Search

Abstract Sestrin2 (Sesn2) has been previously confirmed to be a stress-response molecule. However, the influence of Sesn2 on myogenic differentiation remains elusive. This study was conducted to analyze the role of Sesn2 in the myogenic differentiation of C2C12 myoblasts and related aspects in mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Our results showed that knockdown of Sesn2 reduced the myogenic differentiation capacity of C2C12 myoblasts. Predictive analysis from two databases suggested that miR-182-5p is a potential regulator of Sesn2. Further experimental validation revealed that overexpression of miR-182-5p decreased both the protein and mRNA levels of Sesn2 and inhibited myogenesis of C2C12 myoblasts. These findings suggest that miR-182-5p negatively regulates myogenesis by repressing Sesn2 expression. Extending to an in vivo model of DMD, knockdown of Sesn2 led to decreased Myogenin (Myog) expression and increased Pax7 expression, while its overexpression upregulated Myog levels and enhanced the proportion of slow-switch myofibers. These findings indicate the crucial role of Sesn2 in promoting myogenic differentiation and skeletal muscle regeneration, providing potential therapeutic targets for muscular dystrophy.

Abstract Background Medical school learning environment (MSLE) has a holistic impact on students’ psychosomatic health, academic achievements, and personal development. Students in different grades perceive MSLE in different ways. Thus, it is essential to investigate the specific role of student’s grade in the perception of MSLE. Methods Using the Johns Hopkins Learning Environment Scale (JHLES) as a quantification instrument for the perception level of MSLE, 10,901 medical students in 12 universities in China were categorized into low or high JHLES group according to their questionnaires. We investigated the relationship between student’s grade and JHLES category by univariate analysis employing Pearson Chi-square test and Welch’s ANOVA. Then multivariable logistic regression analysis confirmed the predictive efficacy of student’s grade. A nomogram concerning the prediction of low JHLES score probability in medical students was also constructed. Results A significant difference between two JHLES categories among students in different grades was observed (p

Abstract Background The epidemiology and risk factors for postoperative complications related to free flap reconstruction in head and neck cancer patients admitted to the Intensive Care Unit (ICU) are unknown. Methods We performed a retrospective cohort study of patients with free flap reconstruction of head and neck cancer between September 2015 and April 2023 admitted to the ICU of Beijing Tongren Hospital. The univariate and multivariate analyses were used to explore the risk factors for postoperative complications related to free flap reconstruction admitted to ICU, including flap necrosis, bleeding, fistula, and infection. Results A total of 239 patients were included in this study, and 38 (15.9%) patients had postoperative complications related to free flap reconstruction. The median length of ICU stay was 1 day (interquartile range, 1–2 days). Multivariate analysis found that low BMI (P

Abstract Background This study sought to investigate the prognostic value of basement membrane (BM)-associated gene expressions in oral cancer. Methods We harvested and integrated data on BM-associated genes (BMGs), the oral cancer transcriptome, and clinical information from public repositories. After identifying differentially expressed BMGs, we used Cox and Lasso regression analyses to create a BMG-based risk score for overall survival at various intervals. We then validated this score using the GSE42743 cohort as a validation set. The prognostic potential of the risk scores and their relations to clinical features were assessed. Further, we conducted functional pathway enrichment, immune cell infiltration, and immune checkpoint analyses to elucidate the immunological implications and therapeutic potential of the BMG-based risk score and constituent genes. To confirm the expression levels of the BMG LAMA3 in clinical samples of oral cancer tissue, we performed quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. Results The BMGs LAMA3, MMP14, and GPC2 demonstrated notable prognostic significance, facilitating the construction of a BMG-based risk score. A higher risk score derived from BMGs correlated with a poorer survival prognosis for oral cancer patients. Moreover, the risk-associated BMGs exhibited a significant relationship with immune function variability (P

Abstract Background Global human activities were significantly impacted by the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by the 2019 novel coronavirus. This study aimed to investigate the prevalence and genotype distribution of HPV infection in Central Fujian Province during the pandemic. Methods Cervical samples were collected from 21,612 outpatients and 12,664 females who underwent physical examinations and HPV screening at the People’s Hospital of Fujian Province in Fuzhou from April 2020 to April 2023. HPV detection and genotyping were conducted using PCR hybridization. Results The overall HPV infection rate was 16.1% during the COVID-19 pandemic, with the outpatient group exhibiting a greater infection rate (19.0%) than did the healthy group (12.3%). The top five high-risk HPV (HR-HPV) genotypes in both groups were HPV52, HPV53, HPV58, HPV16, and HPV51. Additionally, HPV81 and HPV43 were the two most common low-risk HPV (LR-HPV) genotypes in the patient group, while HPV81 and HPV42 were the two most common LR-HPV genotypes in the healthy group. The highest prevalence of HPV infection was observed in individuals aged ≤ 24 years (28.4%, 95% CI 25.9–30.9), followed by those aged ≥ 55 years (23.6%, 95% CI 21.6–24.7) and other age groups. The prevalence decreased from 23.0% (95% CI 22.4–23.7) in 2018–2019 to 13.8% (95% CI 12.0-15.5) in 2023. Conclusion This study provides valuable insights into the prevalence and genotypes of HPV infection in the female population of Central Fujian Province from 2020 to 2023. The findings indicate that the prevalence of HPV infection in Central Fujian Province remains relatively low compared to the national average. Furthermore, the prevalence of HPV decreased during the COVID-19 pandemic; however, as the pandemic waned, there was potential for an increase in HPV infection rates. Therefore, it is crucial to strengthen HPV screening and vaccination strategies to prevent the potential spread of HPV.

Abstract Background Fostering empathy has been continuously emphasized in the global medical education. Empathy is crucial to enhance patient-physician relationships, and is associated with medical students’ academic and clinical performance. However, empathy level of medical students in China and related influencing factors are not clear. Methods This was a cross-sectional study among medical students in 11 universities. We used the Jefferson Scale of Empathy Student-version of Chinese version to measure empathy level of medical students. Factors associated with empathy were identified by the univariate and multivariate logistic regression analyses. Based on the variables identified above, the nomogram was established to predict high empathy probability of medical students. Receiver operating characteristic curve, calibration plot and decision curve analysis were used to evaluate the discrimination, calibration and educational utility of the model. Results We received 10,901 samples, but a total of 10,576 samples could be used for further analysis (effective response rate of 97.02%). The mean empathy score of undergraduate medical students was 67.38 (standard deviation = 9.39). Six variables including gender, university category, only child or not, self-perception doctor-patient relationship in hospitals, interest of medicine, Kolb learning style showed statistical significance with empathy of medical students (P

Abstract Background Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. Methods Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. Results Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P

Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.

Abstract Background The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood. Methods In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRβ, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib. Results Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5: 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation. Conclusion Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.

Chemotherapeutics can induce immunogenic cell death (ICD) in tumor cells, offering new possibilities for cancer therapy. However, the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment (TME). Here, we developed a pH/reactive oxygen species (ROS) dual-response system to enhance chemoimmunotherapy for melanoma. The system productively accumulated in tumors by specific binding of phenylboronic acid (PBA) to sialic acids (SA). The nanoparticles (NPs) rapidly swelled and released quercetin (QUE) and doxorubicin (DOX) upon the stimulation of tumor microenvironment (TME). The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice, significantly enhancing the effects of the combination. Our study revealed DOX was an ICD inducer, stimulating immune responses and promoting maturation of dendritic cells (DCs). Additionally, QUE served as a TME regulator by inhibiting the cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) axis, which influenced various immune cells, including increasing cytotoxic T cells (CLTs) infiltration, promoting M1 macrophage polarization, and reducing regulatory T cells (Tregs) infiltration. The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment. This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

Abstract Background Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. Results We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV’s impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. Conclusions This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution.

Abstract Selective molecular recognition is an important alternative to the energy-intensive industrial separation process. Porous coordination polymers (PCPs) offer designing platforms for gas separation because they possess precise controllability over structures at the molecular level. However, PCPs-based gas separations are dominantly achieved using strong adsorptive sites for thermodynamic recognition or pore-aperture control for size sieving, which suffer from insufficient selectivity or sluggish kinetics. Developing PCPs that work at high temperatures and feature both high uptake capacity and selectivity is urgently required but remains challenging. Herein, we report diffusion-rate sieving of propylene/propane (C3H6/C3H8) at 300 K by constructing a PCP material whose global and local dynamics cooperatively govern the adsorption process via the mechanisms of the gate opening for C3H6 and the diffusion regulation for C3H8, respectively, yielding substantial differences in both uptake capacity and adsorption kinetics. Dynamic separation of an equimolar C3H6/C3H8 mixture reveals outstanding sieving performance with a C3H6 purity of 99.7% and a separation factor of 318.

BackgroundMigraine is a common primary headache that has a significant impact on patients’ quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background.ObjectiveThe aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort.MethodsIn this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom’s MALDI-TOF iPLEX platform.ResultsIn univariate analysis, ANKDD1B rs904743 showed significant differences in genotype and allele distribution between migraineurs and controls. Furthermore, a machine learning approach was used to perform multivariate analysis. The results of the Random Forest algorithm indicated that ANKDD1B rs904743 was a significant risk factor for migraine susceptibility in China. Additionally, subgroup analysis by the Boruta algorithm showed a significant association between this SNP and migraine comorbid depression. Migraineurs with depression have been observed to have worse scores on the Beck Anxiety Inventory (BAI) and the Migraine Disability Assessment Scale (MIDAS).ConclusionThe study indicates that there is an association between ANKDD1B rs904743 and susceptibility to migraine with and without depression in Chinese patients.

BackgroundStudy engagement is regarded important to medical students’ physical and mental wellbeing. However, the relationship between learning environment of medical schools and the study engagement of medical students was still unclear. This study was aimed to ascertain the positive effect of learning environment in study engagement.MethodsWe collected 10,901 valid questionnaires from 12 medical universities in China, and UWES-S was utilized to assess the study engagement levels. Then Pearson Chi-Square test and Welch’s ANOVA test were conducted to find the relationship between study engagement and learning environment, and subgroup analysis was used to eradicate possible influence of confounding factors. After that, a multivariate analysis was performed to prove learning environment was an independent factor, and we constructed a nomogram as a predictive model.ResultsWith Pearson Chi-Square test (p

Abstract Background Rural settlements are undergoing significant changes under the rapid urbanisation, and understanding their evolution characteristics and surrounding land use will provide a basis for land spatial planning. This study takes Pingnan County, Fujian Province, China as study area, reveals the characteristics of spatial–temporal evolution and surrounding land use transition of settlements during 1985–2020 through landscape metrics, spatial “hot spot” analysis, scale classification statistics, rank-size model, Gini index, land use transition matrix. Results The results show that: (1) Concerning the size and morphological characteristics, the settlements have witnessed a considerable increase in number and scale while remaining stable in shape. (2) Regarding spatial distribution characteristics, the settlements became more evenly spread, forming three main hotspot clusters. (3) Concerning scale structure characteristics, there are significant differences in scale, growth rates, and polarisation of settlements; the polarisation of large settlements shifted from a marked divergence before 2010 to a more balanced trend after 2010. (4) The land use transition around settlements differed in buffer zones and periods. During 1985–2010, settlement expansion heavily depended on cropland, depleting nearby resources, with an increase of woodland and grassland. During 2010–2020, expansion integrated cropland, woodland, and grassland, with cropland growth mainly encroaching on woodland and grassland. Conclusions The study's findings are significant for optimising rural settlement structure in mountains and promoting sustainable land resource use.

Abstract This study focuses on the application of deep learning for transforming semantic point clouds into semantic Building Information Models (BIM) to create a Heritage Digital Twin, centering on Taoping Village, a site of historical and cultural significance in Sichuan, China. Utilizing advanced technologies such as unmanned aerial vehicles and terrestrial laser scanning, we capture detailed point cloud data of the village. A pivotal element of our methodology is the KP-SG neural network, which exhibits outstanding overall performance, particularly excelling in accurately identifying 11 categories. Among those categories, buildings and vegetation, achieves recognition rates of 81% and 83% respectively, and a 2.53% improvement in mIoU compared to KP-FCNN. This accuracy is critical for constructing detailed and accurate semantic BIM models of Taoping Village, facilitating comprehensive architecture and landscape analysis. Additionally, the KP-SG’s superior segmentation capability contributes to the creation of high-fidelity 3D models, enriching virtual reality experiences. We also introduce a digital twin platform that integrates diverse datasets, their semantic information, and visualization tools. This platform is designed to support process automation and decision-making and provide immersive experiences for tourists. Our approach, integrating semantic BIM models and a digital twin platform, marks a significant advancement in preserving and understanding traditional villages like Taoping and demonstrates the transformative potential of deep learning in cultural heritage conservation.

Abstract Background Copy number variation (CNV) of X chromosome can lead to a variety of neonatal abnormalities, especially for male fetuses. In recent years, due to the high sensitivity and high specificity of NIPS, its application has gradually expanded from chromosome aneuploidy to CNV. Few prenatal cases involving the detection of Xq duplication and deletion by NIPS have been reported, but it is of great significance for genetic counseling. Case presentation A 36-year-old woman was referred for prenatal diagnosis and genetic counseling at 17 weeks of gestation because of abnormal result of noninvasive prenatal screening (NIPS). Multiple congenital malformations, hydrocephalus, and enlarged gallbladder were observed by prenatal ultrasound. Amniocentesis revealed the karyotype of the fetus as 46, XN, add(X) (p22.2) and the result of chromosomal microarray analysis was arr[hg19] Xq27.1q28(138,506,454–154896094) × 2 and arr[hg19] Xp22.33p22.32(168,551–5,616,964) × 1. CNV-seq showed that the mother shares a 16.42 Mb duplication in the Xq27.1-q28 region and a 2.97 Mb deletion in the Xp22.33-p22.32 region. After genetic counseling, the couple chose to terminate the pregnancy. Conclusion The combination of NIPS and CMA would be of values in detection of subchromosomal duplications and/or deletions at fetal stage. The detection of X chromosome aberration in a male fetus should give suspicion of the possibility of maternal inheritance.

Genomic selection (GS) has been widely used in livestock, which greatly accelerated the genetic progress of complex traits. The population size was one of the significant factors affecting the prediction accuracy, while it was limited by the purebred population. Compared to directly combining two uncorrelated purebred populations to extend the reference population size, it might be more meaningful to incorporate the correlated crossbreds into reference population for genomic prediction. In this study, we simulated purebred offspring (PAS and PBS) and crossbred offspring (CAB) base on real genotype data of two base purebred populations (PA and PB), to evaluate the performance of genomic selection on purebred while incorporating crossbred information. The results showed that selecting key crossbred individuals via maximizing the expected genetic relationship (REL) was better than the other methods (individuals closet or farthest to the purebred population, CP/FP) in term of the prediction accuracy. Furthermore, the prediction accuracy of reference populations combining PA and CAB was significantly better only based on PA, which was similar to combine PA and PAS. Moreover, the rank correlation between the multiple of the increased relationship (MIR) and reliability improvement was 0.60–0.70. But for individuals with low correlation (Cor(Pi, PA or B), the reliability improvement was significantly lower than other individuals. Our findings suggested that incorporating crossbred into purebred population could improve the performance of genetic prediction compared with using the purebred population only. The genetic relationship between purebred and crossbred population is a key factor determining the increased reliability while incorporating crossbred population in the genomic prediction on pure bred individuals.

Abstract Background Gelsemium elegans is a traditional Chinese medicinal plant and temperature is one of the key factors affecting its growth. RAV (related to ABI3/VP1) transcription factor plays multiple roles in higher plants, including the regulation of plant growth, development, and stress response. However, RAV transcription factor in G. elegans has not been reported. Results In this study, three novel GeRAV genes (GeRAV1-GeRAV3) were identified from the transcriptome of G. elegans under low temperature stress. Phylogenetic analysis showed that GeRAV1-GeRAV3 proteins were clustered into groups II, IV, and V, respectively. RNA-sequencing (RNA-seq) and real-time quantitative PCR (qRT-PCR) analyses indicated that the expression of GeRAV1 and GeRAV2 was increased in response to cold stress. Furthermore, the GeRAV1 gene was successfully cloned from G. elegans leaf. It encoded a hydrophilic, unstable, and non-secretory protein that contained both AP2 and B3 domains. The amino acid sequence of GeRAV1 protein shared a high similarity of 81.97% with Camptotheca acuminata CaRAV. Subcellular localization and transcriptional self-activation experiments demonstrated that GeRAV1 was a nucleoprotein without self-activating activity. The GeRAV1 gene was constitutively expressed in the leaves, stems, and roots of the G. elegans, with the highest expression levels in roots. In addition, the expression of the GeRAV1 gene was rapidly up-regulated under abscisic acid (ABA), salicylic acid (SA), and methyl jasmonate (MeJA) stresses, suggesting that it may be involved in hormonal signaling pathways. Moreover, GeRAV1 conferred improved cold and sodium chloride tolerance in Escherichia coli Rosetta cells. Conclusions These findings provided a foundation for further understanding on the function and regulatory mechanism of the GeRAV1 gene in response to low-temperature stress in G. elegans.

BackgroundIncreasing evidence has suggested that alterations in the gut microbiome are correlated with autoimmune neurologic disorders, yet the causal relationship between them has yet to be established.MethodsFrom the published genome-wide association study (GWAS) summary statistics, we obtained data on the gut microbiota and three autoimmune neurologic disorders (Multiple Sclerosis, Guillain-Barré Syndrome, and Myasthenia Gravis). We then implemented a two-sample Mendelian Randomization (MR) to determine the causal relationship between the gut microbiota and the diseases. To validate the results, we conducted a series of sensitivity analyses. Finally, to verify the direction of causality, a reverse-causality analysis was done.ResultsWe discovered that a higher relative abundance of the genus Ruminococcus2 (OR: 1.213, 95% CI: 1.006–1.462, p = 0.043, PFDR = 0.048) and the genus Roseburia (OR: 1.255, 95% CI: 1.012–1.556, p = 0.038, PFDR = 0.048) were associated with a higher risk of MS. Furthermore, the higher the abundance of the class Mollicutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, PFDR = 0.021), the genus Eubacterium (hallii group) (OR: 2.787, 95% CI: 1.140–6.816, p = 0.025, PFDR = 0.025), and the phylum Tenericutes (OR: 3.016, 95% CI: 1.228–7.411, p = 0.016, PFDR = 0.021) was linked to a greater probability of GBS. Additionally, the higher the abundance of the genus Ruminococcaceae UCG005 (OR: 2.450, 95% CI: 1.072–5.598, p = 0.034, PFDR = 0.036), the genus Holdemania (OR: 2.437, 95% CI: 1.215–4.888, p = 0.012, PFDR = 0.024), genus Lachnoclostridium (OR: 3.681, 95% CI: 1.288–10.521, p = 0.015, PFDR = 0.025) and the genus Eubacterium (ruminantium group) (OR: 2.157, 95% CI: 1.211–3.843, p = 0.003, PFDR = 0.016) correlated with a greater chance of MG occurrence. No SNPs were identified as outliers through sensitivity analysis. Then, the results of the reverse MR analysis did not indicate any reverse causality.ConclusionOur findings demonstrate a causal relationship between the gut microbiota and three autoimmune neurologic disorders, providing novel insights into the mechanisms of these autoimmune neurologic disorders that are mediated by gut microbiota.

Abstract. As one of the most malignant tumors worldwide, lung cancer, fueled by metastasis, has shown rising mortality rates. However, effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step, complicated, and progressive nature. Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment. However, drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response. Consequently, adverse effects occur, such as autoimmunity, from the non-specific immune activation and non-specific inflammation in off-target organs. Nanocarriers that improve drug solubility, permeability, stability, bioavailability, as well as sustained, controlled, and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects. In particular, nanomedicine-based immunotherapy can be utilized to target tumor metastasis, presenting a promising therapeutic strategy for lung cancer. Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment; the breaking away of primary tumors, circulating tumor cell dissemination, and premetastatic niche formation cause distant secondary site colonization. In this review, we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer. We also discuss prospects for the emerging field and the clinical translation potential of these techniques.

Abstract Purpose Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. Methods A case–control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. Results Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (β = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged

Abstract Background Studies exploring influencing factors of emotional engagement among medical students are scarce. Thus, we aimed to identify influencing factors of medical students’ emotional engagement. Methods We carried out a multi-center cross-sectional study among 10,901 medical students from 11 universities in China. The Chinese version of Utrecht Work Engagement Scale-Student version (UWES-S) was used to evaluate emotional engagement level of medical students. The predictors related to engagement level were determined by the logistic regression analysis. Furthermore, we constructed a nomogram to predict emotional engagement level of medical students. Results A total of 10,576 sample were included in this study. The mean emotional engagement score was 74.61(± 16.21). In the multivariate logistic regression model, we found that males showed higher engagement level compared with females [odds ratio (OR) (95% confidence interval (CI)): 1.263 (1.147, 1.392), P

Abstract Background Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic. Methods High-throughput sequence was used to screened the key circRNAs transmitted by extracellular vesicles (EVs) from CAFs to pancreatic cancer cells. The associations between EV-packaged circBIRC6 and chemotherapy responsiveness were validated in a cohort of 82 cases of advanced PDAC patients. Then, the effects of EV-packaged circBIRC6 on CAF-induced oxaliplatin resistance were investigated by flow cytometry, colony formation, viability of pancreatic cancer organoids in vitro and by xenograft models in vivo. RNA pulldown, RNA immunoprecipitation, and sites mutation assays were used to reveal the underlying mechanism. Results We identified a circRNA, circBIRC6, is significantly upregulated in CAF-derived EVs and is positively associated with oxaliplatin-based chemoresistance. In vitro and in vivo functional assays showed that CAF-derived EV-packaged circBIRC6 enhance oxaliplatin resistance of pancreatic cancer cells and organoids via regulating the non-homologous end joining (NHEJ) dependent DNA repair. Mechanistically, circBIRC6 directly binds with XRCC4 and enhanced the interaction of XRCC4 with SUMO1 at the lysine 115 residue, which facilitated XRCC4 chromatin localization. XRCC4K115R mutation dramatically abrogated the EV-packaged circBIRC6 induced effect. Moreover, combination of antisense oligonucleotide inhibitors against circBIRC6 with Olaparib dramatically suppressed chemoresistance in patient-derived xenograft models. Conclusions Our study revealed that EV-packaged circBIRC6 confer oxaliplatin resistance in PDAC by mediating SUMOylation of XRCC4, introducing a promising predictive and therapeutic target for PDAC on oxaliplatin resistance.

In this study LiFePO4/C composite particles were synthesized using five different carbon sources via a one-step sol-gel method. La-doped LiFePO4 was also synthesized using the sol-gel method. The XRD pattern of LixLayFePO4 (x = 0.9~1.0, y = 0~0.1) after being calcined at 700 °C for 10 h indicates that as the doping ratio increased, the sample’s cell volume first increased then decreased, reaching a maximum value of 293.36 Å3 (x = 0.94, y = 0.06). The XRD patterns of Li0.92La0.08FePO4 after being calcined at different temperatures for 10 h indicate that with increasing calcination temperature, the (311) diffraction peak drifted toward a smaller diffraction angle. Similarly, the XRD patterns of Li0.92La0.08FePO4 after being calcined at 700 °C for different durations indicate that with increasing calcination times, the (311) diffraction peak drifted toward a larger diffraction angle. The infrared spectrum pattern of LixLayFePO4 (x = 0.9~1.0, y = 0~0.1) after being calcined at 700 °C for 10 h shows absorption peaks corresponding to the vibrations of the Li–O bond and PO43- group. An SEM analysis of LixLayFePO4 (x = 1, y = 0; x = 0.96, y = 0.04; x = 0.92, y = 0.08) after being calcined at 700 °C for 10 h indicates that the particles were irregular in shape and of uniform size. The hysteresis loops of Li0.92La0.08FePO4 after being calcined at 600 °C, 700 °C, or 800 °C for 10 h indicate that with increasing calcination temperature, the Ms gradually increased, while the Mr and Hc decreased, with minimum values of 0.08 emu/g and 58.21 Oe, respectively. The Mössbauer spectra of LixLayFePO4 (x = 1, y = 0; x = 0.96, y = 0.04; x = 0.92, y = 0.08) after being calcined at 700 °C for 10 h indicate that all samples contained Doublet(1) and Doublet(2) peaks, dominated by Fe2+ compounds. The proportions of Fe2+ were 85.5% (x = 1, y = 0), 89.9% (x = 0.96, y = 0.04), and 96.0% (x = 0.92, y = 0.08). The maximum IS and QS of Doublet(1) for the three samples were 1.224 mm/s and 2.956 mm/s, respectively.

Amid global industrialization and urbanization, mountainous rural settlements, especially those in metropolitan fringe area, are experiencing significant spatial changes in location and scale. This study takes Pingnan County, Fujian Province, China, as an example. Utilizing land use data and employing methods including standard deviation ellipse, average nearest neighbor index, kernel density estimation, spatial hotspot detection, binary logistic regression model, and Geodetector, this study aims to scientifically identify the spatial pattern characteristics and influencing factors of its settlements. The results show that: (1) The spatial distribution of settlements in Pingnan County is biased toward the southern part of the county; the center of settlement's spatial distribution is located south of the junction of Gufeng Town and Pingcheng Town; the spatial distribution trend of settlements is north-east-southwest. Settlements are generally aggregated, and the aggregation degree of Gufeng Town is obviously lower than that of other towns. (2) The density distribution of settlements presents a “core-periphery” structure and a “north-south linear” structure in space; the spatial pattern characteristics show high-density, large patches in Gufeng Town, high-density, small patches in Changqiao Town, Tangkou Town and Gantang Town, and medium-density or low-density, small patches in other towns. (3) Settlement location is mainly affected by the elevation, distance to cultivated land, and distance to main roads, while settlement scale is mainly affected by slope, relief degree of land surface, and distance to urban centers. The interaction between these factors exhibits enhancement effects, with natural terrain and location conditions exerting the most prominent influence. These findings underscore the strong constraints posed by natural topography on mountainous rural settlements in metropolitan fringe areas, coupled with a more pronounced influence from socio-economic factors. The study's results hold significant implications for optimizing the layout of such settlements, guiding land spatial planning, and promoting rural revitalization.

Contractor’s consummate performance behavior (CPB) is the key to achieve consummate performance. However, the mechanism of reasonable contract risk allocation incentives for Contractor’s CPB is unknown. The objective of this study is to reveal the effective ways to encourage contractor’s CPB by contract risk allocation based on the contract reference point theory and selecting the contractor’s trust perception and fair perception as mediating variables. Through an empirical analysis of the valid questionnaires collected, the results are as follows: (1) Although the economic benefits generated by reasonable contract risk allocation can induce contractor’s fair perception, fair perception has no mediating effect in the relationship between contract risk allocation and contractor’s CPB; (2) The cooperative value generated by reasonable contract risk allocation can induce contractor’s trust perception, and trust perception plays a part mediating role between contract risk allocation and contractor’s CPB. The findings also provide insights into how risk allocation facilitates contractor’s CPB in the construction industry.

Abstract Magnetization in a ferromagnetic layer could be manipulated by the spin-orbit torque whose generation commonly relies on the spin-orbit coupling from the adjacent heavy-metal layer within the bilayer. The fact that the magnetic topological insulator possesses both the ferromagnetic order with perpendicular anisotropy and inherent spin-orbit coupling inspires to realize such a torque-induced magnetization switching without forming any heterostructure with other materials. Here, only using a single layer of magnetically-doped topological insulator Cr:(Bi,Sb)2Te3, we realize a magnetization switching only by applying a large dc current. Assisted by the magnetic history, such a switching behaves nonvolatile under zero field but becomes volatile otherwise, as consistently shown by magnetoelectric transports and magneto-optical Kerr effect measurements. Static and quasistatic current are found to be equivalent for the switching. We propose that this switching may associate with the torque resulted from the spin-orbit coupling and the compositional asymmetry in the Cr-profile of the single layer.

To clarify the mechanism of resistance of Bacillus velezensis TP-1 to gray mold, a marker strain TP-1R was screened for resistance to 300 μg/mL of rifampicin by an antibiotic marker method in this study. The genetic stability of the resistance of the marker strains and their antagonism to gray mold of grapes were studied, and their colonization in grapes and their effect on the activity of defence enzymes in the grapes were analysed. The results showed that the labeled strain could still grow stably in the medium containing rifampicin after 15 times of subculture, and the antagonistic effect of the labeled strain against gray mold was not significantly different from that of the original strain. The colonization amount of the labeled strain reached the peak of 4.32×106 CFU/g on the 15th day of storage (20 ℃), and was still 3.11×106 CFU/g on the 30th day of storage, indicating that strain TP-1 could be stably colonized on grapes. Inoculation of strain TP-1 fermentation broth could effectively inhibit the occurrence of gray mold and resultantly reduced the decay rate of grapes. During storage, the activity of grape defence enzymes PAL, PPO and APX increased first and then decreased, and the activity of the three enzymes in the group treated with the antagonistic bacterium TP-1 was significantly higher than CK (P

Abstract The quasi-1D chiral edge states in a quantum anomalous Hall insulator are dissipationless, while the 2D helical surface states in a topological insulator are insensitive to spin-independent scatterings due to the topological protection. Both serve as essential ingredients for topological electronics. Here, we integrate these states into a single device using selective area epitaxy based on the molecular beam epitaxy technique. The chiral edge state comes from the quantum anomalous Hall insulator Cr:(Bi,Sb)2Te3, while the helical surface state comes from the intrinsic topological insulator (Bi,Sb)2Te3 which only interfaces with a partial edge of the former, forming a selective-area heterostructure. At the heterointerface, the chiral state in Cr:(Bi,Sb)2Te3 is allowed to be scattered into (Bi,Sb)2Te3 so that the incoming current will be redistributed according to the coordination between the chirality and helicity. Our device enables the collaboration between chiral and helical states for low-dissipative transport with tunable current dimension.

Abstract Rhabdomyolysis is a syndrome potentially fatal and has been associated with selective serotonin reuptake inhibitors (SSRIs) treatment in a few case reports. Herein, we purpose to establish the correlation between SSRIs use and rhabdomyolysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. We conducted an analysis on reports that were submitted to the FAERS database during the period between January 1, 2004, and December 31, 2022. Four algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), were employed to quantify the signals of rhabdomyolysis associated with SSRIs. In total, 16,011,277 non-duplicated reports were obtained and analyzed. Among 33,574 reports related to rhabdomyolysis, SSRIs were classified as primary suspected drug in 889 cases. Disproportionality analysis identified a positive signal between rhabdomyolysis and SSRIs (ROR: 2.86, 95% CI 2.67–3.05; PRR: 2.84, χ2: 1037.16; IC0.25 = 1.39; EBGM0.5 = 2.64). Among six SSRIs, fluvoxamine had the strongest signal (ROR: 11.64, 95% CI 8.00–16.93; PRR: 11.38, χ2: 265.51; IC0.25 = 2.41; EBGM0.5 = 8.31), whereas no significant signal of rhabdomyolysis was detected for paroxetine (ROR: 1.83, 95% CI 1.55–2.15; PRR: 1.82, χ2: 53.82; IC0.25 = 0.73; EBGM0.5 = 1.59). After excluding cases co-administered with statins, the signal of rhabdomyolysis associated with SSRIs remains significant. Our analysis reveals that there are differences in safety signals among six SSRIs in respect to the risk of rhabdomyolysis, with fluvoxamine displaying the highest risk signal, while paroxetine did not show a significant signal. Given the potentially lethal nature of rhabdomyolysis, healthcare professionals should inform patients of the potential risk of rhabdomyolysis associated with SSRIs prior to initiating treatment.

Abstract Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found that roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application is limited by its hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed a pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) that targeted both CD44 and folate receptors, and investigated its pharmacological mechanism. In rat RA model, the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA, as well as strongly reducing inflammatory cytokine levels and promoting tissue repair. Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA. Since the balance of pro- and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA, this reprogramming is likely responsible for the anti-RA effect. Furthermore, we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA, but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.

Inonotus obliquus, a medicinal fungus, has garnered significant attention in scientific research and medical applications. In this study, protoplasts of the I. obliquus HS819 strain were prepared using an enzymatic method and achieved a regeneration rate of 5.83%. To enhance polysaccharide production of I. obliquus HS819, atmospheric and room temperature plasma (ARTP) technology was employed for mutagenesis of the protoplasts. Through liquid fermentation, 32 mutant strains exhibiting diverse characteristics in morphology, color of the fermentation broth, mycelial pellet size, and biomass were screened. Secondary screening identified mutant strain A27, which showed a significant increase in polysaccharide production up to 1.67 g/L and a mycelial dry weight of 17.6 g/L, representing 137.67% and 15% increases compared to the HS819 strain, respectively. Furthermore, the fermentation period was reduced by 2 days, and subsequent subculture cultivation demonstrated stable polysaccharide production and mycelial dry weight. The genome resequencing analysis of the HS819 strain and mutant strain A27 revealed 3790 InDel sites and mutations affecting 612 functional genes associated with polysaccharide synthesis. We predict that our findings will be helpful for high polysaccharide production through genetic engineering of I. obliquus.

Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.

Metastasis is the leading cause of cancer-related death. Despite extensive treatment, the prognosis for patients with metastatic cancer remains poor. In addition to conventional surgical resection, radiotherapy, immunotherapy, chemotherapy, and targeted therapy, various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects. However, nanomedicines exhibit certain limitations in clinical applications, such as rapid clearance from the body, low biological stability, and poor targeting ability. Biomimetic methods utilize the natural biomembrane to mimic or hybridize nanoparticles and circumvent some of these limitations. Considering the involvement of immune cells in the tumor microenvironment of the metastatic cascade, biomimetic methods using immune cell membranes have been proposed with unique tumor-homing ability and high biocompatibility. In this review, we explore the impact of immune cells on various processes of tumor metastasis. Furthermore, we summarize the synthesis and applications of immune cell membrane-based nanocarriers increasing therapeutic efficacy against cancer metastases via immune evasion, prolonged circulation, enhanced tumor accumulation, and immunosuppression of the tumor microenvironment. Moreover, we describe the prospects and existing challenges in clinical translation.

Objective Dynamization of the external fixator, defined as gradually decreasing construct‐stability of the fixator, is widely accepted as a method for treatment during the late phase of the bone healing process. However, the dynamization is mostly based on the subjective experience of orthopaedists at present, without unified standards and a clear theoretical basis. The objective of the study is to investigate the influence of the dynamization operations on the tibial mechanical properties with a hexapod circular external fixator and standardize the dynamization process. Methods A 3D‐printed tibial defects model with Young's modulus of 10.5 GPa and Poisson's ratio of 0.32 simulated the clinically fractured bone. A 10 × ∅ 45 mm silicone sample with Young's modulus of 2.7 MPa and Poisson's ratio of 0.32 simulated the callus in the fracture site. Furthermore, a hexapod circular external fixator whose struts were coded from #1 to #6 was fixed on the model with six half‐pins (5 mm diameter). Corresponding to the action of removing and loosening the struts, 17 dynamization operations are designed. For each construct after different dynamization operations, the mechanical environment changes in the fracture site were recorded by a triaxle forces sensor under gradually increasing external load from 0 to 500 N. Results The results show that the bone axial load‐sharing ratio of each construct in the removal group was generally higher than that in the loosening group. The ratio increased from 92.51 ± 0.74% to 102.68 ± 0.27% with the number of operated struts rising from 2 to 6. Besides, the constructions with the same number of operated struts but with different strut codes such as constructions 3–5, had similar bone axial load‐sharing ratios. In addition, the proposed dynamization method of the hexapod circular external fixator can gradually increase the bone axial load‐sharing ratio from 90.73 ± 0.19% to 102.68 ± 0.27% and maintain the bone radial load‐sharing ratio below 8%. Conclusion The laboratory study verified the effects of the type of operations and the number of operated struts on the bone axial load‐sharing ratio, as well as the slight influence of the choice of the strut code. Besides, a dynamization method of the hexapod circular external fixator was proposed to increase the bone axial load‐sharing ratio gradually.

Urban green spaces shaped by the post-industrial landscape possess distinctive characteristics and aesthetic features due to the exceptional properties of industrial remains. Previous studies have indicated that various types of urban green spaces without industrial remains, such as urban parks, waterfronts, and streets, have a positive impact on the public's physiological and psychological well-being. However, the extent and mechanisms of the public's response to post-industrial landscapes remain unclear. To investigate mechanisms of public perceptions of and preferences for post-industrial landscape types and elements, we conducted quantitative analysis by coupling multimodal data and comparative or difference analyses among urban green spaces. We conducted a randomized controlled experiment with 48 participants who viewed images of different combinations of post-industrial landscapes in a distraction-free environment. After a pause, Positive-Negative perception and Preference questionnaires were completed. Eye tracking data were recorded during the experiment. Changes in electrodermal activity and heart rate variability were used to measure physiological stress. This study employed Pearson's correlation model to examine the relationships between objective data and subjective data. The ANOVA test was utilized to investigate the variability of objective and subjective data across different groups. Additionally, a multiple-stepwise regression model was employed to analyze the specific influencing factors and their respective degrees of influence. We found that (1) artificial landscape elements in post-industrial landscapes were more appealing to participants and heightened their sense of stress; natural landscape elements can alleviate stress and promote restoration. (2) The percentage of flowering shrub and tree elements was significantly positively correlated with preference, while the percentage of ground-covering plant elements was significantly negatively correlated with preference. (3) Industrial construction was significantly positively correlated with the sense of historical value while industrial construction and pavement elements negatively correlated with preference. However, pavement elements significantly mitigated the sense of insecurity, poor accessibility, and pollution risk. (4) Industrial construction and pavement distinguished the post-industrial landscape from other green spaces without industrial remains while maximizing historical value and curiosity helped increase positive effects. Although impact mechanisms of natural elements in other green spaces without industrial remains showed homogeneous similarities, the scene composed of industrial mixed with natural elements may lead to different perceptions. Our findings indicate that multimodal data coupled with comparative analysis of multiple green space types can help to fully identify mechanisms by which landscape types and elements influence public perceptions and preferences. This understanding can help increase public satisfaction with post-industrial landscapes and enable researchers to determine the sustainability of post-industrial sites using interrogative design.

Abstract Background The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial, and more high‐level clinical evidence is needed. This study aimed to evaluate the outcome of extended pancreatoduodenectomy (EPD) with retroperitoneal nerve resection in pancreatic head cancer. Methods This multicenter randomized trial was performed at 6 Chinese high‐volume hospitals that enrolled patients between October 3, 2012, and September 21, 2017. Four hundred patients with stage I or II pancreatic head cancer and without specific pancreatic cancer treatments (preoperative chemotherapy or chemoradiation) within three months were randomly assigned to undergo standard pancreatoduodenectomy (SPD) or EPD, with the latter followed by dissection of additional lymph nodes (LNs), nerves and soft tissues 270° on the right side surrounding the superior mesenteric artery and celiac axis. The primary endpoint was overall survival (OS) by intention‐to‐treat (ITT). The secondary endpoints were disease‐free survival (DFS), mortality, morbidity, and postoperative pain intensity. Results The R1 rate was slightly lower with EPD (8.46%) than with SPD (12.56%). The morbidity and mortality rates were similar between the two groups. The median OS was similar in the EPD and SPD groups by ITT in the whole study cohort (23.0 vs. 20.2 months, P = 0.100), while the median DFS was superior in the EPD group (16.1 vs. 13.2 months, P = 0.031). Patients with preoperative CA19–9 < 200.0 U/mL had significantly improved OS and DFS with EPD (EPD vs. SPD, 30.8 vs. 20.9 months, P = 0.009; 23.4 vs. 13.5 months, P < 0.001). The EPD group exhibited significantly lower locoregional (16.48% vs. 35.20%, P < 0.001) and mesenteric LN recurrence rates (3.98% vs. 10.06%, P = 0.022). The EPD group exhibited less back pain 6 months postoperation than the SPD group. Conclusions EPD for pancreatic head cancer did not significantly improve OS, but patients with EPD treatment had significantly improved DFS. In the subgroup analysis, improvements in both OS and DFS in the EPD arm were observed in patients with preoperative CA19–9 < 200.0 U/mL. EPD could be used as an effective surgical procedure for patients with pancreatic head cancer, especially those with preoperative CA19–9 < 200.0 U/mL.

YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), an m6A reader, has a role in the development and progression of breast cancer as well as the immunological microenvironment. The networks of competing endogenous RNA in cancer have received much attention in research. In tumor gene therapy, the regulatory networks of m6A and competing endogenous RNA are increasingly emerging as a new route. We evaluated the relationship between the YTHDF1 expression, overall survival, and clinicopathology of breast cancer using TCGA, PrognoScan, and other datasets. We used Western blot to demonstrate that YTHDF1 is substantially expressed in breast cancer tissues. Furthermore, we explored YTHDF1′s functions in the tumor mutational burden, microsatellite instability, and tumor microenvironment. Our findings indicate that YTHDF1 is a critical component of the m6A regulatory proteins in breast cancer and may have a particular function in the immunological microenvironment. Crucially, we investigated the relationship between YTHDF1 and the associated competitive endogenous RNA regulatory networks, innovatively creating three such networks (Dehydrogenase/Reductase 4-Antisense RNA 1-miR-378g-YTHDF1, HLA Complex Group 9-miR-378g-YTHDF1, Taurine Up-regulated 1-miR-378g-YTHDF1). Furthermore, we showed that miR-378g could inhibit the expression of YTHDF1, and that miR-378g/YTHDF1 could impact MDA-MB-231 proliferation. We speculate that YTHDF1 may serve as a biomarker for poor prognosis and differential diagnosis, impact the growth of breast cancer cells via the ceRNA network axis, and be a target for immunotherapy against breast cancer.

Additive manufacturing, particularly the laser powder bed fusion (LPBF) technique, has ushered in a new era of intricate metallic component fabrication, leveraging the exceptional performance of the Ti6Al4V alloy. However, the intricate mechanical behavior of additively manufactured Ti6Al4V, particularly its anisotropic attributes stemming from non-equilibrium microstructures, presents a formidable challenge. In this study, we embark on a comprehensive exploration of the anisotropic mechanical properties exhibited by LPBFed Ti6Al4V alloy. The interplay between microstructure and tensile response is unraveled by integrating experimental investigations with crystal plasticity finite element (CPFE) simulations. The acquired empirical data with CPFE model predictions are harmonized through systematic tensile tests along distinct processing orientations. The results unveil the genesis of plastic anisotropy within the LPBFed Ti6Al4V alloy, ascribed to the emergence of columnar grains meticulously aligned along the building direction, despite the intricate material microstructure inherent to additive manufacturing. These findings collectively furnish a holistic comprehension of the intricate nexus between material attributes and the mechanical manifestations intrinsic to metal components realized through additive manufacturing modalities.

Osteoarthritis (OA) is a common joint disease characterized by chronic pain, and the perception of pain is closely associated with brain function and neuropeptide regulation. Rehmannia is common plant herb with anti-inflammatory and analgesic properties that is used to treat OA. However, it is unclear whether Rehmannia alleviates OA-related pain via regulation of neuropeptides and brain function. We examined the pain relief regulatory pathway in OA after treatment with Rehmannia by verifying the therapeutic effect of Rehmannia alcohol extract in vivo and vitro and exploring of the potential mechanism underlying the analgesic effect of Rahmanian using functional magnetic resonance imaging and measuring neuropeptide secretion. Our results showed that Rehmannia alcohol extract and the related active ingredient, Rehmannioside D, can delay cartilage degradation and alleviate inflammation in OA rats. The Rehmannia alcohol extract can also relieve OA pain, reduce the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP), and reverse the pathological changes in the cerebral cortex and hippocampus. Our research results demonstrate that Rehmannia alleviates OA pain by protecting cartilage, preventing the stimulation of inflammatory factors on neuropeptide secretion, and influencing the relevant functional areas of the brain.

Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA).Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator.Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group.Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile.Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).

BackgroundBreast cancer (BC) is the most common cancer in women and is highly heterogeneous. BC can be classified into four molecular subtypes based on the status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker protein Ki-67. However, they can only be obtained by biopsy or surgery, which is invasive. Radiomics can noninvasively predict molecular expression via extracting the image features. Nevertheless, there is a scarcity of data available regarding the prediction of molecular biomarker expression using ultrasound (US) images in BC.ObjectivesTo investigate the prediction performance of US radiomics for the assessment of molecular profiling in BC.MethodsA total of 342 patients with BC who underwent preoperative US examination between January 2013 and December 2021 were retrospectively included. They were confirmed by pathology and molecular subtype analysis of ER, PR, HER2 and Ki-67. The radiomics features were extracted and four molecular models were constructed through support vector machine (SVM). Pearson correlation coefficient heatmaps are employed to analyze the relationship between selected features and their predictive power on molecular expression. The receiver operating characteristic curve was used for the prediction performance of US radiomics in the assessment of molecular profiling.Results359 lesions with 129 ER- and 230 ER+, 163 PR- and 196 PR+, 265 HER2- and 94 HER2+, 114 Ki-67- and 245 Ki-67+ expression were included. 1314 features were extracted from each ultrasound image. And there was a significant difference of some specific radiomics features between the molecule positive and negative groups. Multiple features demonstrated significant association with molecular biomarkers. The area under curves (AUCs) were 0.917, 0.835, 0.771, and 0.896 in the training set, while 0.868, 0.811, 0.722, and 0.706 in the validation set to predict ER, PR, HER2, and Ki-67 expression respectively.ConclusionUltrasound-based radiomics provides a promising method for predicting molecular biomarker expression of ER, PR, HER2, and Ki-67 in BC.

Abstract Background Hashimoto’s thyroiditis (HT) is an autoimmune disease. Recent studies have found that the gut microbiota may play an important role in inducing HT, but there are no systematic studies on the changes in the gut microbiota during the development of HT. Methods In this study, 16S rDNA high-throughput sequencing technology in combination with the Kruskal–Wallis test, CCA/RDA analysis, Spearman correlation analysis, and other statistical methods were used to analyze the effects of age, gender, hormones, and other environmental factors on gut microbiota by comparing the differences in the microbiota at different stages of HT development. Results The results showed that there were differences in the gut microbiota composition between healthy people (HCA) and in patients with HT. Lachnoclostridium, Bilophila, and Klebsiella were enriched in the HCA group, while Akkermansia, Lachnospiraceae, Bifidobacterium, Shuttleia, and Clostriworthdia were enriched in the HT group. Environmental factors analysis revealed that the Bifidobacterium and Klebsiella were two groups of bacteria that have undergone dramatic changes in HCA and HT, and mainly affected by gender. Romboutsia and Haemophilus regulated by the hormone of free triiodothyronine (FT3) may promote the development of HT, while Faecalibacterium and Lachnospiraceae regulated by free thyroxine (FT4) may protect the host. Conclusions Comprehensive studies have shown that gender is an important factor affecting gut microbial composition, but with the development of HT, hormones, age, and TSH begin to become dominant factors.

【Objective】Four genetic parameters including days to 100 kg (DAYS_100), average daily gain (ADG_100), loin muscle area (LMA_100) and average back fat thickness (BFT_100) at 100 kg body weight in a Landrace pig population were estimated, and the correlations between traits as well as genetic and phenotypic progress of the four traits were analyzed, which could provide a basis for the genetic improvement of the target population.【Method】Records of growth traits of Landrace pigs were collected in a core breeding pig farm in Guangxi from 2002 to 2020. A fixed effect analysis on the factors affecting the growth traits of Landrace pigs was conducted by R software. In addition, the genetic parameters of the four traits were estimated with DMU software and a multi-trait animal model. Furthermore, the genetic correlations and phenotypic correlations between these traits, genetic progress and phenotypic progress were evaluated.【Result】The estimated heritability for the four growth traits of Landrace pigs, including DAYS_100, ADG_100, LMA_100 and BFT_100 were 0.399, 0.391, 0.433 and 0.421, respectively, and all of them had medium to high heritability. Both genetic correlation and phenotypic correlation between DAYS_100 and ADG_100 were significantly negative, with correlation coefficient -0.997 and -0.992, respectively. In general, the phenotypic trend of DAYS_100 was rising while the phenotypic trends of ADG_100, LMA_100 and BFT_100 were declining; the genetic trends of ADG_100 and BFT_100 showed an overall upward trend while the trends of DAYS_100 and LMA_100 were generally downward.【Conclusion】The four growth traits of Landrace pigs are medium-high heritability traits, therefore, their genetic progress can be accelerated through direct selection. There is a strong correlation between DAYS_100 and ADG_100. The management of phenotypic measurement of pig farms and the selection of target traits for pig population breeding have an important impact on the performance of growth traits. In addition, the improvements in farm production management and changes in breed structure may influence genetic progress.

Background: Hyperchloremia is associated with increased mortality in critically ill patients. The objective of this study was to investigate the association between increased chloride levels and mortality outcomes in intracerebral hemorrhage (ICH) patients admitted to the intensive care unit (ICU). Methods: We performed a retrospective study of all patients diagnosed with ICH and included in the Medical Information Mart for Intensive Care (MIMIC-Ⅲ) from 2001 to 2012. Inclusion criteria were the first diagnosis of ICH, ICU length of stay (LOS) over 72 h, and not receiving hypertonic saline treatment. Serum chloride perturbation within 72 h of admission was evaluated as a predictor of outcomes. The increase in chloride from baseline was dichotomized based on an increase in chloride in 72 h (≤5 mmol/L or >5 mmol/L). The primary outcome was 90-day mortality. Results: A total of 376 patients (54.5% male, median age 70 years, interquartile range:58–79 years) were included. The overall 90-day mortality was 32.2% (n=121), in-hospital mortality was 25.8% (n=97), and Day 2 acute kidney injury (AKI) occurred in 29.0% (n=109) of patients. The prevalence of hyperchloremia on admission, during the first 72 h, and an increase in chloride (>5 mmol/L) were 8.8%, 39.4%, and 42.8%, respectively. After adjusting for confounders, the hazard ratio of increase in chloride (>5 mmol/L) was 1.66 (95% confidence interval:1.05–2.64, P=0.031). An increase in chloride (>5 mmol/L) was associated with a higher odds ratio for 90-day mortality in both the AKI and non-AKI groups. Conclusions: An increase in chloride from baseline is common in adult patients with ICH admitted to ICU. The increase is significantly associated with elevated mortality. These results support the significance of diligently monitoring chloride levels in these patients.

Conventional eye treatment formulation such as eye drops has shortcomings including low drug utilization and poor patient compliance. The contact lens(CL), well-known as visual correction lens, is considered to be a more promising ophthalmic drug delivery vehicle owing to its good biocompatibility, long-term wearing comfort, prolonged drug residence time and improved bioavailability. In order to improve the drug loading efficiency and prolong the release time, researchers have developed a variety of strategies to modify traditional CL, including the introduction of vitamin E molecular barrier, application of molecular imprinting technology of CL, increasing interactions between the drug and polymer matrix by introducing special genes, and incorporation of nanocarriers or drug-loaded polymer films. In this paper, the preparation methods and pros and cons of drug-loaded CL are reviewed. At last, the existing problems and future developments of CL as ophthalmic drug delivery carrier are briefly discussed.

Abstract Background To estimate the incidence, risk factors, and impact on mortality and functional outcomes for early coagulopathy after the return of spontaneous circulation (ROSC) in pediatric out-of-hospital cardiac arrest (OHCA) patients. Methods A post hoc analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) trial was conducted. Early coagulopathy was defined as presence of at least one of the following coagulation abnormalities upon admission: international standard ratio (INR), platelets, and age-adjusted activated partial thromboplastin time (APTT) within 6 h after OHCA and before therapeutic hypothermia initiation. The outcomes included 28-day mortality and functional prognosis. Multivariable logistic regression models were used to explore risk factors and association between early coagulopathy and outcomes. Results Of the 227 patients included, 152 (67%) were male and the median age was 2.3 years [interquartile range (IQR), 0.7–8.6 years]. The overall 28-day mortality was 63%. The incidence of early coagulopathy was 46%. Lower age, longer duration of chest compression, lower temperature, and higher white blood cell (WBC) upon admission increased the risk of early coagulopathy. Early coagulopathy [OR, 2.20 (95% CI, 1.12–4.39), P = 0.023] was independently associated with 28-day mortality after adjusting for confounders. Conclusions Early coagulopathy occurred in almost half of pediatric patients with OHCA. Lower age, longer duration of chest compression, lower temperature, and higher WBC increased the risk. The development of early coagulopathy was independently associated with increased mortality.