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Abstract Small extracellular vesicles (sEV) have emerged as a novel mode of intercellular material transport and information transmission. It has been suggested hormones may regulate the production and function of sEV. However, the specific impact of growth hormone-releasing hormone (GHRH) on pituitary sEV production and the role of sEV in the regulation of the GHRH-GH-IGF axis has not been previously reported. The results of the present study demonstrated that GHRH increased the production of pituitary sEV by promoting the expression of Rab27a. More importantly, GHRH induced alterations in protein and miRNA levels within GH3-sEV components. Notably, GH3-sEV with GHRH treatment exhibited the enhanced ability to impede BRL 3A cell proliferation and the expression of IGF-1. Conclusively, for the first time, we corroborate the influence of GHRH on pituitary sEV, thereby presenting novel evidence for how sEV participates in the balance of the GHRH-GH-IGF axis. Importantly, this study provides new insight into a novel balance mechanism mediated by sEV within the endocrine system. Graphical Abstract

Abstract Sea cucumbers are predominant deposit feeders in benthic ecosystems, providing protective benefits to coral reefs by reducing disease prevalence. However, how they receive sufficient nutrition from seabed sediments remains poorly understood. Here, we investigate Holothuria leucospilota, an ecologically significant tropical sea cucumber, to elucidate digestive mechanisms underlying marine deposit-feeding. Genomic analysis reveals intriguing evolutionary adaptation characterized by an expansion of digestive carbohydrase genes and a contraction of digestive protease genes, suggesting specialization in digesting microalgae. Developmentally, two pivotal dietary shifts, namely, from endogenous nutrition to planktonic feeding, and from planktonic feeding to deposit feeding, induce changes in digestive tract enzyme profiles, with adults mainly expressing carbohydrases and lipases. A nuanced symbiotic relationship exists between gut microbiota and the host, namely, specific resident bacteria supply crucial enzymes for food digestion, while other bacteria are digested and provide assimilable nutrients. Our study further identifies Holothuroidea lineage-specific lysozymes that are restrictedly expressed in the intestines to support bacterial digestion. Overall, this work advances our knowledge of the evolutionary innovations in the sea cucumber digestive system which enable them to efficiently utilize nutrients from seabed sediments and promote food recycling within marine ecosystems.

Abstract Ovarian cancer (OC) is one of the most prevalent and lethal gynecological malignancies, with high mortality primarily due to its aggressive nature, frequent metastasis, and resistance to standard therapies. Recent research has highlighted the critical role of extracellular vesicles (EVs) in these processes. EVs, secreted by living organisms and carrying versatile and bioactive cargoes, play a vital role in intercellular communication. Functionally, the transfer of cargoes orchestrates multiple processes that actively affect not only the primary tumor but also local and distant pre-metastatic niche. Furthermore, their unique biological properties position EVs as novel therapeutic targets and promising drug delivery systems, with potential profound implications for cancer patients. This review summarizes recent progress in EV biology, delving into the intricate mechanisms by which EVs contribute to OC metastasis and drug resistance. It also explores the latest advances and therapeutic potential of EVs in the clinical context of OC. Despite the progress made, EV research in OC remains in its nascent stages. Consequently, this review presents existing research limitations and suggests avenues for future investigation. Altogether, the review aims to elucidate the critical roles of EVs in OC and spotlight their promising potential in this field.

Abstract Background Ailanthone (Ail) extracted from medicinal plants has played an anticancer role in multiple cancers, while there is no research about Ail in renal cell carcinoma (RCC). Methods In the present study, we performed CCK-8 and flow cytometry to assess the effect of Ail on cell viability, apoptosis and cycle. We also performed tandem mass tags (TMT)-labeled quantitative proteomic technology and bioinformatic analysis to identify the functional pathway and proteins of Ail in RCC. Results The results showed Ail could inhibit cell viability and induce cell apoptosis. Proteomic profiling identified 1732 differentially expressed proteins in cells treated with Ail, compared to the negative control group. Gene ontology function annotation and Gene Set Enrichment Analysis (GSEA) were performed to identified the involved biological processes, molecular function and pathway. Results of GSEA proved the enrichment of Deps in EZH2 targets. The comparison between Deps and EZH2 co-expressed genes revealed 44 overlapped genes and we identified 4 hub genes (CDC20, CEP55, TOP2A, and UBE2C) associated with RCC progression. The molecular docking study revealed a moderate to tight binding potential of Ail and EZH2, and western blotting showed EZH2 was suppressed after cells treated with Ail. Conclusion Altogether, we identified the anticancer role of Ail in RCC, including inhibition of cell proliferation and induction of apoptosis. The results also screened the key proteins mediate the function of Ail, which have laid a theoretical foundation for elucidating the applications of Ail in clinical research.

Abstract Knee osteoarthritis (KOA) is a common chronic joint disease globally. Synovial inflammation plays a pivotal role in its pathogenesis, preceding cartilage damage. Identifying biomarkers in osteoarthritic synovial tissues holds promise for early diagnosis and targeted interventions. Gene expression profiles were obtained from the Gene Expression Omnibus database. Subsequent analyses included differential expression gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) on the combined datasets. We performed functional enrichment analysis on the overlapping genes between DEGs and module genes and constructed a protein–protein interaction network. Using Cytoscape software, we identified hub genes related to the disease and conducted gene set enrichment analysis on these hub genes. The CIBERSORT algorithm was employed to evaluate the correlation between hub genes and the abundance of immune cells within tissues. Finally, Mendelian randomization analysis was utilized to assess the potential of these hub genes as biomarkers. We identified 46 differentially expressed genes (DEGs), comprising 20 upregulated and 26 downregulated genes. Using WGCNA, we constructed a gene co-expression network and selected the most relevant modules, resulting in 24 intersecting genes with the DEGs. KEGG enrichment analysis of the intersecting genes identified the IL-17 signaling pathway, associated with inflammation, as the most significant pathway. Cytoscape software was utilized to rank the candidate genes, with JUN, ATF3, FOSB, NR4A2, and IL6 emerging as the top five based on the Degree algorithm. A nomogram model incorporating these five genes, supported by ROC curve analysis, validated their diagnostic efficacy. Immune infiltration and correlation analysis revealed that macrophages were significantly associated with JUN (p

Abstract Zingiber striolatum Diels is a unique medicine food homology plant native to China. In recent years, due to severe habitat destruction, studying the impact of climate change on the distribution of wild resources is of great significance for the ecological conservation and artificial cultivation of Z. striolatum. This study collected 141 valid species distribution records, and 37 environmental variables, and projected two future climate scenarios (SSP126 and SSP585) for two periods (2050s and 2090s). By employing Pearson analysis, Maximum Entropy Model (MaxEnt), and Geographic Information System (ArcGIS), we predicted the potential suitable habitats for Z. striolatum under present and future climates, as well as identified the dominant environmental variables influencing its distribution. The results indicated that the MaxEnt model performed well (AUC > 0.9) with high accuracy and reliability. The dominant environmental factors included Precipitation of driest quarter (39.0 ~ 473.8 mm), Precipitation of wettest quarter (593.2 ~ 1269.4 mm), Temperature annual range (9.8 ~ 28.6℃), and Mean diurnal range (6.5 ~ 9.6℃). The highly suitable areas for Z. striolatum were mainly distributed in western and southern Yunnan, northern and western Guangxi, Guangdong, Fujian, and central Hainan. Under future climate change, the centroid of the total suitable area for Z. striolatum is projected to shift towards the southwest (Yungui Plateau) at higher elevations.

The success of messenger RNA (mRNA) vaccines in controlling COVID-19 has warranted further developments in new technology. Currently, their quality control process largely relies on low-resolution electrophoresis for detecting chain breaks. Here, we present an approach using multi-primer reverse transcription sequencing (MPRT-seq) to identify degradation fragments in mRNA products. Using this in-house-made mRNA containing two antigens and untranslated regions (UTRs), we analyzed the mRNA completeness and degradation pattern at a nucleotide resolution. We then analyzed the sensitive base sequence and its correlation with the secondary structure. Our MPRT-seq mapping shows that certain sequences on the 5′ of bulge–stem–loop structures can result in preferential chain breaks. Our results agree with commonly used capillary electrophoresis (CE) integrity analysis but at a much higher resolution, and can improve mRNA stability by providing information to remove sensitive structures or sequences in the mRNA sequence design.

Abstract Globally, poverty and illness are linked, attracting widespread attention. In China, illness contributes to about 40% of rural poverty. This study sought to investigate how healthcare-seeking behavior differs between impoverished and non-impoverished populations within the same Chinese healthcare delivery system. It also sought to understand how differences should be considered when assessing spatial accessibility to provide more accurate recommendations for healthcare resource optimization and promote village revitalization and health equity in China. Methodologically, a survey conducted in May 2019 in Enshi Prefecture (a national impoverished region in Hubei Province, China) collected data on healthcare resource utilization regarding the inpatient and outpatient needs of both impoverished and non-impoverished populations. A Chi-square test compared their respective healthcare-seeking behaviors in three respects (e.g., preference for healthcare institution type, transportation mode, and travel time). Baidu Map data with healthcare institution locations and real-life travel times were then incorporated to assess spatial access to different types of healthcare institutions. Results showed that in Enshi, the most widespread village clinics (low-level) were generally the most utilized healthcare institutions for outpatient visits, with patients usually walking for about 30 min. The middle-level Township Health Centers (THCs) and high-level public hospitals were the most used for inpatient visits, with patients willing to drive up to 30 min to THCs and 60 min to hospitals. Comparatively, the impoverished have more frequent service demands but tend to choose lower-level healthcare institutions, with longer travel times and limited transportation modes. Although 75% of Enshi’s area was covered within 30 min by village clinics and 51% of the villages were within 60 min’ drive to hospitals, considerable areas remain under-served compared with the shortest travel time targets in China. In conclusion, spatial access to healthcare resources in Enshi must be further improved, especially by strengthening the service capacity of primary healthcare institutions to address the healthcare needs of Enshi’s impoverished population. The disparity in healthcare-seeking behavior between different population groups should be fully considered to effectively allocate limited healthcare resources to promote health equity for vulnerable populations as proposed in international and domestic policies.

Abstract Hyperlipidemia and hypertension might play a role in cardiac fibrosis, in which a heterogeneous population of fibroblasts seems important. However, it is unknown whether CD34+ progenitor cells are involved in the pathogenesis of heart fibrosis. This study aimed to explore the mechanism of CD34+ cell differentiation in cardiac fibrosis during hyperlipidemia. Through the analysis of transcriptomes from 50,870 single cells extracted from mouse hearts and 76,851 single cells from human hearts, we have effectively demonstrated the evolving cellular landscape throughout cardiac fibrosis. Disturbances in lipid metabolism can accelerate the development of fibrosis. Through the integration of bone marrow transplantation models and lineage tracing, our study showed that hyperlipidemia can expedite the differentiation of non-bone marrow-derived CD34+ cells into fibroblasts, particularly FABP4+ fibroblasts, in response to angiotensin II. Interestingly, the partial depletion of CD34+ cells led to a notable reduction in triglycerides in the heart, mitigated fibrosis, and improved cardiac function. Furthermore, immunostaining of human heart tissue revealed colocalization of CD34+ cells and fibroblasts. Mechanistically, our investigation of single-cell RNA sequencing data through pseudotime analysis combined with in vitro cellular studies revealed the crucial role of the PPARγ/Akt/Gsk3β pathway in orchestrating the differentiation of CD34+ cells into FABP4+ fibroblasts. Through our study, we generated valuable insights into the cellular landscape of CD34+ cell-derived cells in the hypertrophic heart with hyperlipidemia, indicating that the differentiation of non-bone marrow-derived CD34+ cells into FABP4+ fibroblasts during this process accelerates lipid accumulation and promotes heart failure via the PPARγ/Akt/Gsk3β pathway.

Abstract Background There has long been clinical disagreement over the resumption of antiplatelet therapy in patients with primary intracranial hemorrhage (ICH). This meta-analysis aimed to systematically evaluate the efficacy and safety of restarting antiplatelet therapy after ICH among different races and ethnicities. Methods All relevant medical studies involving adults with antiplatelet-associated ICH published in PubMed, The Cochrane Library and Chinese National Knowledge Infrastructure from inception to March 2024 were sourced. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects model to assess the strength of association between resumption of antiplatelet therapy and our outcomes.The review was not registered and the review protocol was not prepared. Results Thirty-five studies were included, with 9758 ICH patients. Subgroup analysis revealed that restarting antiplatelet therapy was associated with a significantly higher risk of recurrence or aggravation of cerebral hemorrhage in Asians[OR = 1.48, 95% CI (1.13–1.94), P = 0.004]; in Caucasians, on the contrary, reinitiation of antiplatelet therapy was not associated with a significantly higher risk of recurrence or aggravation of cerebral hemorrhage [OR = 0.85, 95% CI (0.67–1.06), P = 0.149]. Reinitiation of antiplatelet therapy was associated with a significantly lower risk of cerebral infarction [OR = 0.61, 95% CI (0.39–0.96), P = 0.033]. Restarting antiplatelet therapy after cerebral hemorrhage was not associated with a higher incidence rate of mortality [OR = 0.79, 95% CI (0.57, 1.08), P = 0.138], myocardial infarction [OR = 2.40, 95%CI (0.53,10.79), P = 0.253], hemiparesis [OR = 0.38, 95%CI (0.03,4.81), P = 0.451], neurological deficit [OR = 0.86,95%CI(0.32,2.33),P = 0.766]. Conclusion Reinstitution of antiplatelet therapy after ICH was associated with a lower risk of thromboembolic complications.Resumption of antiplatelet therapy was not associated with a higher incidence of cerebral hemorrhage in Caucasians, but may be associated with a higher risk of cerebral hemorrhage recurrence in Asian populations.

Abstract Three-dimensional (3D) imaging of individual atoms is a critical tool for discovering new physical phenomena and developing new technologies in microscopic systems. However, the current single-atom-resolved 3D imaging methods are limited to static circumstances or a shallow detection range. Here, we demonstrate a generic dynamic 3D imaging method to track the extensive motion of single ions by exploiting the engineered point-spread function (PSF). We show that the image of a single ion can be engineered into a helical PSF, thus enabling single-snapshot acquisition of the position information of the ion in the trap. A preliminary application of this technique is demonstrated by recording the 3D motion trajectory of a single trapped ion and reconstructing the 3D dynamical configuration transition between the zig and zag structures of a 5-ion crystal. This work opens the path for studies on single-atom-resolved dynamics in both trapped-ion and neutral-atom systems.

Abstract Background There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. Methods We integrated druggable genome data, cis‐eQTL/cis‐pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia‐related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome‐wide MR (Phe‐MR) approach and investigated actionable drugs for target genes using available databases. Results MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA‐DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up‐regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007–0.018, P = 1.2*10−5) and higher grip strength (OR: 0.96, 95% CI: 0.94–0.98, P = 4.2*10−5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21–0.26, P = 1.8*10−94), higher grip strength (OR: 0.82, 95% CI: 0.75–0.90, P = 2.1*10−5), and faster walking pace (beta: 0.03, 95% CI: 0.02–0.05, P = 8.5*10−6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06–0.11, P = 6.1*10−13; blood pQTL, beta: 0.05, 95% CI: 0.03–0.07, P = 3.8*10−09)], as well as the down‐regulation of HLA‐DRA [lower ALM (beta: ‐0.09, 95% CI: −0.11 to −0.08, P = 5.4*10−36) and lower grip strength (OR: 1.13, 95% CI: 1.07–1.20, P = 1.8*10−5)] and COL15A1 [higher ALM (muscle eQTL, beta: ‐0.07, 95% CI: −0.10 to −0.04, P = 3.4*10−07; blood pQTL, beta: ‐0.05, 95% CI: −0.06 to −0.03, P = 1.6*10−07)], decreased the risk of sarcopenia. AURKA in blood (beta: ‐0.16, 95% CI: −0.22 to −0.09, P = 2.1*10−06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10−05) tissues showed an inverse relationship with sarcopenia risk. The Phe‐MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. Conclusions Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA‐DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

The paper analyses the spatial and temporal characteristics of extreme precipitation in the upper reaches of the Yangtze River through extreme precipitation indicators based on the trend method, the Mann–Kendall trend test, and the rescaled extreme deviation extreme deviation using daily precipitation data from 1961 to 2021. The following conclusions were obtained: The overall precipitation in the upper reaches of the Yangtze River is reduced, and the number of rainy days is reduced. The frequency of extreme precipitation is generally reduced, but the spatial difference in the intensity of extreme precipitation is greater, which makes the occurrence of extreme precipitation more concentrated and more destructive. Extreme precipitation indicators showed relatively large fluctuations after 2000, especially in terms of extreme precipitation intensity. The frequency of extreme precipitation in the upper reaches of the Yangtze River is the highest in the main stream of the Yangtze River Basin and the Wujiang River Basin, the intensity of extreme precipitation is in the Jialing River and the Wujiang River Basin, and the accumulation of extreme precipitation is the highest in the Jialing River and the Wujiang River Basin, whereas the maximum value of the station extreme precipitation intensity and frequency is in the Minjiang River Basin. HIGHLIGHTS The overall extreme precipitation characteristics of the upper reaches of the Yangtze River under climate change were analysed.; Differences in extreme precipitation characteristics of the first-tier tributaries of the upper Yangtze River were analysed.; Changes in water resources in the upper reaches of the Yangtze River have a major impact on China's economy, food security, and energy resources.;

Abstract Background Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course. Design & methods In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome. Results By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P

Abstract Steroids are cholesterol-derived biomolecules that play an essential role in biological processes. These substances used as growth promoters in animals are strictly regulated worldwide. Targeted assays are the conventional methods of monitoring steroid abuse, with limitations: only detect known metabolites. Metabolism leads to many potential compounds (isomers), which complicates the analysis. Thus, to overcome these limitations, non-targeted analysis offers new opportunities for a deeper understanding of metabolites related to steroid metabolism. Molecular networking (MN) appears to be an innovative strategy combining high-resolution mass spectrometry and specific data processing to study metabolic pathways. In the present study, two databases and networks of steroids were constructed to lay the foundations for the implementation of the GNPS-MN approach. Steroids of the same family were grouped together, nandrolone and testosterone were linked to other analogues. This network and associated database were then applied to a few urine samples in order to demonstrate the annotation capacity in steroidome study. The results show that MN strategy could be used to study steroid metabolism and highlight biomarkers.

Abstract Background Non-syndromic tooth agenesis (NSTA) is a type of ectodermal dysplasia (ED) in which patients with non-syndromic oligodontia may only affect teeth. No pathological findings were found in other tissues of the ectodermal. Herein, we report a case of a NSTA patient with severe dental anxiety and poor oral health. Case presentation A 5-year-old boy without systemic diseases presented as a patient with oligodontia, extensive caries, and periapical periodontitis. Molecular genetic analysis found a mutation in the Ectodysplasin A (EDA) gene, confirming the diagnosis of NSTA. Conclusion Tooth agenesis (TA) is the most common ectodermal developmental abnormality in humans. Non-syndromic oligodontia patients often seek treatment in the department of stomatology. Because of their complex oral conditions, these patients should be provided with a systematic and personalized treatment plan.

Abstract The small Extracellular vesicles (sEV) has been recognized to be significant for intercellular communication due to their ability to transfer important cellular cargoes like miRNAs through circulation. The pituitary gland has not been clearly known about the role of its secreted sEV under normal physiological conditions. And Liver disease is a global public health burden. The present study is the first to investigate the effect of pituitary sEV on the liver. Sequencing and qRT-PCR revealed miR-143-3p is one of the richest in the pituitary sEV. MiR-143 Knockout (KO) mice resulted in a remarkable decrease in insulin-like growth factor 1 (IGF-1) levels and a significant increase in insulin-like growth factor binding protein 5 (IGFBP5) levels along with a reduction in liver primary cell growth. More importantly, compared with miR-143-KO-sEV, WT-sEV possesses a more robust capacity to improve miR-143 KO mice liver repair through the Wnt/β-catenin pathway after an acute injury caused by carbon tetrachloride (CCl4). Our results indicate that pituitary-derived sEV promotes hepatocyte proliferation and liver repair by its cargo miR-143-3p and provides new insight into the regulation mechanism of the pituitary-liver axis, and open a new window for endocrine regulation by using sEV.

Abstract Background Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance feed palatability and improve growth performance. Emulsifiers can be used as potential feed supplements to improve dietary energy utilization and maintain the efficient productivity of broilers. Therefore, further investigation is warranted to evaluate whether dietary emulsifier supplementation can improve the efficiency of fat utilization in the diet of yellow-feathered broilers. In the present study, the effects of adding emulsifier to the diet on lipid metabolism and the performance of yellow-feathered broilers were tested. A total of 240 yellow-feasted broilers (21-day-old) were randomly divided into 4 groups (6 replicates per group, 10 broilers per replicate, half male and half female within each replicate). The groups were as follows: the control group (fed with basal diet), the group fed with basal diet supplemented with 500 mg/kg emulsifier, the group fed with a reduced oil diet (reduced by 1%) supplemented with 500 mg/kg emulsifier, and the group fed with a reduced oil diet supplemented with 500 mg/kg emulsifier. The trial lasted for 42 days, during which the average daily feed intake, average daily gain, and feed-to-gain ratio were measured. Additionally, the expression levels of lipid metabolism-related genes in the liver, abdominal fat and each intestinal segment were assessed. Results The results showed that compared with the basal diet group, (1) The average daily gain of the basal diet + 500 mg/kg emulsifier group significantly increased (P

The genus Alternaria has a global distribution and consists of a diverse group of pathogens. Plant-pathogenic Alternaria spp. can reduce the crop yield and pose serious threats to agricultural production. The pathogen A. mali is recognised as the key the pathogenic mechanism in the early defoliation of apples, which produces the host specific toxin (HST) that was named as an apple specific toxin (a specialised toxin of A. alternata pv. mali, AM toxin). The phenomenon of horizontal transfer of the AM toxin gene from different strains of A. alternata was found, and the relationship between the AM toxin and pathogenicity was confirmed. The representative strain A. tuberculata with the AM toxin gene was co-cultured with sixteen Alternaria strains without the AM toxin gene. As a result, four strains from different Alternaria species obtained the AM toxin gene, which indicated that the AM toxin gene can transfer among different Alternaria species. The AM toxin gene is easy to be lost after subculture, and high temperature and low nutrition can promote this loss. The symptoms of the Alternaria pathogen with or without the AM toxin gene are obviously different on the host. When infected by a pathogen with the AM toxin gene, green spots formed on the apple leaves, and rotten disease spots appeared in the fruit carpels. Contrary to this, when infected by a pathogen without this gene, only small epidermal spots without chlorosis formed on the apple leaves, and mildew-heart spots appeared in the fruit carpels.

Abstract To evaluate the predictive and prognostic value of fibroblast growth factor 21 (FGF21) levels in retinal artery occlusion (RAO) patients. In this case–control study, serum FGF21 levels were detected by using the ELISA method. Multivariable logistic regression analyses were performed to evaluate the significance of FGF21 in assessing the risk of developing RAO and its impact on vision and concurrent ischemic stroke. Compared with control group, serum FGF21 levels were significantly higher (median [IQR] = 230.90[167.40,332.20] pg/ml) in RAO patients. Multivariate logistic regression analysis showed that elevated serum FGF21 levels were associated with a higher risk of RAO occurrence (P = 0.025, OR [95%CI] = 9.672 [2.573, 36.359]) after adjustment for multiple confounding factors. Higher serum FGF21 levels were negatively associated with visual acuity improvement (P = 0.029, OR [95%CI] = 0.466[0.235, 0.925]) and positively correlated with concurrent ischemic stroke (P = 0.04, OR [95% CI] = 1.944[1.029, 3.672]) in RAO patients. Elevated serum FGF21 levels could promote the development of RAO and indicate worse visual prognosis and increase the risk of concurrent ischemic stroke, which might help clinicians early diagnose and treat RAO patients.

ObjectivesTo investigate the clinical value of hemodynamic parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) in predicting glioma genotypes including isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and the tumor proliferation index (Ki-67) noninvasively. And to compare the diagnostic performance of parameters of distributed parameter (DP)model and extended Tofts (Ex-Tofts) model.Materials and methodsDynamic contrast-enhanced MRI (DCE-MRI) data of patients with glioma were prospectively enrolled from April 2021 to May 2023. The imaging data were analyzed using DP and Ex-Tofts model for evaluating the perfusion and permeability characteristics of glioma. Comparisons were performed according to IDH genotype in all glioma patients and 1p/19q codeletion in IDH mutation glioma patients. Receiver operating characteristic (ROC) curves were generated for DCE-MRI parameters. The Spearman rank correlation coefficients were calculated between DCE MRI parameters and Ki-67 index.ResultsIn IDH-mutation gliomas, a higher blood flow (F) was found in 1p/19q codeletion gliomas than in 1p/19q intact gliomas. No parameter derived from Ex-Tofts model showed significant differences in predicting 1p/19q status. Fractional volume of interstitial space (Ve) derived from both the DP and Ex-Tofts models exhibited optimal performance in predicting IDH genotype (AUC = 0.818, 0.828, respectively). Ve also showed the highest correlations with Ki-67 LI within their respective models in all gliomas (ρ = 0.62, 0.61), indicating comparable moderate positive associations. Ki-67ConclusionDP model showed a clear advantage in predicting 1p/19q status compared to Ex-Tofts model. The DP and Ex-Tofts models performed similarly in predicting IDH mutation and Ki-67 index.

ABSTRACT Lactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption. Recent evidence suggests that the gut microbiome may influence lactose levels in the gut. However, there is limited understanding regarding the alterations in microbiota and metabolism between individuals with LI and non-LI. This study conducted a paired-sample investigation utilizing data from the American Gut Project (AGP) and performed metagenomic and untargeted metabolomic analyses in a Chinese cohort to explore the interaction between the gut microbiome and serum metabolites. In addition, fecal microbiota transplantation (FMT) experiments were conducted to further examine the impact of the LI-associated gut microbiome on inflammatory outcomes. We identified 14 microbial genera that significantly differed between LI and controls from AGP data. Using a machine learning approach, group separation was predicted based on seven species and nine metabolites in the Chinese cohort. Notably, increased levels of Escherichia coli in the LI group were negatively correlated with several metabolites, including PC (22:6/0:0), indole, and Lyso PC, while reduced levels of Faecalibacterium prausnitzii and Eubacterium rectale were positively correlated with indole and furazolidone. FMT-LI rats displayed visceral hypersensitivity and an altered gut microbiota composition compared to FMT-HC rats. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI, which was confirmed by FMT-LI rats showing higher expression of ERK and RAS, along with increased concentrations of proinflammatory cytokines. This study provides valuable insights into the disrupted microbial and metabolic traits associated with LI, emphasizing potential microbiome-based approaches for its prevention and treatment.IMPORTANCELactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms after lactose consumption due to a deficiency of lactase. There is limited understanding regarding the microbiota and metabolic alterations between individuals with LI and non-LI. This study represents the first exploration to investigate metagenomic and metabolomic signatures among subjects with lactose intolerance as far as our knowledge. We identified 14 microbial genera in the Western cohort and 7 microbial species, along with 9 circulating metabolites in the Chinese cohort, which significantly differed in LI patients. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI patients. This finding was confirmed by FMT-LI rats, exhibiting increased expression of ERK and RAS, along with higher concentrations of pro-inflammatory cytokines. Our study provides insights into the disrupted functional and metabolic traits of the gut microbiome in LI, highlighting potential microbiome-based approaches for preventing and treating LI.

Acute retinal ischemia and ischemia-reperfusion injury are the primary causes of retinal neural cell death and vision loss in retinal artery occlusion (RAO). The absence of an accurate mouse model for simulating the retinal ischemic process has hindered progress in developing neuroprotective agents for RAO. We developed a unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) mouse model using silicone wire embolization combined with carotid artery ligation. The survival of retinal ganglion cells and visual function were evaluated to determine the duration of ischemia. Immunofluorescence staining, optical coherence tomography, and haematoxylin and eosin staining were utilized to assess changes in major neural cell classes and retinal structure degeneration at two reperfusion durations. Transcriptomics was employed to investigate alterations in the pathological process of UPOAO following ischemia and reperfusion, highlighting transcriptomic differences between UPOAO and other retinal ischemia-reperfusion models. The UPOAO model successfully replicated the acute interruption of retinal blood supply observed in RAO. 60 min of Ischemia led to significant loss of major retinal neural cells and visual function impairment. Notable thinning of the inner retinal layer, especially the ganglion cell layer, was evident post-UPOAO. Temporal transcriptome analysis revealed various pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during the non-reperfusion and reperfusion periods. A pronounced increase in microglia within the retina and peripheral leukocytes accessing the retina was observed during reperfusion periods. Comparison of differentially expressed genes (DEGs) between the UPOAO and high intraocular pressure models revealed specific enrichments in lipid and steroid metabolism-related genes in the UPOAO model. The UPOAO model emerges as a novel tool for screening pathogenic genes and promoting further therapeutic research in RAO.

ABSTRACT: Bisphenol A (BPA) is widely applied in plastic products, which will produce immunotoxicity to organisms after spilling in the environment, and become a kind of endocrine disruptor. Selenium (Se) is an essential trace element and plays an important role in maintaining redox homeostasis and immune function. BPA exposure and Se deficiency often occur together in livestock and poultry farming, however, studies on the effects of joint exposure on chicken immunotoxins have not been reported. Therefore, this study established a chicken spleen and MDCC-MSB1 cell model under the combined effects of BPA exposure or/and Se deficiency. Transcriptomic analysis showed that BPA exposure and/or Se deficiency induced differential enrichment of positive regulatory pathways such as NLRP3 inflammatory complex assembly, inflammatory response and cellular oxidative stress response. In the -Se+BPA group, pathological damage was significantly increased, Se content decreased, BPA accumulation, oxidative stress and pyroptosis. Meanwhile, the roles and mechanisms of oxidative stress and pyroptosis in BPA exposure or/and Se deficiency-induced splenic tissue injury were investigated by using IF and qRT-PCR methods. The results showed that joint BPA exposure with Se deficiency resulted in more significant changes in the above outcomes than 1 of them. The oxidative stress inhibitor NAC effectually reduced Se deficiency and BPA-induced oxidative stress and pyroptosis, further suggests that oxidative stress mediated Se deficiency or/and BPA-induced pyroptosis. This study revealed that BPA exposure and Se deficiency induced spleen pyroptosis in chickens via the ROS/NLRP3 pathway. These results provide the theoretical basis for the toxicity of BPA in poultry and enrich the toxicological mechanism of combined exposure of Se deficiency and environmental toxins.

Purpose: This study aimed to investigate the prevalence of refractive error (RE) and risk factors for myopia among older adults in the Han and various minority ethnic groups across seven provinces in China. Methods: This cross-sectional study forms a part of the ophthalmic dataset of the China National Health Survey (CNHS). Face-to-face interviews and ophthalmic examinations were conducted in seven provinces located in western and northern China. The age- and sex-adjusted prevalence of RE among Han and seven other ethnic groups aged 50–80 years were compared. A mixed-effects model was used to identify the risk factors associated with RE. Results: A total of 12,902 participants, including 8800 Han and 4102 from ethnic minorities, were included in the study. The age- and sex-adjusted prevalence of myopia, high myopia, hyperopia, and astigmatism ranged from 15.3 % (Manchu) to 22.9 % (Han), 0.2 % (Yugur) to 2.8 % (Han), 21.6 % (Tibetan) to 48.9 % (Uyghur), and 38.7 % (Yi) to 57.5 % (Manchu) across different ethnicities, respectively. Compared to the Han population, the Mongolian (odds ratios (OR) 0.62, 95 % confidence interval (CI) 0.46–0.84, p = 0.002), Tibetan (OR 0.66, 95 % CI 0.52–0.85, p = 0.001), Uyghur (OR 0.63, 95 % CI 0.49–0.80, p 18.5 kg/m2 (all p 24 kg/m2 (p = 0.038 in the >24.0 ≤ 27.0 kg/m2 group or p = 0.041 in the >27.0 kg/m2 group) were less likely to have high myopia. Factors associated with a higher prevalence of hyperopia included older age (all p

IntroductionOsteosarcoma is a common type of bone cancer characterized by a poor prognosis due to its metastatic nature. The tumor microenvironment (TME) plays a critical role in tumor metastasis and therapy response. Therefore, our study aims to explore the metastatic mechanism of osteosarcoma, potentially opening new avenues for cancer treatment.MethodsIn this study, we collected data from the GSE152048, GSE14359, and GSE49003 datasets. Differentially expressed genes (DEGs) were identified in osteosarcoma cases with primary and metastatic features using R software and the limma package. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate metastasis-related genes. A protein–protein interaction (PPI) network was established using the STRING database to further analyze these metastasis-associated genes. The abundances of different cell types with a mixed cell population were estimated using the CIBERSORT approach. The scRNA-seq data were analyzed by the Seurat package in R software, and intercellular communications were elucidated using the CellChat R package.ResultsIn this study, 92 DEGs related to metastasis were identified, including 41 upregulated and 51 downregulated genes in both the GSE14359 and GSE49003 datasets. Metastasis-associated pathways were identified, including those involving the cyclin-dependent protein kinase holoenzyme complex, transferase complex, transferring phosphorus-containing groups, SCF ubiquitin ligase complex, and the serine/threonine protein kinase complex. KEGG and PPI network analyses revealed 15 hub genes, including Skp2, KIF20A, CCNF, TROAP, PHB, CKS1B, MCM3, CCNA2, TRIP13, CENPM, Hsp90AB1, JUN, CKS2, TK1, and KIF4A. Skp2 has been known as an E3 ubiquitin ligase involved in osteosarcoma progression. The proportion of CD8+ T cells was found to be higher in metastatic osteosarcoma tissues, and high expression of PHB was associated with a favorable prognosis in osteosarcoma patients. Additionally, 23 cell clusters were classified into eight cell types, including chondrocytes, MSC, T cells, monocytes, tissue stem cells, neurons, endothelial cells, and macrophages. The 15 hub genes were expressed across various cell types, and interactions between different cell types were observed.ConclusionOur study reveals the intricate communication between tumor microenvironment components and tumor metastasis in osteosarcoma.

Fishborne trematode (FBT) is an important group of parasites that are endemic worldwide to a certain extent. However, despite the epidemiological significance, the species and phylogenetic evolution characteristics of FBT metacercariae have not been well studied. In this study, a total of 600 Pseudorasbora parva (P. parva) specimens were collected from Qiqihar, 61.8% (371/600) were found to be infected with trematode metacercariae. A total of three kinds of trematodes metacercariae were obtained, and they were identified as Clonorchis sinensis (C. sinensis), Metorchis orientalis (M. orientalis), and Metorchis taiwanensis (M. taiwanensis) by morphological and phylogenetic analysis with infection rates of 47.7% (286/600), 15.5% (93/600), and 23.7% (142/600), respectively. Meanwhile, a survey of the three trematodes metacercariae showed that the infection rate of C. sinensis metacercariae was the highest in September, up to 66% (66/100), and the lowest in June at 26% (26/100). The infection rate of M. orientalis metacercariae was the highest in October at 26% (26/100) and the lowest in June at 5% (5/100). The infection rate of M. taiwanensis metacercariae was at its peak in November at 36% (36/100) and the lowest in July at 15% (15/100). The co-infection of metacercariae of C. sinensis and M. taiwanensis was the most common and reached a peak in October, and their infection rate was higher in autumn than in summer. The peak of infection intensity of metacercariae for C. sinensis, M. orientalis, and M. taiwanensis were different: C. sinensis was 24/g in September, M. orientalis was 7/g in October, and M. taiwanensis was 10/g in November. From the above results, it was confirmed that three species of trematodes metacercaria played an important role in infection of second intermediate hosts in Qiqihar region. Studying the morphological characteristics and sequencing the ITS2 gene for a phylogenetic tree of them will be useful for future molecular evolution, biology, and ecology of trematode metacercariae.

This study explored the mechanism by which forkhead box O-1 (FoxO1) modulates the biological behaviors of bone mesenchymal stem cell (BMSC). Human BMSCs were cultured for 7 days in DMEM containing bone morphogenetic protein-2 (BMP-2) and treated with a short hairpin-FoxO1 plasmid. The study assessed cell proliferation, migration, apoptosis, adenosine triphosphate (ATP) levels, mitochondrial DNA levels, membrane potential, autophagy, and the levels of FoxO1, apoptosis-associated proteins, osteogenic differentiation-associated proteins, mitochondrial fusion and fission proteins and mitochondrial autophagy-related proteins. The cells were also treated with the mitochondrial fusion activator MASM7 and the mitochondrial autophagy activator carbonyl cyanide 3-chlorophenylhydrazone. The study evaluated whether mitochondrial dynamics and autophagy activation could rescue the FoxO1 knockdown-induced changes in BMSC biological behaviors, mitochondrial dynamics, and mitochondrial autophagy. BMP-2-induced BMSCs exhibited up-regulated FoxO1 expression, enhanced proliferation and migration, and induced osteogenic differentiation, while FoxO1 knockdown inhibited BMP-2-induced BMSC proliferation, migration and osteogenic differentiation, increased apoptosis, and affected mitochondrial dynamics and autophagy. Promoting mitochondrial fusion partially reversed the regulatory effects of FoxO1 downregulation on mitochondrial autophagy and the inhibitory effects of FoxO1 silencing on BMP-2-induced BMSC biological behaviors. Activated mitochondrial autophagy facilitated the homeostasis of mitochondrial dynamics and partially counteracted the inhibitory effects of FoxO1 knockdown on BMP-2-induced BMSC biological behaviors. In conclusion, FoxO1 regulates mitochondrial dynamics and autophagy to modulate the osteogenic differentiation of BMP-2-induced human BMSCs.

BackgroundTo identify the risk factors and construct a predictive model for early recurrence of hepatitis B virus(HBV-)- related hepatocellular carcinomas(HCCs) after radical resection.Data and methodsA total of 465 HBV-related HCC patients underwent radical resections between January 1, 2012 and August 31, 2018.Their data were collected through the inpatient information management system of the First Affiliated Hospital of University of Science and Technology of China. Survival and subgroup analyses of early recurrence among male and female patients were performed using Kaplan-Meier curves. The independent risk factors associated with early postoperative tumor recurrence were analyzed using multivariate Cox proportional hazards regression model. Based on these independent risk factors, a risk function model for early recurrence was fitted, and a column chart for the prediction model was drawn for internal and external validation.ResultsA total of 181 patients developed early recurrences, including 156 males and 25 females. There was no difference in the early recurrence rates between males and females. Tumor diameters>5cm, microvascular invasion and albumin level5 cm, microvascular invasion, and albumin level

DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.

Cotton leaf curl Multan virus (CLCuMuV), a serious viral disease causative agent in cotton plants in South Asia, is transmitted by the Bemisia tabaci cryptic species complex in a persistent circulative manner. A previous study indicated that Asia II-7 whiteflies could transmit CLCuMuV, while Mediterranean (MED) whiteflies failed to transmit CLCuMuV. However, little is known about the genes involved in this process. In this study, Asia II-7 and MED B. tabaci were utilized to determine transcriptomic responses after 48 h of acquisition access periods (AAPs). Result of Illumina sequencing revealed that, 14,213 and 8,986 differentially expressed genes (DEGs) were identified. Furthermore, DEGs related to the immune system and metabolism of Asia II-7 and MED in response to CLCuMuV-infected plants were identified and analyzed using Gene Ontologies (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the number of related DEGs in MED was lower than that of Asia II-7. The most abundant groups of DEGs between both viruliferous and aviruliferous whitefly species were the zf-C2H2 family of transcription factors (TFs). Notably, in comparison to viruliferous MED, Asia II-7 exhibited more DEGs related to cathepsin biosynthesis. Overall, this study provides the basic information for investigating the molecular mechanism of how begomoviruses affect B. tabaci metabolism and immune response either as vector cryptic species or non-vector species.

BackgroundFor medical diagnosis, clinicians typically begin with a patient’s chief concerns, followed by questions about symptoms and medical history, physical examinations, and requests for necessary auxiliary examinations to gather comprehensive medical information. This complex medical investigation process has yet to be modeled by existing artificial intelligence (AI) methodologies. ObjectiveThe aim of this study was to develop an AI-driven medical inquiry assistant for clinical diagnosis that provides inquiry recommendations by simulating clinicians’ medical investigating logic via reinforcement learning. MethodsWe compiled multicenter, deidentified outpatient electronic health records from 76 hospitals in Shenzhen, China, spanning the period from July to November 2021. These records consisted of both unstructured textual information and structured laboratory test results. We first performed feature extraction and standardization using natural language processing techniques and then used a reinforcement learning actor-critic framework to explore the rational and effective inquiry logic. To align the inquiry process with actual clinical practice, we segmented the inquiry into 4 stages: inquiring about symptoms and medical history, conducting physical examinations, requesting auxiliary examinations, and terminating the inquiry with a diagnosis. External validation was conducted to validate the inquiry logic of the AI model. ResultsThis study focused on 2 retrospective inquiry-and-diagnosis tasks in the emergency and pediatrics departments. The emergency departments provided records of 339,020 consultations including mainly children (median age 5.2, IQR 2.6-26.1 years) with various types of upper respiratory tract infections (250,638/339,020, 73.93%). The pediatrics department provided records of 561,659 consultations, mainly of children (median age 3.8, IQR 2.0-5.7 years) with various types of upper respiratory tract infections (498,408/561,659, 88.73%). When conducting its own inquiries in both scenarios, the AI model demonstrated high diagnostic performance, with areas under the receiver operating characteristic curve of 0.955 (95% CI 0.953-0.956) and 0.943 (95% CI 0.941-0.944), respectively. When the AI model was used in a simulated collaboration with physicians, it notably reduced the average number of physicians’ inquiries to 46% (6.037/13.26; 95% CI 6.009-6.064) and 43% (6.245/14.364; 95% CI 6.225-6.269) while achieving areas under the receiver operating characteristic curve of 0.972 (95% CI 0.970-0.973) and 0.968 (95% CI 0.967-0.969) in the scenarios. External validation revealed a normalized Kendall τ distance of 0.323 (95% CI 0.301-0.346), indicating the inquiry consistency of the AI model with physicians. ConclusionsThis retrospective analysis of predominantly respiratory pediatric presentations in emergency and pediatrics departments demonstrated that an AI-driven diagnostic assistant had high diagnostic performance both in stand-alone use and in simulated collaboration with clinicians. Its investigation process was found to be consistent with the clinicians’ medical investigation logic. These findings highlight the diagnostic assistant’s promise in assisting the decision-making processes of health care professionals.

Microsatellite DNA (SSR) is extensively used as molecular markers in diverse fields, including molecular ecology, conservation biology, and molecular breeding. Nevertheless, the efficient and easy acquisition of high-quality SSR molecular markers for economically cultured marine animals remains a challenge. Holothuria leucospilota is an economically and ecologically important tropical sea cucumber. Recently, artificial breeding and cultivation of this species have been reported. However, there is still a lack of highly polymorphic SSR molecular markers for geographical population differentiation and genetic breeding. This study aims to develop and utilize SSR markers from genomic data to assess the genetic variation and population structure of H. leucospilota in the South China Sea. A comprehensive pipeline was created, integrating microsatellite discovery, primer design, and assessment into a single platform. Through this, 15 highly polymorphic microsatellite loci were identified and validated. The results revealed high genetic diversity and low genetic differentiation among H. leucospilota populations. Larval dispersal and ocean currents in the South China Sea were identified as the primary factors influencing genetic connectivity between populations. In addition, the artificial culture and releasing of H. leucospilota have influenced the genetic structure of their wild populations in the South China Sea. This study provides a pipeline for identifying SSR markers within genome data, and applies it to assess the genetic diversity and structure of H. leucospilota. The outcomes of this research are expected to be beneficial and applicable to the future aquaculture of tropical sea cucumbers.

BackgroundChondrosarcomas are common primary malignant bone tumors; however, comprehensive bibliometric analysis in this field has not yet been conducted. Therefore, this study aimed to explore the research hotspots and trends in the field of chondrosarcoma through bibliometric analysis to help researchers understand the current status and direction of research in the field.MethodsArticles and reviews related to chondrosarcoma published between 2003 and 2022 were retrieved from the Web of Science. Countries, institutions, authors, journals, references, and keywords in this field were visualized and analyzed using CtieSpace and VOSviewer software.ResultsBetween 2003 and 2022, 4,149 relevant articles were found. The number of articles published on chondrosarcoma has increased significantly annually, mainly from 569 institutions in China and the United States, and 81 in other countries. In total, 904 authors participated in the publication of studies related to chondrosarcomas. Over the past 20 years, articles on chondrosarcoma have been published in 958 academic journals, with Skeletal Radiology having the highest number of publications. Furthermore, keywords such as “gene expression,” “radiotherapy,” “experience,” and “apoptosis” have been popular in recent years.ConclusionOver the past 20 years, the global trend in chondrosarcoma research has primarily been clinical research, with basic research as a supplement. In the future, communication and exchange between countries and institutions should be strengthened. Further, the future main research hotspots in the field of chondrosarcoma include mutated genes and signaling pathways, precision surgical treatment, proton therapy, radiation therapy, chemotherapy, immunotherapy, and other aspects.

Additively manufactured (AM) components—either made by laser-powder bed fusion or wire and arc additive manufacturing—typically contain process-related defects on and near surfaces that can be removed by machining. Various studies have shown that post-treatment, such as machining significantly improves the fatigue strength of AM parts. To this day, however, hardly any studies have investigated the fatigue strength of post-treated additively manufactured components with notches. In this study, fatigue tests were performed on plain and notched specimens to determine and compare the crack initiation and crack propagation behavior due to different manufacturing-related effects. Tests were performed on specimens produced by the two aforementioned AM processes and compared to specimens taken from wrought sheets. The fatigue strength of AM materials is influenced by microstructure, defects, residual stress, and notches. PBF-LB/M specimens exhibit the highest fatigue strength in plain, notch-free conditions, attributed to differences in microstructure and static strength affecting fatigue crack initiation. Notched specimens show larger differences among materials, with PBF-LB/M having shorter fatigue crack propagation life related to line-type defect clusters, while the plain PBF-LB/M specimens are less affected as their fatigue strength is primarily determined by fatigue crack initiation.

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is an important manifestation and mechanism of pulmonary vascular remodeling. Resolvin D1 (RvD1) is an endogenous lipid mediator promoting the resolution of inflammation. However, the role of RvD1 on EndMT in PH remains unknown. Here, we aimed to investigate the effect and mechanisms of RvD1 on the treatment of PH. We showed that RvD1 and its receptor FPR2 expression were markedly decreased in PH patients and both chronic hypoxia-induced PH (CH-PH) and sugen 5416/hypoxia-induced PH (SuHx-PH) mice models. RvD1 treatment decreased right ventricular systolic pressure (RVSP) and alleviated right ventricular function, and reduced pulmonary vascular remodeling and collagen deposition in the perivascular of both two PH mice models. Then, RvD1 inhibited EndMT in both the lungs of PH mice models and primary cultured human umbilical vein endothelial cells (HUVECs) treated with TGF-β and IL-1β. Moreover, RvD1 inhibited EndMT by downregulating Smad2/3 phosphorylation in vivo and in vitro via FPR2. In conclusion, our date suggest that RvD1/FPR2 axis prevent experimental PH by inhibiting endothelial-mensenchymal-transition and may be a therapeutic target for PH.

Abstract Background Enhancing angiogenesis may be an effective strategy to promote functional recovery after ischemic stroke. Inflammation regulates angiogenesis. Microglia are crucial cells that initiate inflammatory responses after various brain injuries. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays a role in regulating brain injury. This study aimed to explore the effects of NEAT1-regulated microglial polarization on the neovascularization capacity of cerebrovascular endothelial cells and the underlying molecular regulatory mechanisms. Methods Mouse cerebral arterial endothelial cells (mCAECs) were co-cultured with BV-2 cells in different groups using a Transwell system. NEAT1 expression levels were measured by fluorescence quantitative reverse transcription PCR. Levels of IL-1β, IL-6, TNF-α, Arg-1, IL-4, and IL-10 were determined using ELISA. Expression levels of CD86 and CD163 were detected by immunofluorescence. The neovascularization capacity of mCAECs was assessed using CCK-8, Transwell, Transwell-matrigel, and tube formation assays. Label-free quantification proteomics was carried out to identify differentially expressed proteins. Protein levels were measured by Western blotting. Results NEAT1 overexpression induced M1 polarization in BV-2 cells, whereas NEAT1 knockdown blocked lipopolysaccharide-induced M1 polarization in microglia. NEAT1-overexpressing BV-2 cells suppressed the angiogenic ability of mCAECs, and NEAT1-knocking BV-2 cells promoted the angiogenic ability of mCAECs under lipopolysaccharide treatment. Label-free quantitative proteomic analysis identified 144 upregulated and 131 downregulated proteins that were induced by NEAT1 overexpression. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the Kyoto Encyclopedia of Genes and Genomes analysis of the differentially expressed proteins. Further verification showed that NEAT1 inactivated the AMPK signaling pathway. Moreover, the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide reversed the effect of NEAT1 on BV-2 polarization and the regulatory effect of NEAT1-overexpressing BV-2 cells on the angiogenic ability of mCAECs. Conclusions NEAT1 inhibits the angiogenic activity of mCAECs by inducing M1 polarization of BV-2 cells through the AMPK signaling pathway. This study further clarified the impact and mechanism of NEAT1 on microglia and the angiogenic ability of cerebrovascular endothelial cells.

Abstract Background Flexible hybrid teaching has become the new normal of basic medical education in the postepidemic era. Identifying ways to improve the quality of curriculum teaching and achieve high-level talent training is a complex problem that urgently needs to be solved. Over the course of the past several semesters, the research team has integrated design thinking (DT) into undergraduate teaching to identify, redesign and solve complex problems in achieving curriculum teaching and professional talent training objectives. Methods This study is an observational research. A total of 156 undergraduate stomatology students from Jining Medical University in 2021 were selected to participate in two rounds of online flipped teaching using the design thinking EDIPT (empathy, definition, idea, prototype, and test) method. This approach was applied specifically to the chapters on the respiratory system and female reproductive system. Data collection included student questionnaires, teacher-student interviews, and exam scores. GraphPad Prism software was used for data analysis, and the statistical method was conducted by multiple or unpaired t test. Results According to the questionnaire results, the flipped classroom teaching design developed using design thinking methods received strong support from the majority of students, with nearly 80% of students providing feedback that they developed multiple abilities during the study process. The interview results indicated that teachers generally believed that using design thinking methods to understand students' real needs, define teaching problems, and devise instructional design solutions, along with testing and promptly adjusting the effectiveness through teaching practices, played a highly positive role in improving teaching and student learning outcomes. A comparison of exam scores showed a significant improvement in the exam scores of the class of 2021 stomatology students in the flipped teaching chapters compared to the class of 2020 stomatology students, and this difference was statistically significant. However, due to the limitation of the experimental chapter scope, there was no significant difference in the overall course grades. Conclusion The study explores the application of design thinking in histology and embryology teaching, revealing its positive impact on innovative teaching strategies and students' learning experience in medical education. Online flipped teaching, developed through design thinking, proves to be an effective and flexible method that enhances student engagement and fosters autonomous learning abilities.

Abstract G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class of drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects or allosteric effects, and biased signaling or balanced signaling, characterize the complexity of GPCR dynamic features. In this study, we first review the structural advancements, activation mechanisms, and functional diversity of GPCRs. We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years. Particularly, an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms. Finally, we highlight how the widespread GPCR-druggable allosteric sites can guide structure- or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

Abstract Central retinal artery occlusion (CRAO) is an acute retinal ischaemic disease, but early diagnosis is challenging due to a lack of biomarkers. Blood samples were collected from CRAO patients and cataract patients. Gene expression profiles were distinct between arterial/venous CRAO blood (A–V group) and venous CRAO/control blood (V–C group) samples. Differentially expressed genes (DEGs) were subjected to GO and KEGG enrichment analyses. Hub genes were identified by Cytoscape and used to predict gene interactions via GeneMANIA. Immune cell infiltration was analysed by CIBERSORT. More than 1400 DEGs were identified in the A–V group and 112 DEGs in the V–C group compared to controls. The DEGs in both groups were enriched in the ribosome pathway, and those in the V–C group were also enriched in antigen processing/MHC pathways. Network analysis identified ribosomal proteins (RPS2 and RPS5) as the core genes of the A–V group and MHC genes (HLA-F) as the core genes of the V–C group. Coexpression networks showed ribosomal involvement in both groups, with additional immune responses in the V–C group. Immune cell analysis indicated increased numbers of neutrophils and T cells. Ribosomal and MHC-related genes were identified as potential CRAO biomarkers, providing research directions for prevention, diagnosis, treatment and prognosis.

Objective To explore the diagnostic value of combined detection of serum high mobility group protein B1 （HMGB1） and soluble myeloid cell trigger receptor-1 （sTREM-1） in sepsis complicated with acute kidney injury （AKI）. MethodsFrom January 1, 2020 to January 31, 2022, 156 hospitalized septic patients were retrospectively selected and 68 healthy subjects in the same period were selected as control group. The serum levels of HMGB1 and sTREM-1 were compared between two groups. And the influencing factors of sepsis complicated with AKI were examined by multivariate Logistic regression. The diagnostic value of serum level of HMGB1/sTREM-1 for sepsis complicated with AKI was explored by receiver characteristic curve. Results The serum levels of HMGB1 [172 530（133 870, 204 010） to 83 720（63 480, 99 870） ng/L] and sTREM-1[（49.56 ± 8.03）ng/L vs（24.96 ± 5.24）ng/L] were significantly higher in sepsis group than those in control group （P＜0.05）. Multivariate Logistic analysis revealed that serum creatinine（OR = 1.079, 95%CI:1.037-1.122）, HMGB1 （OR = 1.933, 95%CI:1.376-2.714） and sTREM-1 （OR = 1.201, 95%CI:1.101-1.309） were independent risk factors for sepsis complicated with AKI （P＜0.05）. The working characteristic curve indicated that HMGB1 plus sTREM-1 [area under the curve （AUC） = 0.928, 95%CI:0.876-0.963] offered a higher sensitivity, specificity and accuracy in diagnosing sepsis complicated with AKI than HMGB1 （AUC = 0.790, 95%CI:0.718-0.851） and sTREM-1 （AUC = 0.778, 95%CI:0.705-0.840）. Conclusion The serum levels of HMGB1 and sTREM-1 are significantly up-regulated in septic patients. Both are independent risk factors for sepsis complicated with AKI.

Agronomic measures are the key to promote the sustainable development of ratoon rice by reducing the damage from mechanical crushing to the residual stubble of the main crop, thereby mitigating the impact on axillary bud sprouting and yield formation in ratoon rice. This study used widely recommended conventional rice Jiafuzhan and hybrid rice Yongyou 2640 as the test materials to conduct a four-factor block design field experiment in a greenhouse of the experimental farm of Fujian Agricultural and Forestry University, China from 2018 to 2019. The treatments included fertilization and no fertilization, alternate wetting and drying irrigation and continuous water flooding irrigation, and plots with and without artificial crushing damage on the rice stubble. At the same time, a 13C stable isotope in-situ detection technology was used to fertilize the pot experiment. The results showed significant interactions among varieties, water management, nitrogen application and stubble status. Relative to the long-term water flooding treatment, the treatment with sequential application of nitrogen fertilizer coupled with moderate field drought for root-vigor and tiller promotion before and after harvesting of the main crop, significantly improved the effective tillers from low position nodes. This in turn increased the effective panicles per plant and grains per panicle by reducing the influence of artificial crushing damage on rice stubble and achieving a high yield of the regenerated rice. Furthermore, the partitioning of 13C assimilates to the residual stubble and its axillary buds were significantly improved at the mature stage of the main crop, while the translocation rate to roots and rhizosphere soil was reduced at the later growth stage of ratooning season rice. This was triggered by the metabolism of hormones and polyamines at the stem base regulated by the interaction of water and fertilizer at this time. We therefore suggest that to achieve a high yield of ratoon rice with low stubble height under mechanized harvesting, the timely application of nitrogen fertilizer is fundamental, coupled with moderate field drying for root-vigor preservation and tiller promotion before and after the mechanical harvesting of the main crop.

In order to obtain Mg alloys with fine microstructures and high mechanical performances, a novel friction-based processing method, name as “constrained friction processing (CFP)”, was investigated. Via CFP, defect-free Mg-Zn-Ca rods with greatly refined grains and high mechanical properties were produced. Compared to the previous as-cast microstructure, the grain size was reduced from more than 1 mm to around 4 µm within 3 s by a single process cycle. The compressive yield strength was increased by 350% while the ultimate compressive strength by 53%. According to the established material flow behaviors by “tracer material”, the plastic material was transported by shear deformation. From the base material to the rod, the material experienced three stages, i.e. deformation by the tool, upward flow with additional tilt, followed by upward transportation. The microstructural evolution was revealed by “stop-action” technique. The microstructural development at regions adjacent to the rod is mainly controlled by twinning, dynamic recrystallization (DRX) as well as particle stimulated nucleation, while that within the rod is related to DRX combined with grain growth.

BackgroundRegional differences in economic development, natural environment, health care level, and social structure may lead to differences in the provincial distribution of the health status of the elderly population. ObjectiveTo explore the provincial distribution characteristics, regional differences, and influencing factors of the self-assessed health of the elderly population, with the aim of providing a policy basis for improving the health of the elderly population and promoting healthy aging according to local conditions. MethodsUsing 31 provinces (municipalities and autonomous regions) in China as the basicstudy unit and based on the method of Wagstaff, the self-rated health data of the elderly population (aged 60 years and above) in each province from the 2010 and 2020 national censuses and the 2015 1% National Population Sample Survey were converted into ill-health scores as a measure of self-assessed health, and higher scores represented worse health status perception. Global Moran's I was used to evaluate spatial autocorrelation, range [−1, 1], with a value of 1 as a perfect clustered pattern. Local Moran's I was used to evaluate the tendency of local autocorrelation, and high-high aggregation/low-low aggregation indicated that both target province and its neighboring provinces showed higher/lower ill-health scores. Spatial econometric models were selected by Lagrange multiplier test and Hausman test to explore influencing factors of the self-assessed health of the elderly population. ResultsIn 2010, 2015, and 2020, the national ill-health scores of the elderly population were 1.831, 1.873, and 1.547, respectively, and the corresponding Global Moran's I statistics were 0.347, 0.482, and 0.511, respectively (P

Abstract Background Calmodulins (CaMs)/CaM-like proteins (CMLs) are crucial Ca2+-binding sensors that can decode and transduce Ca2+ signals during plant development and in response to various stimuli. The CaM/CML gene family has been characterized in many plant species, but this family has not yet been characterized and analyzed in peanut, especially for its functions in response to Ralstonia solanacearum. In this study, we performed a genome-wide analysis to analyze the CaM/CML genes and their functions in resistance to R. solanacearum. Results Here, 67, 72, and 214 CaM/CML genes were identified from Arachis duranensis, Arachis ipaensis, and Arachis hypogaea, respectively. The genes were divided into nine subgroups (Groups I-IX) with relatively conserved exon‒intron structures and motif compositions. Gene duplication, which included whole-genome duplication, tandem repeats, scattered repeats, and unconnected repeats, produced approximately 81 pairs of homologous genes in the AhCaM/CML gene family. Allopolyploidization was the main reason for the greater number of AhCaM/CML members. The nonsynonymous (Ka) versus synonymous (Ks) substitution rates (less than 1.0) suggested that all homologous pairs underwent intensive purifying selection pressure during evolution. AhCML69 was constitutively expressed in different tissues of peanut plants and was involved in the response to R. solanacearum infection. The AhCML69 protein was localized in the cytoplasm and nucleus. Transient overexpression of AhCML69 in tobacco leaves increased resistance to R. solanacearum infection and induced the expression of defense-related genes, suggesting that AhCML69 is a positive regulator of disease resistance. Conclusions This study provides the first comprehensive analysis of the AhCaM/CML gene family and potential genetic resources for the molecular design and breeding of peanut bacterial wilt resistance.

Abstract Laryngopharyngeal reflux disease (LPRD) is a condition characterized by the regurgitation of stomach and duodenal contents into the laryngopharynx, with variable and non-specific symptoms. Therefore, developing an accurate symptom scale for different regions is essential. Notably, the symptoms of “dryness and burning sensation in the laryngopharynx or mouth” are prevalent among the Chinese population but are often omitted from conventional symptom assessment scales, such as the Reflux Symptom Index (RSI) and Reflux Symptom Score-12 (RSS-12) scales. To address this gap, our study incorporated the symptoms into the RSI and RSS-12 scales, developing the RSI-10/RSS-13 scales. Afterward, we assessed the role of the new scale’s reliability (Cronbach’s α and test–retest reliability), construct validity (confirmatory factor analysis and confirmatory factor analysis), and diagnostic efficiency. Our study encompassed 479 participants (average = 39.5 ± 13.4 years, 242 female) and 91 (average = 34.01 ± 13.50 years, 44 female) completed 24 h MII-pH monitoring. The Cronbach’s α values of 0.80 and 0.82 for the RSI-10 and RSS-13 scales, respectively. RSI-10 and RSS-13 exhibited strong test–retest reliability (ICCs = 0.82–0.96) and diagnostic efficacy (AUC = 0.84–0.85). Furthermore, the factor analysis identified the RSS-13 and its three sub-scales (ear-nose-throat, digestive tract, respiratory tract) exhibited good to excellent structural validity (χ2/df = 1.95, P

Abstract Background Domesticated pigs serve as an ideal animal model for biomedical research and also provide the majority of meat for human consumption in China. Porcine intramuscular fat content associates with human health and diseases and is essential in pork quality. The molecular mechanisms controlling lipid metabolism and intramuscular fat accretion across tissues in pigs, and how these changes in response to pig breeds, remain largely unknown. Results We surveyed the tissue-resident cell types of the porcine jejunum, colon, liver, and longissimus dorsi muscle between Lantang and Landrace breeds by single-cell RNA sequencing. Combining lipidomics and metagenomics approaches, we also characterized gene signatures and determined key discriminating markers of lipid digestibility, absorption, conversion, and deposition across tissues in two pig breeds. In Landrace, lean-meat swine mainly exhibited breed-specific advantages in lipid absorption and oxidation for energy supply in small and large intestinal epitheliums, nascent high-density lipoprotein synthesis for reverse cholesterol transport in enterocytes and hepatocytes, bile acid formation, and secretion for fat emulsification in hepatocytes, as well as intestinal-microbiota gene expression involved in lipid accumulation product. In Lantang, obese-meat swine showed a higher synthesis capacity of chylomicrons responsible for high serum triacylglycerol levels in small intestinal epitheliums, the predominant characteristics of lipid absorption in muscle tissue, and greater intramuscular adipcytogenesis potentials from muscular fibro-adipogenic progenitor subpopulation. Conclusions The findings enhanced our understanding of the cellular biology of lipid metabolism and opened new avenues to improve animal production and human diseases. Video Abstract

Abstract Aims Patients with high‐flow arteriovenous (AV) access are at risk of developing high‐output cardiac failure (HOCF) and subsequent hospitalization. However, diagnosing HOCF is challenging and often requires invasive procedures. The role of systemic vascular resistance (SVR) in diagnosing HOCF is underestimated, and its predictive value is limited. Our study aims to identify non‐invasive risk factors for HOCF to facilitate early diagnosis and timely surgical interventions. Methods and results We included 109 patients with high‐flow AV access who underwent serial echocardiography. The retrospective cohort was divided into two groups based on their hospitalization due to HOCF. The two groups were matched for age and gender. After a mean follow‐up of 25.1 months, 19 patients (17.4%) were hospitalized due to HOCF. The two groups had similar baseline characteristics. However, the HOCF group had a higher value of vascular access blood flow (Qa) (2168 ± 856 vs. 1828 ± 617 mL/min; P = 0.045). Echocardiographic analysis revealed that the HOCF group had more pronounced left ventricular diastolic dysfunction (E/e′: 21.1 ± 7.3 vs. 16.2 ± 5.9; P = 0.002), more severe pulmonary hypertension (right ventricular systolic pressure: 41.4 ± 16.7 vs. 32.2 ± 12.8; P = 0.009), a higher Doppler‐derived cardiac index (CI) (4.3 ± 0.8 vs. 3.7 ± 1.1; P = 0.031), and a lower Doppler‐derived estimated SVR (eSVR) value (5.5 ± 0.3 vs. 6.9 ± 0.2; P = 0.002) than the non‐HOCF group. Using multivariable Cox regression analysis, a low eSVR value (