogenome at the species level. This study introduces the first complete mitogenome of G. ouachitensis, providing valuable molecular information for phylogenetic and conservation genetics analyses of G. ouachitensis.

Abstract Introduction Bipolar disorder (BD) is a chronic psychiatric disorder that combines hypomania or mania and depression. The study aims to investigate the research areas associated with cognitive function in bipolar disorder and identify current research hotspots and frontier areas in this field. Methodology Publications related to cognitive function in BD from 2012 to 2022 were searched on the Web of Science Core Collection (WoSCC) database. VOSviewer, CiteSpace, and Scimago Graphica were used to conduct this bibliometric analysis. Results A total of 989 articles on cognitive function in BD were included in this review. These articles were mainly from the United States, China, Canada, Spain and the United Kingdom. Our results showed that the journal “Journal of Affective Disorders” published the most articles. Apart from “Biploar disorder” and “cognitive function”, the terms “Schizophrenia”, “Meta analysis”, “Rating scale” were also the most frequently used keywords. The research on cognitive function in bipolar disorder primarily focused on the following aspects: subgroup, individual, validation and pathophysiology. Conclusions The current concerns and hotspots in the filed are: “neurocognitive impairment”, “subgroup”, “1st degree relative”, “mania”, “individual” and “validation”. Future research is likely to focus on the following four themes: “Studies of the bipolar disorder and cognitive subgroups”, “intra-individual variability”, “Validation of cognitive function tool” and “Combined with pathology or other fields”.

Abstract Background In observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres. Methods A genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results. Results A strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248—3.531, p = 0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results. Conclusions The present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans.

Abstract Introduction Interrupted time series (ITS) design is a commonly used method for evaluating large-scale interventions in clinical practice or public health. However, improperly using this method can lead to biased results. Objective To investigate design and statistical analysis characteristics of drug utilization studies using ITS design, and give recommendations for improvements. Methods A literature search was conducted based on PubMed from January 2021 to December 2021. We included original articles that used ITS design to investigate drug utilization without restriction on study population or outcome types. A structured, pilot-tested questionnaire was developed to extract information regarding study characteristics and details about design and statistical analysis. Results We included 153 eligible studies. Among those, 28.1% (43/153) clearly explained the rationale for using the ITS design and 13.7% (21/153) clarified the rationale of using the specified ITS model structure. One hundred and forty-nine studies used aggregated data to do ITS analysis, and 20.8% (31/149) clarified the rationale for the number of time points. The consideration of autocorrelation, non-stationary and seasonality was often lacking among those studies, and only 14 studies mentioned all of three methodological issues. Missing data was mentioned in 31 studies. Only 39.22% (60/153) reported the regression models, while 15 studies gave the incorrect interpretation of level change due to time parameterization. Time-varying participant characteristics were considered in 24 studies. In 97 studies containing hierarchical data, 23 studies clarified the heterogeneity among clusters and used statistical methods to address this issue. Conclusion The quality of design and statistical analyses in ITS studies for drug utilization remains unsatisfactory. Three emerging methodological issues warranted particular attention, including incorrect interpretation of level change due to time parameterization, time-varying participant characteristics and hierarchical data analysis. We offered specific recommendations about the design, analysis and reporting of the ITS study.

Background: Mesangial cell (MC)-mediated immune inflammatory injury is a basic pathological process in glomerulonephritis. However, due to the limited drug accumulation and serious adverse effects, it remains challenging to explore a rational delivery system integrating high efficiency and low toxicity to deliver anti-inflammatory drugs to the glomerular MC region. Results: Salvianolic acid B (SAB)-loaded hybrid membrane biomimetic nanovesicles (SAB@HMVs) were developed by fusing erythrocyte membrane nanovesicles with mesenchymal stem cells biomimetic membrane nanovesicles. SAB@HMVs had a spheroidal structure, low cytotoxicity, particle size of 143.83 ± 1.33 nm and exhibited a high drug loading capacity (7.02 %±0.30 %) along with a good sustained release function. The in vitro anti-inflammatory results revealed that HMVs were effectively taken up by MCs and showed significant anti-inflammatory activity. Furthermore, in vivo pharmacodynamic studies revealed that SAB@HMVs could deliver SAB to kidney tissue and elicit an effective anti-inflammatory response to improve the pathological changes in the glomerular mesangial region, significantly reducing the levels of cytokines and alleviating kidney inflammation. Especially, noteworthy was the observation that SAB@HMVs augmented the renal delivery of SAB, downregulated the gene expression of p38 MAPK and NF-κB, inhibited the levels of MMP9 and TNF-α proteins as well as elevated the level of iκB protein, indicating that the anti-inflammatory mechanism of SAB@HMVs should be based on regulating MAPK and NF-κB signaling pathways. Conclusion: We provided a novel strategy to increase nanovesicles accumulation in MCs with the potential to exert anti-inflammatory regulatory effects in glomerulonephritis. Furthermore, this biomimetic hybrid membrane loaded with pure drugs may offer a functional platform to address multiple clinical needs.

BackgroundMetabolic dysregulation represents a defining characteristic of Type 2 diabetes (T2DM). Nevertheless, there remains an absence of substantial evidence establishing a direct causal link between circulating blood metabolites and the promotion or prevention of T2DM. In addressing this gap, we employed Mendelian randomization (MR) analysis to investigate the potential causal association between 1,091 blood metabolites, 309 metabolite ratios, and the occurrence of T2DM.MethodsData encompassing single-nucleotide polymorphisms (SNPs) for 1,091 blood metabolites and 309 metabolite ratios were extracted from a Canadian Genome-wide association study (GWAS) involving 8,299 participants. To evaluate the causal link between these metabolites and Type 2 diabetes (T2DM), multiple methods including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode were employed. p-values underwent correction utilizing False Discovery Rates (FDR). Sensitivity analyses incorporated Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, Steiger test, leave-one-out analysis, and single SNP analysis. The causal effects were visualized via Circos plot, forest plot, and scatter plot. Furthermore, for noteworthy, an independent T2DM GWAS dataset (GCST006867) was utilized for replication analysis. Metabolic pathway analysis of closely correlated metabolites was conducted using MetaboAnalyst 5.0.ResultsThe IVW analysis method utilized in this study revealed 88 blood metabolites and 37 metabolite ratios demonstrating a significant causal relationship with T2DM (p < 0.05). Notably, strong causal associations with T2DM were observed for specific metabolites: 1-linoleoyl-GPE (18:2) (IVW: OR:0.930, 95% CI: 0.899–0.962, p = 2.16 × 10−5), 1,2-dilinoleoyl-GPE (18:2/18:2) (IVW: OR:0.942, 95% CI: 0.917–0.968, p = 1.64 × 10−5), Mannose (IVW: OR:1.133, 95% CI: 1.072–1.197, p = 1.02 × 10−5), X-21829 (IVW: OR:1.036, 95% CI: 1.036–1.122, p = 9.44 × 10−5), and Phosphate to mannose ratio (IVW: OR:0.870, 95% CI: 0.818–0.926, p = 1.29 × 10−5, FDR = 0.008). Additionally, metabolic pathway analysis highlighted six significant pathways associated with T2DM development: Valine, leucine and isoleucine biosynthesis, Phenylalanine metabolism, Glycerophospholipid metabolism, Alpha-Linolenic acid metabolism, Sphingolipid metabolism, and Alanine, aspartate, and glutamate metabolism.ConclusionThis study identifies both protective and risk-associated metabolites that play a causal role in the development of T2DM. By integrating genomics and metabolomics, it presents novel insights into the pathogenesis of T2DM. These findings hold potential implications for early screening, preventive measures, and treatment strategies for T2DM.

The fermentation process for Jiang-flavored baijiu using sorghum as the raw material involves a variety of microorganisms. However, the specific physicochemical characteristics of sorghum and microbial composition on its surface have not been fully elucidated. We aimed to perform a comprehensive comparative analysis of the variations in physicochemical properties and surface microflora in waxy sorghum samples from three prominent production regions in China (Renhuai, Jinsha, and Duyun). Multivariate statistical assessments were conducted that incorporated local soil and climate variables. The results showed that Cyanobacteria, unclassified bacteria, Proteobacteria, Firmicutes, and Bacteroidota were the dominant bacteria in these regions. These bacteria were associated with ethyl acetate, ethyl caprylate, ethyl lactate, and butyl groups, which synergistically produce flavorful compounds. The surface bacterial communities were affected by soil total phosphorus, altitude, diurnal temperature range, monthly mean temperature, precipitation, and effective accumulated temperature. The findings of this study provide a new perspective on microorganisms related to Jiang-flavored baijiu and can help establish a reference for the stability of liquor quality.

Background Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.Methods Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.Results EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.Conclusions MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.

Abstract We provide a remote sensing derived dataset for large-scale ground-mounted photovoltaic (PV) power stations in China of 2020, which has high spatial resolution of 10 meters. The dataset is based on the Google Earth Engine (GEE) cloud computing platform via random forest classifier and active learning strategy. Specifically, ground samples are carefully collected across China via both field survey and visual interpretation. Afterwards, spectral and texture features are calculated from publicly available Sentinel-2 imagery. Meanwhile, topographic features consisting of slope and aspect that are sensitive to PV locations are also included, aiming to construct a multi-dimensional and discriminative feature space. Finally, the trained random forest model is adopted to predict PV power stations of China parallelly on GEE. Technical validation has been carefully performed across China which achieved a satisfactory accuracy over 89%. Above all, as the first publicly released 10-m national-scale distribution dataset of China’s ground-mounted PV power stations, it can provide data references for relevant researchers in fields such as energy, land, remote sensing and environmental sciences.

Abstract Background Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. Methods With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. Results A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist’s intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. Conclusion DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

Type 2 diabetes mellitus is a chronic metabolic disease characterized by insulin resistance, with high morbidity and mortality worldwide. Due to the tightly intertwined connection between the insulin resistance pathway and the PI3K/AKT signaling pathway, regulating the PI3K/AKT pathway and its associated targets is essential for hypoglycemia and the prevention of type 2 diabetes mellitus. In recent years, metabolites isolated from traditional Chinese medicine has received more attention and acceptance for its superior bioactivity, high safety, and fewer side effects. Meanwhile, numerous in vivo and in vitro studies have revealed that the metabolites present in traditional Chinese medicine possess better bioactivities in regulating the balance of glucose metabolism, ameliorating insulin resistance, and preventing type 2 diabetes mellitus via the PI3K/AKT signaling pathway. In this article, we reviewed the literature related to the metabolites of traditional Chinese medicine improving IR and possessing therapeutic potential for type 2 diabetes mellitus by targeting the PI3K/AKT signaling pathway, focusing on the hypoglycemic mechanism of the metabolites of traditional Chinese medicine in type 2 diabetes mellitus and elaborating on the significant role of the PI3K/AKT signaling pathway in type 2 diabetes mellitus. In order to provide reference for clinical prevention and treatment of type 2 diabetes mellitus.

The master cylinder of most pump trucks is equipped with a waterproof valve, whose purpose is to prevent water from the tank from entering the master cylinder. Once waterproof valve fails to failure, the waterproof valve at the main cylinder can only be supported by a BS seal (this seal is very easy to fail), which results in oil emulsification and pollution of the hydraulic system. Therefore, a fault diagnosis method combining a multi-sensor high-dimensional time-domain feature expansion map (MHTFEM) with an attentional convolutional capsule network (ACCN) is proposed. In this method, the raw vibration signals acquired by all sensors are first preprocessed to generate a high-dimensional feature matrix. Then the different high-dimensional feature matrices are stitched, expanded and generated into grayscale images, followed by randomly dividing the training set and the testing set. Finally, the training set is brought into the ACCN for training and the testing set is brought into the network model for fault type identification. A test bench was built to confirm the effectiveness of the method for waterproof valve fault diagnosis. This provides a method to achieve intelligent fault diagnosis of construction machinery to ensure its reliability.

Rapid and accurate identification of lactic acid bacteria (LAB) species would greatly improve the screening rate for functional LAB. Although many conventional and molecular methods have proven efficient and reliable, LAB identification using these methods has generally been slow and tedious. Single-cell Raman spectroscopy (SCRS) provides the phenotypic profile of a single cell and can be performed by Raman spectroscopy (which directly detects vibrations of chemical bonds through inelastic scattering by a laser light) using an individual live cell. Recently, owing to its affordability, non-invasiveness, and label-free features, the Ramanome has emerged as a potential technique for fast bacterial detection. Here, we established a reference Ramanome database consisting of SCRS data from 1,650 cells from nine LAB species/subspecies and conducted further analysis using machine learning approaches, which have high efficiency and accuracy. We chose the ensemble meta-classifier (EMC), which is suitable for solving multi-classification problems, to perform in-depth mining and analysis of the Ramanome data. To optimize the accuracy and efficiency of the machine learning algorithm, we compared nine classifiers: LDA, SVM, RF, XGBoost, KNN, PLS-DA, CNN, LSTM, and EMC. EMC achieved the highest average prediction accuracy of 97.3% for recognizing LAB at the species/subspecies level. In summary, Ramanomes, with the integration of EMC, have promising potential for fast LAB species/subspecies identification in laboratories and may thus be further developed and sharpened for the direct identification and prediction of LAB species from fermented food.

Abstract Neuro‐COVID, a condition marked by persistent symptoms post‐COVID‐19 infection, notably affects various organs, with a particular focus on the central nervous system (CNS). Despite scant evidence of SARS‐CoV‐2 invasion in the CNS, the increasing incidence of Neuro‐COVID cases indicates the onset of acute neurological symptoms early in infection. The Omicron variant, distinguished by heightened neurotropism, penetrates the CNS via the olfactory bulb. This direct invasion induces inflammation and neuronal damage, emphasizing the need for vigilance regarding potential neurological complications. Our multicenter study represents a groundbreaking revelation, documenting the definite presence of SARS‐CoV‐2 in the cerebrospinal fluid (CSF) of a significant proportion of Neuro‐COVID patients. Furthermore, notable differences emerged between RNA‐CSF‐positive and negative patients, encompassing aspects such as blood–brain barrier integrity, extent of neuronal damage, and the activation status of inflammation. Despite inherent limitations, this research provides pivotal insights into the intricate interplay between SARS‐CoV‐2 and the CNS, underscoring the necessity for ongoing research to fully comprehend the virus's enduring effects on the CNS. The findings underscore the urgency of continuous investigation Neuro‐COVID to unravel the complexities of this relationship, and pivotal in addressing the long‐term consequences of COVID‐19 on neurological health.

Slow transit constipation (STC) is a common and debilitating condition characterized by delayed colonic transit and difficulty in fecal expulsion, significantly impacting patients’ physical and mental wellbeing as well as their overall quality of life. This study investigates the therapeutic potential of Liqi Tongbian Decoction (LTD) in the treatment of STC, especially in cases involving the context of Qi stagnation, through a multifaceted approach involving the modulation of intestinal flora and short-chain fatty acids (SCFAs). We employed a rat model of STC with Qi Stagnation Pattern, established using the “loperamide + tail-clamping provocation method,” to explore the effects of LTD on fecal characteristics, intestinal motility, and colonic pathology. Importantly, LTD exhibited the ability to increase the richness, diversity, and homogeneity of intestinal flora while also modulating the composition of microorganisms. It significantly increased the production of SCFAs, especially butyric acid. Moreover, LTD exerted a substantial influence on the synthesis of serotonin (5-HT) by modulating the expression of tryptophan hydroxylase (TPH) and interacting with the 5-HT4 receptor (5-HT4R), resulting in enhanced colonic motility. Correlation analyses revealed a positive correlation between certain bacterial genera, such as Lachnospiraceae_NK4A136 spp. and Clostridiales spp. and the concentrations of butyric acid and 5-HT. These results suggest a mechanistic link between microbiome composition, SCFAs production, and 5-HT synthesis. These findings highlight the potential of LTD to alleviate STC by facilitating a beneficial interplay among intestinal flora, SCFAs production, and 5-HT-mediated colonic motility, providing novel insights into the management of STC with Qi Stagnation Pattern.

BackgroundBipolar disorder (BD) is a complex and serious psychiatric condition primarily characterized by bipolar depression, with the underlying genetic determinants yet to be elucidated. There is a substantial body of literature linking psychiatric disorders, including BD, to oxidative stress (OS). Consequently, this study aims to assess the relationship between BD and OS by identifying key hub genes implicated in OS pathways.MethodsWe acquired gene microarray data from GSE5392 through the Gene Expression Omnibus (GEO). Our approach encompassed differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Protein-Protein Interaction (PPI) Network analysis to pinpoint hub genes associated with BD. Subsequently, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to identify hub genes relevant to OS. To evaluate the diagnostic accuracy of these hub genes, we performed receiver operating characteristic curve (ROC) analysis on both GSE5388 and GSE5389 datasets. Furthermore, we conducted a study involving ten BD patients and ten healthy controls (HCs) who met the special criteria, assessing the expression levels of these hub genes in their peripheral blood mononuclear cells (PBMCs).ResultsWe identified 411 down-regulated genes and 69 up-regulated genes for further scrutiny. Through WGCNA, we obtained 22 co-expression modules, with the sienna3 module displaying the strongest association with BD. By integrating differential analysis with genes linked to OS, we identified 44 common genes. Subsequent PPI Network and WGCNA analyses confirmed three hub genes as potential biomarkers for BD. Functional enrichment pathway analysis revealed their involvement in neuronal signal transduction, oxidative phosphorylation, and metabolic obstacle pathways. Using the Cytoscape plugin “ClueGo assay,” we determined that a majority of these targets regulate neuronal synaptic plasticity. ROC curve analysis underscored the excellent diagnostic value of these three hub genes. Quantitative reverse transcription-PCR (RT-qPCR) results indicated significant changes in the expression of these hub genes in the PBMCs of BD patients compared to HCs.ConclusionWe identified three hub genes (TAC1, MAP2K1, and MAP2K4) in BD associated with OS, potentially influencing the diagnosis and treatment of BD. Based on the GEO database, our study provides novel insights into the relationship between BD and OS, offering promising therapeutic targets.

Abstract Background There is an increasing number of cases of aldosterone- and cortisol-producing adenomas (A/CPAs) reported in the context of primary aldosteronism (PA). Most of these patients have PA complicated with subclinical Cushing's syndrome; cases of apparent Cushing's syndrome (CS) complicated with aldosteronism are less reported. However, Co-secretory tumors were present in the right adrenal gland, a cortisol-secreting adenoma and an aldosterone-producing nodule (APN) were present in the left adrenal gland, and aldosterone-producing micronodules (APMs) were present in both adrenal glands, which has not been reported. Here, we report such a case, offering profound insight into the diversity of clinical and pathological features of this disease. Case presentation The case was a 45-year-old female from the adrenal disease diagnosis and treatment centre in West China Hospital of Sichuan University. The patient presented with hypertension, moon-shaped face, central obesity, fat accumulation on the back of the neck, disappearance of cortisol circadian rhythm, ACTH 30 (ng/dL)/(ng/mL/h), and plasma aldosterone concentration > 10 ng/dL after saline infusion testing. Based on the above, she was diagnosed with non-ACTH-dependent CS complicated with PA. Adrenal vein sampling showed no lateralization for cortisol and aldosterone secretion in the bilateral adrenal glands. The left adrenocortical adenoma was removed by robot-assisted laparoscopic resection. However, hypertension, fatigue and weight gain were not alleviated after surgery; additionally, purple striae appeared in the lower abdomen, groin area and inner thigh, accompanied by systemic joint pain. One month later, the right adrenocortical adenoma was also removed. CYP11B1 were expressed in the bilateral adrenocortical adenomas, and CYP11B2 was also expressed in the right adrenocortical adenomas. APN existed in the left adrenal gland and APMs in the adrenal cortex adjacent to bilateral adrenocortical adenomas. After another surgery, her serum cortisol and plasma aldosterone returned to normal ranges, except for slightly higher ACTH. Conclusions This case suggests that it is necessary to assess the presence of PA, even in CS with apparent symptoms. As patients with CS and PA may have more complicated adrenal lesions, more data are required for diagnosis.

Abstract Wheat yellow mosaic virus (WYMV), a soil-borne pathogen, poses a serious threat to global wheat production. Here, we identify a WYMV resistance gene, TaRD21A, that belongs to the papain-like cysteine protease family. Through genetic manipulation of TaRD21A expression, we establish its positive role in the regulation of wheat to WYMV resistance. Furthermore, our investigation shows that the TaRD21A-mediated plant antiviral response relies on the release of a small peptide catalyzed by TaRD21A protease activity. To counteract wheat resistance, WYMV-encoded nuclear inclusion protease-a (NIa) suppress TaRD21A activity to promote virus infection. In resistant cultivars, a natural variant of TaRD21A features a alanine to serine substitution and this substitution enables the phosphorylation of Serine, thereby weakening the interaction between NIa and TaRD21A, reinforcing wheat resistance against WYMV. Our study not only unveils a WYMV resistance gene but also offers insights into the intricate mechanisms underpinning resistance against WYMV.

We applied 24-h Holter monitoring to analyze the characteristics of arrhythmias and heart rate variability in Chinese patients with primary aldosteronism (PA) and compared them with age-, sex-, and blood pressure-matched primary hypertension (PH) patients. A total of 216 PA patients and 261 PH patients were enrolled. The nonstudy data were balanced using propensity score matching (PSM), and the risk variables for developing arrhythmias were then analyzed using logistic regression analysis. Before PSM, the proportion of PA patients with combined atrial premature beats and prolonged QT interval was higher than the corresponding proportion in the PH group. After PSM, the PA group had a larger percentage of transient atrial tachycardia and frequent atrial premature beats, and it had higher heart rate variability metrics. The proportion of unilateral PA combined with multiple ventricular premature beats was higher than that of bilateral PA. Older age, grade 3 hypertension, and hypokalemia were independent risk factors for the emergence of arrhythmias in PA patients. PA patients suffer from a greater prevalence of arrhythmias than well-matched PH patients.

Abstract Background The presence of Aggregated Lymphoid Nodules Area (ALNA) is a notable anatomical characteristic observed in the abomasum of Bactrian camels. This area is comprised of two separate regions, namely the Reticular Mucosal Folds Region (RMFR) and the Longitudinal Mucosal Folds Region (LMFR). The histological properties of ALNA exhibit significant similarities to those of Peyer’s patches (PPs) found in the gastrointestinal system. The functional characteristics of ALNA were examined in relation to mucosal immunity in the gastrointestinal system. Results We used iTRAQ-based proteomic analysis on twelve Bactrian camels to measure the amount of proteins expressed in ALNA. In the experiment, we sampled the RMFR and LMFR separately from the ALNA and compared their proteomic quantification results with samples from the PPs. A total of 1253 proteins were identified, among which 39 differentially expressed proteins (DEPs) were found between RMFR and PPs, 33 DEPs were found between LMFR and PPs, and 22 DEPs were found between LMFR and RMFR. The proteins FLNA, MYH11, and HSPB1 were chosen for validation using the enzyme-linked immunosorbent assay (ELISA), and the observed expression profiles were found to be in agreement with the results obtained from the iTRAQ study. The InnateDB database was utilized to get data pertaining to immune-associated proteins in ALNA. It was observed that a significant proportion, specifically 76.6%, of these proteins were found to be associated with the same orthogroups as human immune-related genes. These proteins are acknowledged to be associated with a diverse range of functions, encompassing the uptake, processing and presentation of antigens, activation of lymphocytes, the signaling pathways of T-cell and B-cell receptors, and the control of actin polymerization. Conclusions The experimental results suggest that there are parallels in the immune-related proteins found in ALNA and PPs. Although there are variations in the structures of LMFR and RMFR, the proteins produced in both structures exhibit a high degree of similarity and perform comparable functions in the context of mucosal immune responses.

Abstract Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

Abstract Background Primary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient. Case presentation A 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died. Conclusion Cushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice.

Abstract Accurate quantification of the absorption properties of brown carbon (BrC) aerosols is crucial to assess the Earth‐atmosphere radiative impacts of BrC. However, the BrC absorption properties were often misestimated in field observations, due to neglecting the contribution of dust absorption. This study solved this problem by coupling a method for calculating the dust concentration into the traditional model for quantifying BrC absorption. The results show that dust absorption was up to 16.8% of the sum of BrC and dust absorption in northwestern China. The potential contribution of dust to the sum of BrC and dust absorption was significantly higher in the Asia‐located studies (0.4%–16.8%) than in the Americas‐located (

Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with cardiorenal vascular diseases. Prolonged hyperglycemia induces renal endothelial dysfunction and damage via metabolic abnormalities, inflammation, and oxidative stress, thereby compromising hemodynamics. Concurrently, fibrotic and sclerotic alterations exacerbate glomerular and tubular injuries. At a macro level, reciprocal communication between the renal microvasculature and systemic circulation establishes a pernicious cycle propelling disease progression. The current management approach emphasizes rigorous control of glycemic levels and blood pressure, with renin-angiotensin system blockade conferring renoprotection. Novel antidiabetic agents exhibit renoprotective effects, potentially mediated through endothelial modulation. Nonetheless, emerging therapies present novel avenues for enhancing patient outcomes and alleviating the disease burden. A precision-based approach, coupled with a comprehensive strategy addressing global vascular risk, will be pivotal in mitigating the cardiorenal burden associated with diabetes.

This study identified the metabolic biomarkers for different clinical phases of bipolar disorder (BD) through metabolomics. BD patients were divided into three groups: patients with BD and depressive episodes (BE, n = 59), patients with BD and mania/hypomania episodes (BH, n = 16), patients with BD and mixed episodes (BM, n = 10), and healthy controls (HC, n = 10). Serum from participants was collected for metabolomic sequencing, biomarkers from each group were screened separately by partial least squares analysis, and metabolic pathways connected to the biomarkers were identified. Compared with the controls, 3-D-hydroxyacetic acid and N-acetyl-glycoprotein showed significant differences in the BE, BH, and BM groups. This study suggests that different clinical types of BD share the same metabolic pathways, such as pyruvate, glycolysis/gluconeogenesis, and ketone body metabolisms. In particular, abnormal glycine, serine, and threonine metabolism was specific to BM; β-glucose, glycerol, lipids, lactate, and acetoacetate metabolites were specific to depressive episodes; the guanidine acetic acid metabolites specific to BH; and the acetic and ascorbic acids were metabolites specific to manic and BM. We screened potential biomarkers for different clinical phases of BD, which aids in BD typing and provides a theoretical basis for exploring the molecular mechanisms of BD.

Abstract The region surrounding the Tibetan Plateau (TP) is widely considered a primary global dust source, with mineral dust comprising a significant proportion of aerosols over the TP. Current research on TP dust has mainly focused on transport from the surrounding deserts, with little focus on dust emissions from the TP's interior. The erodibility factor used by the WRF‐Chem (ERODDEF) is 0 for the TP, so the model cannot simulate the dust emissions inside the plateau. Thus, we constructed a high‐resolution erodibility data set (ERODSDS) based on a reliable dust source distribution and intensity map. Based on the modified EROD map, the WRF‐Chem model was used to simulate dust emissions and direct radiative forcing on the TP in 2018. With the modified EROD map, WRF‐Chem can well simulate the temporal variation and spatial pattern of mineral dust on the plateau, which greatly improves the model's dust emissions simulation accuracy on the TP.

BackgroundThere is a correlation between obesity and 25-hydroxyvitamin D (25OHD) that tends to be negative. However, this relationship varies among different races. In this study, Asian adults with and without obesity were compared in terms of their levels of 25OHD.MethodsWe carried out a cross-sectional analysis on 2664 non-Hispanic Asian adults who participated in the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2018. To examine the connection between obese status, body mass index (BMI), waist circumference (WC) and weight, and 25OHD, we ran multivariate linear regression models and multivariate logistic regression models.ResultsAfter adjusting for all confounding factors, obesity status shows a significant positive correlation with vitamin D deficiency (model 3: OR = 2.318, 95% CI:1.317, 4.082). This positive correlation remains significant in males (males: OR = 2.713, 95% CI: -13.398, 5.217). In all three models, a negative association was observed between obesity status and 25OHD (model 1: β = -4.535, 95% CI: -6.987, -2.083; model 2 β = -4.249, 95% CI: -6.549, -2.039; model 3 β = -1.734, 95% CI: -7.285, 3.816). After controlling for covariates, there was a significant negative correlation between WC and 25OHD when stratified by gender and obesity status in both males with and without obesity (males with obesity: β = -1.461, 95% CI: -2.485, -0.436; males without obesity: β = -0.855. 95% CI: -1.499, -0.210). In males with obesity, there was a very strong positive connection between body weight and 25OHD (β = 0.912, 95% CI: 0.227, 1.597). In addition, neither gender's obese individuals showed a significant link between BMI and 25OHD.ConclusionThis study demonstrated a positive correlation between obesity and vitamin D deficiency and a negative correlation between obesity and 25OHD in Asian American adults. Additionally, among male obese individuals, there was a significant negative correlation between WC and 25OHD, an observation that needs to be validated in further prospective studies.

PurposeTo compare the ability of diffusion parameters obtained by stretched-exponential and kurtosis models of diffusion-weighted imaging (DWI) to distinguish between patients with primary aldosteronism (PA) and healthy controls (HCs) in renal assessment.Materials and methodsA total of 44 participants (22 patients and 22 HCs) underwent renal MRI with an 11 b-value DWI sequence and a 3 b-value diffusion kurtosis imaging (DKI) sequence from June 2021 to April 2022. Binary logistic regression was used to construct regression models combining different diffusion parameters. Receiver-operating characteristic (ROC) curve analysis and comparisons were used to evaluate the ability of single diffusion parameters and combined diffusion models to distinguish between the two groups.ResultsA total of six diffusion parameters (including the cortical anomalous exponent term [α_Cortex], medullary fractional anisotropy [FA_Medulla], cortical FA [FA_Cortex], cortical axial diffusivity [Da_Cortex], medullary mean diffusivity [MD_Medulla] and medullary radial diffusivity [Dr_Medulla]) were included, and 10 regression models were studied. The area under the curve (AUC) of Dr_Medulla was 0.855, comparable to that of FA_Cortex and FA_Medulla and significantly higher than that of α_Cortex, Da_Cortex and MD_Medulla. The AUC of the Model_all parameters was 0.967, comparable to that of Model_FA (0.946) and Model_DKI (0.966) and significantly higher than that of the other models. The sensitivity and specificity of Model_all parameters were 87.2% and 95%, respectively.ConclusionThe Model_all parameters, Model_FA and Model_DKI were valid for differentiating between PA patients and HCs with similar differentiation efficacy and were superior to single diffusion parameters and other models.

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients’ prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs).Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was evaluated.Results: Among the patients taking immunosuppressive medication, PI was observed in 548 (6.9%). The median time of PI occurrence after immunosuppressive therapy was 123.0 (interquartile range: 63.0, 436.0) days. Thirteen statistically significant independent predictors (sex, age, hypertension, DM, malignant tumour, use of biologics, use of CNIs, use of methylprednisolone at 500 mg, use of methylprednisolone at 40 mg, use of methylprednisolone at 40 mg total dose, use of oral glucocorticoids, albumin level, and haemoglobin level) were screened using the LASSO algorithm and multivariate COX regression analysis. The PIP model built on these features performed reasonably well, with the developing C-index of 0.87 (sensitivity: 85.4%; specificity: 81.0%) and validation C-indices of 0.837, 0.829, 0.832 and 0.830 for predicting 90-, 180-, 270- and 360-day PI probability, respectively. The decision curve analysis (DCA) and calibration curves displayed excellent clinical utility and calibration performance of the nomogram.Conclusion: The PIP model presented herein could aid in the prediction of PI risk in individual patients who receive immunosuppressive treatment and help personalise clinical decision-making.

This study addresses the problem of prolonged precooling time and excessive weight loss of fruits and vegetables during postharvest processes. Ice slurry precooling system shows potential but faces challenges like low undercooling and ice blockage. Dispersants are introduced to optimize heat and moisture transfer as well as the flow characteristics of the ice slurry. This research investigates the effects of four dispersants on the performance of an ice slurry-based wet precooling system through experiments. Key parameters analyzed include temperature and humidity in the chamber, cooling rate, and weight loss rate of the tested load. Results show that the addition of dispersants effectively reduces the freezing temperature, enhancing the cooling rate in the system. Among the four dispersants tested, sodium diacetate yields the lowest freezing temperature of −6.4 °C and the highest cooling rate of 0.3 °C min−1. Furthermore, dispersants influence moisture transfer between ice slurry and circulating air, impacting the humidity within the precooling chamber. Notably, the addition of sodium diacetate results in the lowest weight loss rate of 2.74 %. This research shows the potential of using dispersants in ice slurry-based wet precooling systems to enhance the postharvest preservation of fruits and vegetables.

Introduction: MicroRNAs (miRNAs) play a crucial role in regulating gene expression during key developmental processes, including fetal development. Brahman (Bos taurus indicus) and Angus (Bos taurus taurus) cattle breeds represent two major cattle subspecies with strikingly different phenotypes.Methods: We analyzed miRNA expression in liver samples of purebred and reciprocal crosses of Angus and Brahman to investigate breed and parent-of-origin effects at the onset of accelerated fetal growth.Results: We identified eight novel miRNAs in fetal liver samples and 14 differentially expressed miRNAs (DEMs) between purebred samples. Correlation of gene expression modules and miRNAs by breed and parent-of-origin effects revealed an enrichment of genes associated with breed-specific differences in traits such as heat tolerance (Brahman) and fat deposition (Angus). We demonstrate that genes predicted to be targets of DEMs were more likely to be differentially expressed than non-targets (p-value < 0.05). We identified several miRNAs (bta-miR-187, bta-miR-216b, bta-miR-2284c, bta-miR-2285c, bta-miR-2285cp, bta-miR-2419-3p, bta-miR-2419-5p, and bta-miR-11984) that showed similar correlation patterns as bta-miR-2355-3p, which has been associated with the glutamatergic synapse pathway, a key facilitator of heat tolerance. Furthermore, we report Angus-breed-specific miRNAs (bta-miR-2313-5p, btamiR-490, bta-miR-2316, and bta-miR-11990) that may be involved in fat deposition. Finally, we showed that the DEMs identified in fetal liver are involved in Rap1, MAPK, and Ras signalling pathways, which are important for fetal development, muscle development and metabolic traits such as fat metabolism.Conclusion: Our work sheds light on the miRNA expression patterns that contribute to gene expression differences driving phenotypic differences in indicine and taurine cattle.

Abstract Background Maternal history of adverse childhood experiences (ACEs) has been found to be associated with children’s health outcomes. However, the underlying mechanisms were unclear. This study aimed to examine the association between maternal ACEs and behavioral problems in their preschool offspring and to explore the potential mediating role of maternal parenting styles in the association. Methods A cross-sectional study was conducted involving 4243 mother-child dyads in Chengdu, China. Mothers completed the Adverse Childhood Experiences-International Questionnaire (ACE-IQ) to assess their history of ACEs (i.e., physical abuse, emotional abuse, physical neglect, emotional neglect, witnessing domestic violence, household substance abuse, household mental illness, incarcerated household member, parental separation or divorce, parental death, bullying, and community violence), the short Egna Minnen Beträffande Uppfostran Parent Form (S-EMBU-P) to evaluate their parenting styles (i.e., emotional warmth, rejection, and overprotection), and the 48-item Conners’ Parent Rating Scale (CPRS-48) to measure behavioral problems in their children. Logistic regression models were established to examine the association between cumulative number of maternal ACEs and children’s behavioral problems. The mediating role of parenting styles in this association was explored by generalized structural equation models (GSEM). Results Of the participating mothers, 85.8% (n = 3641) reported having experienced at least one type of ACE. Children of mothers with ≥2 ACEs showed a significantly increased risk of behavioral problems across all dimensions, including conduct problems, learning problems, psychosomatic problems, impulsive-hyperactive, anxiety, and hyperactivity index, in both crude and adjusted models (all p-values

Introduction Diabetic nephropathy (DN) is a leading cause of kidney failure. Lysozyme (LYZ) is an essential component of innate immunity and exhibits antibacterial properties. However, LYZ has been reported to induce nephropathy, implying a possible association between impaired renal function and lysozyme expression. Material and methods Bioinformatics analysis was used to predict the hub gene associated with DN, and the differential expression of the hub gene was confirmed using a mouse model. A mouse model of streptozotocin (STZ)-induced diabetic nephropathy was established to investigate the correlation between DN and LYZ expression, and the functionality of LYZ was verified through knockdown and overexpression experiments conducted in vivo. Immunohistochemistry (IHC) was utilized to assess fibrosis-related markers and cytokines, while Masson staining was performed to assess renal fibrosis. Fibroblast proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay. The role of the JAK pathway was confirmed using the JAK inhibitor AG490, and Western blot was used to investigate the underlying mechanisms. Results Mechanistically, 25 mM glucose promotes the expression of LYZ in fibroblastic cells, and LYZ may in turn promote the proliferation of renal interstitial fibroblasts. Western blot shows that glucose can activate STAT3 in an LYZ-dependent manner, and the JAK inhibitor AG490 can partially suppress LYZ-induced STAT3 activation. Furthermore, in vivo observations have revealed that overexpression of LYZ is associated with the senescent phenotype of renal tubular epithelial cells (RTECs). Conclusions Lysozyme promotes kidney fibrosis via the JAK/STAT3 signaling pathway in diabetic nephropathy, and glucose may promote fibroblast proliferation by promoting LYZ auto-secretion.

Abstract. Background:. Stroke is the leading cause of death in China, and predicting the stroke burden could provide essential information guiding the setting of medium- and long-term health policies and priorities. The study aimed to project trends associated with stroke burden in China through 2050, not only in terms of incidence and mortality but also for prevalence and disability-adjusted life years (DALYs). Methods:. Data on stroke rates in incidence, prevalence, deaths, and DALYs in China between 1990 and 2019 were obtained from a recent Global Burden of Disease study. Demographic-specific trends in rates over time were estimated using three models: the loglinear model, the Lee-Carter model, and a functional time series model. The mean absolute percentage error and the root mean squared error were used for model selection. Projections up to 2050 were estimated using the best fitting model. United Nations population data were used to project the absolute numbers through 2050. Results:. From 2019 to 2050, the crude rates for all measures of the stroke burden are projected to increase continuously among both men and women. We project that compared with those in 2019, the incidence, prevalence, deaths, and DALYs because of stroke in China in 2050 will increase by 55.58%, 119.16%, 72.15%, and 20.04%, respectively; the corresponding increases in number were 2.19, 34.27, 1.58, and 9.21 million. The age-standardized rate is projected to substantially decline for incidence (8.94%), death (40.37%), and DALYs (43.47%), but the age-standardized prevalence rate is predicted to increase by 10.82%. By 2050, the burden of stroke among the population aged ≥65 years will increase significantly: by 104.70% for incidence, by 218.48% for prevalence, by 100.00% for death, and by 58.93% for DALYs. Conclusions:. With the aging population in China increasing over the next three decades, the burden of stroke will be markedly increased. Continuous efforts are needed to improve stroke health care and secondary prevention, especially for older adults.

Wheat tiller angle (TA) is an important agronomic trait that contributes to grain production by affecting plant architecture. It also plays a crucial role in high-yield wheat breeding. An association panel and a recombinant inbred line (RIL) population were used to map quantitative trait loci (QTL) for TA. Results showed that 470 significant SNPs with 10.4%–28.8% phenotypic variance explained (PVE) were detected in four replicates by a genome-wide association study (GWAS). Haplotype analysis showed that the TA_Hap_4B1 locus on chromosome 4B was a major QTL to regulate wheat TA. Ten QTL were totally detected by linkage mapping with the RIL population, and QTA.hau-4B.1 identified in six environments with the PVE of 7.88%–18.82% was a major and stable QTL. A combined analysis demonstrated that both TA_Hap_4B1 and QTA.hau-4B.1 were co-located on the same region. Moreover, QTA.hau-4B.1 was confirmed by bulked segregant RNA-Seq (BSR-Seq) analysis. Phenotypic analysis showed that QTA.hau-4B.1 was also closely related to yield traits. Furthermore, TraesCS4B02G049700 was considered as a candidate gene through analysis of gene sequence and expression. This study can be potentially used in cloning key genes modulating wheat tillering and provides valuable genetic resources for improvement of wheat plant architecture.

Introduction: Several approaches to expand human hematopoietic stem cells (HSCs) have been reported, but the ability of these methods to expand long-term hematopoietic stem cells (LT-HSCs) remains to be improved, which limits the application of HSCs-based therapies. Methods: CD34+ cells were purified from umbilical cord blood using MacsCD34 beads, and then cultured for 12 d in a serum-free medium. Flow cytometry was used to detect phenotype, cell cycle distribution, and apoptosis of the cultured cells. Colony-forming cell (CFC) assays can evaluate multi-lineage differentiation potential of HSCs. Real-time polymerase chain reaction was employed to detect the expression of genes related to self-renewal programs and antioxidant activity. DCFH-DA probes were used to evaluate intracellular production of reactive oxygen species (ROS). Determination of the effect of different culture conditions on the balance of cytokine by cytometric bead array. Results: Here, we show a combination, Nicotinamide (NAM) combined with pyrimidoindole derivative UM171, can massively expand LT-HSCs ex vivo, and the expanded cells maintained the capability of self-renewal and multilineage differentiation. Additionally, our data indicated that UM171 promoted self-renewal of HSCs by inducing HSCs entry into the cell cycle and activating Notch and Wnt pathways, but the infinite occurrence of this process may lead to mitochondrial metabolism disorder and differentiation of HSCs. NAM kept HSCs in their primitive and dormant states by reducing intracellular ROS levels and upregulating the expression of stemness related genes, so we believed that NAM can act as a brake to control the above process. Conclusions: The discovery of the synergistic effect of NAM and UM171 for expanding LT-HSCs provides a new strategy in solving the clinical issue of limited numbers of HSCs.

Abstract The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

Abstract Introduction This study conducted an ethnobotanical survey of wild medicinal plants in the multi-ethnic areas of Gansu–Ningxia–Inner Mongolia intersection zone. Traditional knowledge of medicinal plant use in the region was compiled to identify important medicinal plants currently used for treating relevant diseases and to determine species with potential for development. Methods Key informant interviews, semi-structured interviews, participatory rural appraisal methods, and ethnobotanical quantitative evaluation were used to investigate and study the traditional knowledge of local residents' use of wild medicinal plants in the region. The relative importance of the referenced plants was assessed, as well as the prominent species widely used in medicinal applications. Results The study found that the region has a total of 204 wild medicinal plant resources, belonging to 149 genera of 51 families. Among these resources, a total of 50 commonly used plants were identified (44 of which were herbs, some of which were multi-origin), belonging to 27 families, with the most species found in the Asteraceae family, with 11 species. These herbs are mainly used for preventing and treating colds and nourishing health, followed by treatment of fever, stomach problems, and bleeding. The most frequently used medicinal plant in the region is “Ai”, which includes Artemisia argyi Lévl. et Van. and Artemisia kanashiroi Kitam. All respondents provided information about the use of this medicinal plant to varying degrees, followed by Artemisia annua Linn., Ephedra sinica Stapf, Taraxacum mongolicum Hand.-Mazz., Sonchus arvensis Linn., Artemisia capillaris Thunb., among others. Conclusion Our investigation gained a wealth of traditional knowledge about the use of wild herbs, using wild herbs, which plays an important role in the lives of local residents. Especially, the herbs and application methods used for treating colds, bleeding, and stomach problems are worthy of further research and development.

Abstract The Iso-Seq method of full-length cDNA sequencing is suitable to quantify differentially expressed genes (DEGs), transcripts (DETs) and transcript usage (DTU). However, the higher cost of Iso-Seq relative to RNA-seq has limited the comparison of both methods. Transcript abundance estimated by RNA-seq and deep Iso-Seq data for fetal liver from two cattle subspecies were compared to evaluate concordance. Inter-sample correlation of gene- and transcript-level abundance was higher within technology than between technologies. Identification of DEGs between the cattle subspecies depended on sequencing method with only 44 genes identified by both that included 6 novel genes annotated by Iso-Seq. There was a pronounced difference between Iso-Seq and RNA-seq results at transcript-level wherein Iso-Seq revealed several magnitudes more transcript abundance and usage differences between subspecies. Factors influencing DEG identification included size selection during Iso-Seq library preparation, average transcript abundance, multi-mapping of RNA-seq reads to the reference genome, and overlapping coordinates of genes. Some DEGs called by RNA-seq alone appear to be sequence duplication artifacts. Among the 44 DEGs identified by both technologies some play a role in immune system, thyroid function and cell growth. Iso-Seq revealed hidden transcriptional complexity in DEGs, DETs and DTU genes between cattle subspecies previously missed by RNA-seq.

Introduction: Traditional animal- and mineral-based medicines are widely used in the Gansu-Ningxia-Inner Mongolia junction zone, a region with diverse ethnic groups and cultures. This study aims to document, conserve, and explore the potential of these medicines for further research and sustainable development of ethnic medicine.Methods: We interviewed 56 informants from different ethnic backgrounds and analyzed their responses quantitatively. Additionally, a comparative analysis with adjacent regions was conducted, providing invaluable contextual insights.Results: The study unveiled a diverse array of traditional medicines in the Gansu-Ningxia-Inner Mongolia junction zone. A total of 47 animal-based medicines were identified, ranging from insects and scorpios to distinctive animal organs. Of notable significance was Moschus, emerging as a pivotal traditional Chinese medicine resource. In parallel, 12 mineral-based medicines were cataloged, procured both locally and from “pharmacies”. Female informants, frequently local herbal practitioners, demonstrated broader knowledge of medicines. The analysis of 13 villages revealed varying perceptions of medicine importance, underscoring the wealth of traditional knowledge. Specific medicines, such as Feng-Mi and Xie-Zi, were widely used and valued in local healthcare practices for their cultural and medicinal benefits.Conclusion: This study provides a comprehensive overview of traditional animal- and mineral-based medicines in the Gansu-Ningxia-Inner Mongolia junction zone. It highlights the need for preserving and applying these practices in a sustainable manner. It also lays a solid foundation for future research on ethnic medicine, which can contribute to the holistic wellbeing of local communities.

In vitro regeneration was studied to protect the rare Chinese medicinal orchid Liparis nervosa (Thunb.) Lindl. The mixtures of protocorm and seeding and the stem tip were used as explants. The results revealed that the best essential medium for L. nervosa growth was 1/3 MS medium with 25 g · L–1 sucrose, 50 g · L–1 banana puree, 40 g · L–1 mashed potato, and 1.0 g · L–1 AC (MS1); MS1 medium with 0.5 mg · L–1 BA, 0.05 mg · L–1 2,4-D, and 1.5 mg · L–1 NAA was optimal for proliferation. When stem tips were cultured in a proliferation medium, four types of proliferation occurred: basal stem cluster bud (occurring at the basal node), tiller bud (occurring at the root), protocorm-like body (occurring at the plant’s base incision), and high-position bud (occurring on plant stem nodes other than the basal nodes). Four methods produced 10.12 proliferation coefficients. In the MS1 medium with 0.5 mg · L−1 NAA, the plantlets rooted 100%, and the rooted plantlets survived 100% after domestication and transplantation.

ObjectivesThis study aimed to investigate the individual and joint associations of sedentary behaviour, physical activity (PA), sleep and breakfast eating on health-related quality of life (HRQoL) amongst Chinese junior high school students.MethodsData were from 783 junior high school students who participated in a health behaviour and health survey in Jining city of Shandong province of China. HRQoL was measured by the EuroQol five-dimensional questionnaire, youth version (EQ-5D-Y). Multivariable logistic and linear regressions were applied to examine the associations between health behaviours and HRQoL.ResultsMultivariable regression analyses showed that using a computer ≥ 2 h a day (vs. < 2 h/day) is associated with increased likelihood of having health problems in the three EQ-D-Y dimensions, including walking, looking after self and doing usual activities. Lower PA is associated with more problems in feeling worried, sad or unhappy, and with a lower visual analogue scale (VAS) score. Students who had insufficient sleep time (e.g.,

Bromadiolone, as a second-generation coumarin anticoagulant rodenticide, may accidently cause harm to humans and non-target animals when overused or misused due to its high toxicity and long-lasting effects. In some severe cases such as the presence of active bleeding, treatment should involve the administration of hemoperfusion therapy. Nafamostat mesylate is a synthesized protease inhibitor that inhibits most factors in the coagulation process, preventing clotting and ensuring smooth blood flow during the procedure. Nafamostat mesylate helps maintain the efficacy and safety of hemoperfusion treatment. Despite its wide application in Japan, the clinical practice and research of nafamostat mesylate are limited in China, especially for patients undergoing maintenance hemodialysis. This paper reports two cases of bromadiolone poisoning and describes the treatment procedure and therapeutic effect of anticoagulation in hemoperfusion therapy with nafamostat mesylate.

ObjectiveBipolar disorder (BD) and major depressive disorder (MDD) are two common psychiatric disorders. Due to the overlapping clinical symptoms and the lack of objective diagnostic biomarkers, bipolar disorder (BD) is easily misdiagnosed as major depressive disorder (MDD), which in turn affects treatment decisions and prognosis. This study aimed to investigate biomarkers that could be used to differentiate BD from MDD.MethodsNuclear magnetic resonance (NMR) spectroscopy was performed to assess serum metabolic profiles in depressed patients with BD (n = 59), patients with MDD (n = 14), and healthy controls (n = 10). Data was analyzed using partial least squares discriminant analysis, orthogonal partial least squares discriminant analysis and t-tests. Different metabolites (VIP > 1 and p < 0.05) were identified and further analyzed using Metabo Analyst 5.0 to identify relevant metabolic pathways.ResultsThe metabolic phenotypes of the BD and MDD groups were significantly different from those of the healthy controls, and there were different metabolite differences between them. In the BD group, the levels of 3-hydroxybutyric acid, n-acetyl glycoprotein, β-glucose, pantothenic acid, mannose, glycerol, and lipids were significantly higher than those in the healthy control group, and the levels of lactate and acetoacetate were significantly lower than those in the healthy control group. In the MDD group, the levels of 3-hydroxybutyric acid, n-acetyl glycoprotein, pyruvate, choline, acetoacetic acid, and lipids were significantly higher than those of healthy controls, and the levels of acetic acid and glycerol were significantly lower than those of healthy controls.ConclusionGlycerolipid metabolism is significantly involved in BD and MDD. Pyruvate metabolism is significantly involved in MDD. Pyruvate, choline, and acetate may be potential biomarkers for MDD to distinguish from BD, and pantothenic acid may be a potential biomarker for BD to distinguish from MDD.

Abstract Background Cancer is mostly a disease of aging, and older patients with cancer are generally frailer. This study aimed to describe the characteristics and in‐hospital outcomes and explore factors associated with duration, cost, and mortality during first hospitalization, in older patients with cancer admitted to a top‐ranked hospital in China. Methods Data on patients with solid cancer ≥65 years consecutively hospitalized in 2016–2020 were retrieved from the electronic medical records of Ruijin Hospital in Shanghai, China. Baseline characteristics, duration, cost, and mortality during hospitalization were described. Factors associated with duration, cost, and mortality during first hospitalization were explored using multivariable‐adjusted logistic regression. Results 20,650 eligible patients with male proportion of 59% and median age of 70 years were analyzed. 45% of the patients underwent resection in our hospital. Upon first admission, 49% of patients had hypertension, 19% diabetes, 22% weight loss, and 28% risks of malnutrition. The median duration and cost of first hospitalization were 9 days and 32,000 RMB, respectively. 118 (0.6%) and 228 (1.1%) deaths occurred during first and any hospitalization, respectively. For first hospitalization, longer duration and higher cost were positively associated with older ages, male gender, emergency admission, certain tumor locations and histology, histories of diabetes, cirrhosis, and anticoagulant intake, higher body mass index, weight loss, reduced food intake, risk of falling, and worse self‐care ability; in‐hospital mortality was positively associated with age ≥85 years, emergency admission, certain cancer types, histories of hypertension and psychotropic intake, reduced food intake, and worse self‐care ability. Conclusions This study identified certain baseline patient and tumor characteristics, medical and medication histories, changes of weight and food intake, diet, and self‐care ability which were independently associated with in‐hospital outcomes among older patients with cancer admitted to our hospital and which should be paid special attention to. While the factors might not be easily modifiable, our study can help identify patients at higher risks of inferior in‐hospital outcomes.

Abstract Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have made great successes in clinical diagnosis, medical research, and neurological science. MRI provides high resolution anatomical images of tissues/organs, and MRS provides information of the functional molecules related to a specific tissue/organ. However, it is difficult for classic MRI/MRS to selectively image/probe a specific metabolite molecule other than the water or fat in tissues/organs. This greatly limits their applications on the study of the molecular mechanism(s) of metabolism and disease. Herein, we report a series of molecularly targeted MRI/MRS methods to target specific molecules. The optimal control method was used to efficiently prepare the singlet spin orders of varied multi-spin systems and in turn greatly expand the choice of the targeted molecules in the molecularly targeted MRI/MRS. Several molecules, such as N-acetyl-l-aspartic acid (NAA), dopamine (DA), and a tripeptide (alanine-glycine-glycine, AGG), have been used as targeted molecules for molecularly targeted MRI and MRS. We show in vivo NAA-targeted 1H MRS spectrum of a human brain. The high-resolution signal of NAA suggests a promising way to study important issues in molecular biology at the molecular level, e.g., measuring the local pH value of tissue in vivo, demonstrating the high potential of such methods in medicine.

Abstract Background The intergenerational association between maternal adverse childhood experiences (ACEs) and their children’s health-related quality of life (HRQOL) is underexplored. This study aimed to examine such association in Chinese preschool children and to test the moderation role of children’s sex. Methods A cross-sectional study was conducted among 4243 mother–child dyads who attended randomly selected preschools. Mothers self-reported their experience of 12 forms of ACEs, including emotional abuse, physical abuse, emotional neglect, physical neglect, intimate partner violence, substance abuse in the household, incarcerated household member, mental illness in household, parental death, parental separation or divorce, bullying, and community violence. Children’s HRQOL was evaluated through mother report of the Pediatric Quality of Life Inventory version 4.0. Linear regression models were established to estimate the associations between maternal ACEs and their children’s HRQOL sub-scores and total scores. Stratified analysis and test for interaction were further conducted to evaluate whether the associations were moderated by children’s sex. Results Of the included mothers, 85.8% (n = 3641) had reported exposure to at least one ACE, and 22.3% (n = 948) were exposed to three or more ACEs. Compared to children of mothers without any ACE exposure, those of mothers with 1, 2, or ≥ 3 ACEs all had significantly lower scores of physical, social, and school functioning, as well as lower psychosocial health summary score and total scale score in both crude and adjusted models. However, only children of mothers with two or more ACEs had significantly poorer emotional functioning when compared to their counterparts whose mothers had no ACE exposure. A significant dose-response pattern was also observed between the number of maternal ACEs and children’s HRQOL sub-scores and total scores. Stratified analysis revealed sex-specific pattern between maternal ACEs and their children’s HRQOL. Nonetheless, children’s sex was not a significant moderator. Conclusions Our study showed that preschool children of mothers who had any experience of ACEs were at risk of poorer HRQOL. Our findings indicated that screening maternal ACEs in young children and promoting targeted interventions might be a feasible way to mitigate or stop the potential negative intergenerational health and wellbeing implications of ACEs.