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Abstract Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD.

Urolithiasis is a heat-specific disease. Exploring heat-related urolithiasis susceptibility subtypes, economic burden, and modifying factors could assist governments in targeting interventions to reduce the heat-related health risks of urolithiasis morbidity. We collected data on 23,492 patients with upper urinary tract stones (main subtypes of urolithiasis) from 2013 to 2017 in Nanjing, China. We adopted generalized additive quasi-Poisson models to examine the associations between daily mean temperatures and morbidity of upper urinary tract stones, while generalized additive Gaussian models were used to explore the relationships between temperatures and log-transformed medical costs. We examined the modification effects of disease subtypes (kidney and ureteral calculus), sex, and age through stratified analyses and the modification effects of other meteorological factors by introducing interaction terms in the models. We found that short-term summer heat exposure has a statistically significant effect on ureteral calculus morbidity but not on kidney calculus morbidity. For ureter calculus, a 1 °C temperature increase was associated with a 4.36% (95% confidence interval [CI]: 1.94%, 6.83%) increase in daily hospitalization and a 5.44% (95% CI: 2.71%, 8.25%) increase in daily medical costs. The attributable fraction associated with heat (greater than the median value of daily mean temperature, 26.8 °C) was 7.85% (95% empirical confidence interval [eCI]: 3.64%, 11.44%) for hospitalization and 9.36% (95% eCI: 4.91%, 13.14%) for medical costs. The effects of heat on ureter calculus morbidity were significantly higher among the males and those with high sunshine duration than females and those with low sunshine duration. Short-term summer heat exposure was associated with increased morbidity and medical costs of ureteral calculus. Relevant government organizations should take effective intervention measures, including community health education, to reduce the health hazards and economic losses caused by heat.

Abstract Background Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. However, it is still not well understand about the relationship between PCDH15 variants and RP. Methods In this study, we enrolled a Chinese autosomal recessive retinitis pigmentosa (arRP) pedigree and identified the causative gene in the proband by targeted whole exome sequencing (WES). The variants were validated in the family members by Sanger sequencing and co-segregation analysis. Results Novel compound heterozygous, Frame shift variants of the PCDH15 gene, NM_001384140.1:c.4368 − 2147_4368-2131del and NM_001384140.1:c exon19:c.2505del: p. T836Lfs*6 were identified in the arRP pedigree, which co-segregated with the clinical RP phenotypes. The PCDH15 protein is highly conserved among species. Conclusion This is the first study to identify novel compound heterozygous variants c.4368 − 2147_4368-2131del and c.2505del(p.T836Lfs*6) in the PCDH15 gene which might be disease-causing variants, and extending the variant spectra. All above findings may be contribute to genetic counseling, molecular diagnosis and clinical management of arRP disease.

Abstract Translational control plays a crucial role in the regulation of apoptosis, with the EIF4 family serving as one of the mRNA translation factors that modulate the process of mRNA translation based on mRNA characteristics. To address this potential causal role of EIF4 family proteins and breast cancer, Mendelian randomization was employed. The study incorporated four sets of genetics instrumental variables, namely EIF4E, EIF4B, EIF4A, and EIF4EBP2. The outcome variables selected for analysis were the BCAC consortium, which included estrogen receptor positive (ER+) and estrogen receptor negative (ER−) samples. To assess the potential violations of the MR assumption, the primary MR analysis employed inverse variance weighted (IVW), and several sensitivity analyses were conducted. The findings of the two-sample MR analysis indicate that EIF4E has an adverse effect on breast cancer risk (p = 0.028). However, the evidence for the relationship between EIF4E and ER status of breast cancer suggests a weak association with ER+ breast cancer (p = 0.054), but not with ER- breast cancer (p > 0.05). The study findings indicate that EIF4A is not causally linked to the risk of ER+ breast cancer, but is significantly associated with an elevated risk of ER− breast cancer (p = 0.028). However, the evidence is inadequate to support the effects of EIF4B and EIF4EBP2 on breast cancer (p > 0.05). Our results suggest that EIF4 may be a potential factor in the occurrence and development of breast cancer, which may lead to a better understanding of its causes and prevention.

Abstract Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

Abstract Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson’s (STAB1, KCNA10), Alzheimer’s (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson’s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Introduction Sjögren’s syndrome (SS) and rheumatoid arthritis (RA) are two chronic autoimmune diseases. To date, there have been few reports on the overlap between SS and RA in China, especially regarding correlated acute renal failure cases. Material and methods To provide a reference for our clinical peers, this article presents the case report of an elderly female patient who was diagnosed with acute renal failure caused by SS and RA overlap syndrome. Results We also provide a relevant analysis of SS and RA overlap syndrome treatment. Conclusions We also provide a relevant analysis of SS and RA overlap syndrome treatment.

Abstract The cryopreservation and transplantation of ovarian tissue underscore its paramount importance in safeguarding reproductive capacity and ameliorating reproductive disorders. However, challenges persist in ovarian tissue cryopreservation and transplantation (OTC-T), including the risk of tissue damage and dysfunction. Consequently, there has been a compelling exploration into the realm of nanoregulators to refine and enhance these procedures. This review embarks on a meticulous examination of the intricate anatomical structure of the ovary and its microenvironment, thereby establishing a robust groundwork for the development of nanomodulators. It systematically categorizes nanoregulators and delves deeply into their functions and mechanisms, meticulously tailored for optimizing ovarian tissue cryopreservation and transplantation. Furthermore, the review imparts valuable insights into the practical applications and obstacles encountered in clinical settings associated with OTC-T. Moreover, the review advocates for the utilization of microbially derived nanomodulators as a potent therapeutic intervention in ovarian tissue cryopreservation. The progression of these approaches holds the promise of seamlessly integrating nanoregulators into OTC-T practices, thereby heralding a new era of expansive applications and auspicious prospects in this pivotal domain. Graphical Abstract

Abstract Background HIF-1α is thought to be a novel regulator which contributes to carcinogenesis. However, the mechanism underlying the effect of HIF-1α in gliomas remains largely unknown. Methods In the research, we demonstrate that HIF-lα mRNA and protein levels are elevated in glioma cells. The colony formation assays, transwell assays, and wound-healing assays showed that overexpression of HIF-1α promoted proliferation and invasion of glioma cells. Results Overexpression of HIF-lα also increased the expression of inflammatory factors related to pyrolysis (TNF-α, IL-10, and IL-1β) and protein related to pyrolysis signal pathway (NLRP3, ASC, caspase-1, GSDMD, and GSDME). Conclusions Therefore, we speculate that HIF-1α promotes the proliferation and invasion of glial cells by regulating pyrolysis pathway. These results might provide a novel strategy and target for treatment of glioma.

Abstract Background Populations of the plant pathogenic fungus Verticillium dahliae display a complex and rich genetic diversity, yet the existence of sexual reproduction in the fungus remains contested. As pivotal genes, MAT genes play a crucial role in regulating cell differentiation, morphological development, and mating of compatible cells. However, the functions of the two mating type genes in V. dahliae, VdMAT1-1-1, and VdMAT1-2-1, remain poorly understood. Results In this study, we confirmed that the MAT loci in V. dahliae are highly conserved, including both VdMAT1-1-1 and VdMAT1-2-1 which share high collinearity. The conserved core transcription factor encoded by the two MAT loci may facilitate the regulation of pheromone precursor and pheromone receptor genes by directly binding to their promoter regions. Additionally, peptide activity assays demonstrated that the signal peptide of the pheromone VdPpg1 possessed secretory activity, while VdPpg2, lacked a predicted signal peptide. Chemotactic growth assays revealed that V. dahliae senses and grows towards the pheromones FO-a and FO-α of Fusarium oxysporum, as well as towards VdPpg2 of V. dahliae, but not in response to VdPpg1. The findings herein also revealed that VdMAT1-1-1 and VdMAT1-2-1 regulate vegetative growth, carbon source utilization, and resistance to stressors in V. dahliae, while negatively regulating virulence. Conclusions These findings underscore the potential roles of VdMAT1-1-1 and VdMAT1-2-1 in sexual reproduction and confirm their involvement in various asexual processes of V. dahliae, offering novel insights into the functions of mating type genes in this species.

Abstract The eruption of primary teeth is a basic event during physical development of children, which is affected by heredity and environment. This study aimed to analyze the changes in primary teeth eruption among Chinese children with social development. A total of 249,264 healthy children under 2 years were extracted from the 1995, 2005, and 2015 National Survey on the Physical Growth and Development of Children in Nine Cities of China. Their primary teeth were examined and percentiles of primary teeth eruption age were calculated by probit analysis. The median primary teeth eruption age were 6.8 months, 6.7 months, 6.6 months in 1995, 2005 and 2015. Primary teeth eruption age of boys was 0.2 months, 0.3 months, 0.3 months earlier than that of girls in 1995, 2005 and 2015. Primary teeth eruption age was the earliest in children from northern region and was the latest in children from southern region, and this regional difference did not change over time. These findings suggest that primary teeth eruption age slightly advanced with social development, and their gender difference and regional difference have always existed, which supplied some data for understanding the secular trend of primary teeth development in stomatology, pediatrics, anthropology, and other related fields.

BackgroundNivolumab is an effective treatment option for advanced gastric cancer (GC). This study aimed to conduct a systematic review of existing literature to investigate the relationship between immune-related adverse events (irAEs) and the prognosis of patients with GC treated with nivolumab.MethodsWe comprehensively searched four online literature databases: the Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, until 27 March 2024. The outcome measures of interest included: overall survival (OS), progression-free survival (PFS), hazard ratio (HR), median survival ratio (MSR), objective response rate (ORR), and disease control rate (DCR).ResultsA total of six studies, including 393 patients, met the eligibility criteria. The OS (pooled hazard ratio [HR] = 0.4, 95% confidence interval [CI]: 0.3–0.6, p < 0.05) and PFS (pooled HR = 0.5, 95% CI: 0.4–0.6, p < 0.05) of patients with irAEs were significantly superior to individuals without irAEs. The MSR for OS and PFS were 2.5 (95% CI: 1.5-4.1, p < 0.05) and 2.8 (95% CI: 1.9–4.1, p < 0.05), respectively. Regarding the ORR and DCR, we found that the development of irAEs was significantly associated with higher rates: patients with irAEs had an ORR of 24.7% compared to 6.4% in those without irAEs (risk ratio [RR] = 2.6, p < 0.05), and a DCR of 86.0% compared to 30.3% in those without irAEs (RR = 3.2, p < 0.05).ConclusionThere appears to be a significant correlation between the development of irAEs and the better survival benefits with nivolumab in patients with GC.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022341396.

Girder shifting is a common form of seismic damage for girder bridges. Unseating could occur when the displacement of the girder is too large, especially for bridges near faults, because the velocity impulse effect leads to greater displacement responses of structures. Setting metal dampers between girders and piers is a useful way to control the seismic behavior and reduce the risk of unseating. Since metal dampers are inevitably exposed to the erosive service environments, their mechanical properties may degrade due to corrosion. In this paper, a U-shaped metal damper made of stainless steel instead of mild steel (i.e., U-shaped stainless steel damper, which could be named simply as USSSD) is proposed and applied to the seismic reduction design of girder bridges. First, the finite element model (FEM) of the USSSD is built by the ABAQUS, and its force-displacement relationship is obtained based on the skeleton curve, which is fitted by the trilinear kinematic strengthening model. Then, a multi-union long simply supported girder bridge is taken as an example. The FEM of the adopted bridge is established via the Midas Civil to verify the seismic mitigation effect of the proposed USSSD excited by near-fault ground motions. The numerical analyses demonstrate that the unseating may occur without the use of the USSSDs. The relative displacement between the girder and pier is effectively controlled by the USSSDs, and the reduction is more than 50 %. When the bridge is equipped with the USSSDs, both the curvature ductility coefficient of the pier bottom and the maximum drift of the pier tip increase by a limited amplitude, which do not cause additional damage to the piers.

Multiple sclerosis (MS) is an autoimmune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS) that poses significant treatment challenges. Currently, it is believed that inflammatory and neuroprotective reactive astrocytes, along with other resident CNS cells and immune cells, contribute to the pathophysiology of MS. In our study, we found that isoliquiritigenin (ILG), a bioactive chalcone compound, significantly reduces the clinical scores of experimental autoimmune encephalomyelitis (EAE) by 44 % (P < 0.05). Additionally, ILG significantly decreases the pathological scores of spinal cord inflammation and demyelination by 61 % and 65 %, respectively (both P < 0.0001). Furthermore, ILG affects the populations of CD4, Th1, Th17, and Treg cells in vivo. More importantly, ILG significantly promotes the activation of astrocytes in EAE (P < 0.0001). Additionally, ILG treatment indirectly inhibits inflammatory reactive astrocytes and promotes neuroprotective reactive astrocytes. It reduces spleen levels of TNFα, IL1α, C1qa, IL1β, and IL17A by 95 % (P < 0.001), 98 % (P < 0.01), 46 % (P < 0.05), 97 % (P < 0.001), and 60 % (P < 0.001), respectively. It also decreases CNS levels of TNFα, IL1α, C1qa, IL1β, and IL17A by 53 % (P < 0.05), 88 % (P < 0.05), 64 % (P < 0.01), 57 % (P < 0.05), and 60 % (P < 0.001), respectively. These results indicate that ILG exerts an immunoregulatory effect by inhibiting the secretion of pro-inflammatory cytokines. Consequently, ILG inhibits inflammatory reactive astrocytes, promotes neuroprotective reactive astrocytes, alleviates inflammation and improves EAE. These findings provide a theoretical basis and support for the application of ILG in the prevention and treatment of MS.

Tumor stands as one of the principal contributors to global mortality. As research into tumor treatments advances, tumor inhibitors emerge as pivotal milestones in tumor therapy. Among these inhibitors, Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, is critical owing to its close association with tumor cell proliferation and growth, which renders it a critical therapeutic target. This work systematically explores the relationship between the chemical structures of 36 piperidine carboxamide derivatives and their efficacy in inhibiting Karpas-299 tumor cell activity by employing a rigorous 3D-QSAR modeling approach. A robust Topomer CoMFA model was generated and was meticulously validated through ANN neural network analysis (q2 = 0.597, r2 = 0.939, F = 84.401, N = 4, SEE = 0.268). Based on the model, 60 new compounds with desirable inhibitory activities were successfully designed. Combined with Lipinski’s rule and ADMET criteria alongside molecular docking and dynamics simulations, a lead compound with high inhibitory activity and good drug-likeness was selected. Further computational analyses, encompassing free energy landscape and binding free energy calculations, provided compelling evidence of the stable binding conformation of the lead compound and the superior affinity with the target protein at the active site, underscoring its potential therapeutic utility. In summary, this investigation offers valuable insights and methodological guidance for advancing tumor therapy and underscores the promise of piperidine carboxamide derivatives as prospective ALK inhibitors.

A new seismic repair method for reinforced concrete columns, which uses carbon fiber reinforced polymer (CFRP) grids and sprayed engineered cementitious composite (ECC) to form a composite reinforcement jacket, was proposed to improve the seismic performance of concrete columns damaged by earthquakes. Five specimen columns with 250 mm × 250 mm cross section and 1160 mm height were prepared and four different damage degree (no-damage, minor damage, moderate damage and severe damage) was controlled by the comparative specimen under the same amplitude-increasing lateral loading protocol and constant axial load. The pre-damaged columns were repaired and strengthened with three layers of CFRP grids and 25 mm thickness of sprayed ECC. The repaired columns were tested to failure and the effectiveness of the repairing schemes was evaluated by comparing load-carrying capacities, ductility, and energy dissipation. Based on the OpenSees seismic analysis software, a finite element model has been proposed to predict the seismic performance of the strengthened columns. The experimental results showed that the yield load, peak load, and ultimate load of the strengthened RC columns with no damage and slightly damage have significantly increased compared to the control specimen, with an increase range of 15% to 18%. For moderately damaged and severely damaged strengthened columns, the increase in the three characteristic load values is very small, or even reduced. Except for the severely damaged strengthened column, the ductility and energy consumption of other specimens have been improved to varying degrees. The analysis results indicated that the simulated values are in good agreement with the experimental ones, and the established finite element analysis model can be used to predict the seismic performance of strengthened columns.

Abstract Background The Cabrol procedure has undergone various modifications and developments since its invention. However, there is a notable gap in the literature regarding meta-analyses assessing it. Methods A systematic review and meta-analysis was conducted to evaluate the effectiveness and long-term outcomes of the Cabrol procedure and its modifications. Pooling was conducted using random effects model. Outcome events were reported as linearized occurrence rates (percentage per patient-year) with 95% confidence intervals. Results A total of 14 studies involving 833 patients (mean age: 50.8 years; 68.0% male) were included in this meta-analysis. The pooled all-cause early mortality was 9.0% (66 patients), and the combined rate of reoperation due to bleeding was 4.9% (17 patients). During the average 4.4-year follow-up (3,727.3 patient-years), the annual occurrence rates (linearized) for complications were as follows: 3.63% (2.79–4.73) for late mortality, 0.64% (0.35–1.16) for aortic root reoperation, 0.57% (0.25–1.31) for hemorrhage events, 0.66% (0.16–2.74) for thromboembolism, 0.60% (0.29–1.26) for endocarditis, 2.32% (1.04–5.16) for major valve-related adverse events, and 0.58% (0.34–1.00) for Cabrol-related coronary graft complications. Conclusion This systematic review provides evidence that the outcomes of the Cabrol procedure and its modifications are acceptable in terms of mortality, reoperation, anticoagulation, and valve-related complications, especially in Cabrol-related coronary graft complications. Notably, the majority of Cabrol procedures were performed in reoperations and complex cases. Furthermore, the design and anastomosis of the Dacron interposition graft for coronary reimplantation, considering natural anatomy and physiological hemodynamics, may promise future advancements in this field.

Abstract Gestational diabetes mellitus (GDM) is a common complication that occurs during pregnancy. Emerging evidence suggests that immune abnormalities play a pivotal role in the development of GDM. Specifically, regulatory T cells (Tregs) are considered a critical factor in controlling maternal–fetal immune tolerance. However, the specific characteristics and alterations of Tregs during the pathogenesis of GDM remain poorly elucidated. Therefore, this study aimed to investigate the changes in Tregs among pregnant women diagnosed with GDM compared to healthy pregnant women. A prospective study was conducted, enrolling 23 healthy pregnant women in the third trimester and 21 third-trimester women diagnosed with GDM. Participants were followed up until the postpartum period. The proportions of various Treg, including Tregs, mTregs, and nTregs, were detected in the peripheral blood of pregnant women from both groups. Additionally, the expression levels of PD-1, HLA-G, and HLA-DR on these Tregs were examined. The results revealed no significant differences in the proportions of Tregs, mTregs, and nTregs between the two groups during the third trimester and postpartum period. However, GDM patients exhibited significantly reduced levels of PD-1+ Tregs (P

As an important component of lake ecosystems, plankton are often used as indicators to evaluate the health of aquatic ecosystems, such as lakes and reservoirs. The plankton integrity index (P-IBI) is a highly utilized method for evaluating the ecological health of the lakes. This study took Dianchi Lake, located in the Yangtze River Basin, as the research object and analyzed the phytoplankton, zooplankton communities, and environmental factors at 11 sampling points in this lake during the wet season (July) in 2022 and the dry season (February) in 2023. The P-IBI was established to evaluate the health status of this lake ecosystem. The results showed that a total of 83 species of phytoplankton and 31 species of zooplankton were identified in Dianchi Lake, and the number of plankton species in the dry season was significantly higher than that in the wet season. The P-IBI evaluation results for the two hydrological periods were generally “good”. Linear regression analysis showed that there was a certain negative correlation between the P-IBI value and the comprehensive trophic level index (TLI), and the evaluation results were generally in line with the actual situation of the water body. Redundancy analysis (RDA) showed that there was a significant correlation between the P-IBI and its constituent parameters and individual water quality environmental factors, such as total nitrogen (TN) and electrical conductivity (EC). In summary, by reducing errors caused by spatial and temporal changes across various hydrological periods, P-IBI represents a more scientifically rigorous technique for lake water ecological health assessments within a certain time range.

BackgroundFor Rheumatoid Arthritis (RA), a long-term chronic illness, it is essential to identify and describe patient subtypes with comparable goal status and molecular biomarkers. This study aims to develop and validate a new subtyping scheme that integrates genome-scale transcriptomic profiles of RA peripheral blood genes, providing a fresh perspective for stratified treatments.MethodsWe utilized independent microarray datasets of RA peripheral blood mononuclear cells (PBMCs). Up-regulated differentially expressed genes (DEGs) were subjected to functional enrichment analysis. Unsupervised cluster analysis was then employed to identify RA peripheral blood gene expression-driven subtypes. We defined three distinct clustering subtypes based on the identified 404 up-regulated DEGs.ResultsSubtype A, named NE-driving, was enriched in pathways related to neutrophil activation and responses to bacteria. Subtype B, termed interferon-driving (IFN-driving), exhibited abundant B cells and showed increased expression of transcripts involved in IFN signaling and defense responses to viruses. In Subtype C, an enrichment of CD8+ T-cells was found, ultimately defining it as CD8+ T-cells-driving. The RA subtyping scheme was validated using the XGBoost machine learning algorithm. We also evaluated the therapeutic outcomes of biological disease-modifying anti-rheumatic drugs. ConclusionsThe findings provide valuable insights for deep stratification, enabling the design of molecular diagnosis and serving as a reference for stratified therapy in RA patients in the future.

ABSTRACT The clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR-Cas) system widely occurs in prokaryotic organisms to recognize and destruct genetic invaders. Systematic collation and characterization of endogenous CRISPR-Cas systems are conducive to our understanding and potential utilization of this natural genetic machinery. In this study, we screened 39 complete and 692 incomplete genomes of myxobacteria using a combined strategy to dispose of the abridged genome information and revealed at least 19 CRISPR-Cas subtypes, which were distributed with a taxonomic difference and often lost stochastically in intraspecies strains. The cas genes in each subtype were evolutionarily clustered but deeply separated, while most of the CRISPRs were divided into four types based on the motif characteristics of repeat sequences. The spacers recorded in myxobacterial CRISPRs were in high G+C content, matching lots of phages, tiny amounts of plasmids, and, surprisingly, massive organismic genomes. We experimentally demonstrated the immune and self-target immune activities of three endogenous systems in Myxococcus xanthus DK1622 against artificial genetic invaders and revealed the microhomology-mediated end-joining mechanism for the immunity-induced DNA repair but not homology-directed repair. The panoramic view and immune activities imply potential omnipotent immune functions and applications of the endogenous CRISPR-Cas machinery.IMPORTANCEServing as an adaptive immune system, clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR-Cas) empower prokaryotes to fend off the intrusion of external genetic materials. Myxobacteria are a collective of swarming Gram-stain-negative predatory bacteria distinguished by intricate multicellular social behavior. An in-depth analysis of their intrinsic CRISPR-Cas systems is beneficial for our understanding of the survival strategies employed by host cells within their environmental niches. Moreover, the experimental findings presented in this study not only suggest the robust immune functions of CRISPR-Cas in myxobacteria but also their potential applications.

BackgroundCreatinine-cystatin C ratio (CCR) has been demonstrated as an objective marker of sarcopenia in clinical conditions but has not been evaluated as an osteoporosis marker in individuals with normal renal function.MethodsWe selected 271,831 participants with normal renal function from UK Biobank cohort. Multivariable linear/logistic regression and Cox proportional hazards model were used to investigate the phenotypic relationship between CCR and osteoporosis in total subjects and gender-stratified subjects. Based on the genome-wide association study (GWAS) data, linkage disequilibrium regression (LDSC) and Mendelian randomization (MR) analysis were performed to reveal the shared genetic correlations and infer the causal effects, respectively.ResultsAmongst total subjects and gender-stratified subjects, serum CCR was positively associated with eBMD after adjusting for potential risk factors (all P

Background: A new spray adhesive (KYNA-PF127) was established through the combination of thermosensitive hydrogel (Pluronic F127) and KYNA, aimed to investigate the effect of KYNA-PF127 on multi-territory perforator flaps and its possible molecular mechanism. Materials and methods: 36 SD male rats with 250–300 g were randomly divided into 3 groups (n = 12): control group, blank glue group and KYNA-PF127 group. KYNA-PF127 hydrogel was prepared and characterized for its morphology and properties using scanning electron microscopy. CCK-8 assay, scratch wound assay, transwell assay, tube formation assay and Ki67 staining were used to study the effect of KYNA-PF127 on the proliferation, migration, and tube formation of HUVECs. VEGF and FGF2 were measured by qPCR to evaluate the angiogenesis capacity of HUVECs in vitro. In vivo, the effect of each group on the survival area of the cross-zone perforator flap was evaluated, and angiogenesis was evaluated by HE and immunofluorescence (CD31 and MMP-9). The effect of inflammation on skin collagen fibers was assessed by Masson. Immunohistochemistry (SOD1, IL-1β, TNF-α) was used to evaluate the effects of oxidative stress and inflammatory factors on multi-territory flaps. Results: KYNA-PF127 has good sustained release and biocompatibility at 25% concentration. KYNA-PF127 promoted the proliferation, migration, and angiogenesis of HUVECs in vitro. In vivo, the survival area of multi-territory perforator flaps and angiogenic capability have increased after KYNA-PF127 intervention. KYNA-PF127 could effectively reduce the oxidative stress and inflammation of multi-territory perforator flaps. Conclusion: KYNA-PF127 promotes angiogenesis through its antioxidant stress and anti-inflammatory effects, and shows potential clinical value in promoting the survival viability and drug delivery of multi-territory perforator flaps.

ObjectivesIn this study, we compared the dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer. Furthermore, we investigated the potential impact of these changes on the occurrence of toxic side effects.MethodsPatients with gastric cancer who received adjuvant or first-line XELOX/SOX chemotherapy between January 2020 and June 2023 were enrolled. The Brief Conghua Scale was used to assess energy intake, and nutritional management was carried out with reference to the Chinese Guidelines for Nutritional Therapy of Cancer 2020. The NRS 2002 Nutritional Risk Screening Scale, PG-SGA scale, bioelectrical impedance analysis, and dynamic changes in lumbar 3 vertebral skeletal muscle index were compared between baseline and post-chemotherapy in the study. The neutropenia was evaluated using the Common Terminology Criteria for Adverse Events V.5.0, developed by the National Institutes of Health.ResultsDynamic follow-up was completed in 39 cases, with a mean follow-up time of 117.62 ± 43.38 days. The incidence of sarcopenia increased significantly after chemotherapy, escalating from 46.2% to 51.3%. After chemotherapy, the mean L3SMI decreased from 36.00 cm2/m2 to 34.99 cm2/m2. Furthermore, when compared to pre-chemotherapy values, the body composition indexes body mass index (BMI), SL3, fat mass free index (FFMI), lean body mass (LBM), and body surface area (BSA) were significantly reduced after chemotherapy. Regardless of baseline or post-chemotherapy status, the incidence of grade ≥ 3 neutropenia was significantly higher in the sarcopenia group than in the non-sarcopenia group. Furthermore, when the skeletal muscle index decreased during chemotherapy, the incidence of grade ≥ 3 neutropenia was significantly higher in both the sarcopenia and non-sarcopenia groups compared to baseline. When the incidence of grade ≥ 3 neutropenia in the post-chemotherapy sarcopenia group was compared to baseline status, the increase was significantly higher in the sarcopenia group than in the maintenance/increase group.ConclusionsSkeletal muscle mass decreased progressively during XELOX/SOX chemotherapy in gastric cancer patients, followed by a higher incidence of grade ≥ 3 neutropenia.

In the face of the unprecedented public health crisis caused by the novel coronavirus pneumonia epidemic, front-line health workers are under enormous mental pressure. This paper aims to explore the mental health challenges faced by front-line health workers in the early stages of a public health emergency, such as stress, anxiety, and depression. At the same time, the factors that increase their mental stress are analyzed, and practical measures are put forward to prevent and manage mental health problems, aiming at improving the quality of medical treatment during public health emergencies. This paper has some reference value for people engaged in mental health prevention.

Compensatory Health Beliefs (CHBs), the notion that healthy behaviors can offset the negative effects of unhealthy actions, have been widely explored in Western contexts. Yet, their relevance within the Chinese cultural milieu remains underexplored. The primary objective of this research was to develop and validate a Chinese version of the CHBs scale (CHBs-C), addressing the gap in the literature regarding the applicability of CHBs within the Chinese cultural context. A multi-stage translation (from English to Chinese) was first completed, and exploratory factor analysis was conducted (n = 476), yielding the 14-item scale (CHBs-C scale). Confirmatory factor analysis was conducted to assess the validity, and the 2-week test–retest reliability, internal consistency and convergent validity of the scale were also assessed (n = 308). Predict validity was verified through testing the relationships between CHBs and health behaviors and habits (n = 274). Factor analysis showed a different factor structure in Chinese context, with only one factor identical to the original version. The fitness index of the new factor structure was good. However, while the scale exhibited acceptable internal consistency and high test–retest reliability, its convergent validity and predictive validity was found to be limited on a general level. Despite this, significant correlations at the subscale level were identified, highlighting nuanced interactions between CHBs and specific health behaviors within the Chinese population. This study not only establishes the CHBs-C scale as a valid and reliable instrument for assessing compensatory health beliefs in China but also lays the groundwork for further exploration of its applications and the potential cultural adaptability of CHBs.

In order to realize the real-time processing and analysis of astronomical ultra-wide bandwidth signals, this study proposes a sub-band division algorithm based on RFSoC. The algorithm uses Kaiser window to design FIR prototype low-pass filter, adopts critical sampling polyphase filter bank to decompose ultra-wide bandwidth signal into several sub-bands, and encapsulates each sub-band into VDIF data frame and sends it to GPU server. The algorithm is implemented on RFSoC platform, and its effectiveness is verified by simulation and actual observation. The experimental results show that the algorithm can divide the astronomical ultra-wide bandwidth signal into multiple sub-bands in real time, packetize and transmit them to GPU. This research provides reproducible design and project for ultra-wide bandwidth signal sub-band division with low spectrum leakage and aliasing, high data accuracy, and fast processing speed.

In this extensive analysis, we delve into the utilization of advanced hybrid model for molecular separation description via mesoporous materials. The process considered here is adsorption which is utilized for molecular separation in liquid solution. Data for adsorption are obtained in terms of solute concentration by solving mass transfer equations numerically. Then, the data is used for training and validation of several machine learning techniques to establish the hybrid model. For machine learning model, several methods are utilized including three robust tree-based ensemble models, namely Gradient Boosting (GB), Random Forest (RF), and Extra Trees (ET). The methos were utilized to tackle the challenging task of predicting chemical concentrations in a dataset comprising an array of over 19,000 data. These data points are characterized by input variables representing coordinates (x and y), while the output variable encapsulates chemical concentration (C). By subjecting these models to a meticulous optimization process, we achieved substantial enhancements in their predictive capabilities. RF emerged as the standout performer, boasting a remarkable R2 score of 0.99902. ET and GB also demonstrated commendable performance improvements, underscoring the versatility of tree-based ensemble models in delivering precise and reliable predictions for chemical concentrations within intricate and multifaceted datasets.

Over the years, the Shaying River Basin has experienced frequent instances of river pollution. The presence of numerous critical pollutant discharge enterprises and sewage-treatment plants in the vicinity of the Shaying River has transformed it a major tributary with relatively serious pollution challenge within the upper reaches of Huaihe River Basin. To study the sources of manganese (Mn), chromium (Cr), nickel (Ni), arsenic (As), cadmium (Cd) and lead (Pb) in Shaying River water, 123 sets of surface water samples were collected from 41 sampling points across the entire basin during three distinct phases from 2019 to 2020, encompassing normal water period, dry season and wet season. The primary origins of heavy metals in river water were determined by analyzing the heavy metal contents in urban sewage wastewater, industrial sewage wastewater, groundwater, mine water, and the heavy metal contributions from agricultural non-point source pollution. The analytical findings reveal that Mn primarily originates from shallow groundwater used for agricultural irrigation, While Cr mainly is primarily sourced from urban sewage treatment plant effluents, coal washing wastewater, tannery wastewater, and industrial discharge related to metal processing and manufacturing. Ni is mainly contributed by urban sewage treatment plant effluents and industrial wastewater streams associated with machinery manufacturing and metal processing. Cd primarily linked to industrial wastewater, particularly from machinery manufacturing and metal processing facilities, while Pb is predominantly associated with urban sewage treatment plant effluents and wastewater generated in Pb processing and recycling wastewater. These research provides a crucial foundation for addressing the prevention and control of dissolved heavy metals at their sources in the Shaying River.

Abstract As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

Abstract Fusarium head blight (FHB) caused by Fusarium species, seriously threatens the safety of wheat (Triticum aestivum) production. Resistant cultivars and fungicides are frequently used to control these FHB pathogens. However, Fusarium species have been adapting the current FHB control approaches in a manner that raises concern for future FHB control strategies, which could lead to a greater risk of FHB outbreaks. In this study, a total of 521 strains of Fusarium were isolated from Sichuan province of China, to investigate the diversity of Fusarium species and the genes associated with their adaptation. Seven species were identified based on molecular markers and morphological analysis. The virulence assays showed that Fusarium asiaticum (Fa) and Fusarium graminearum (Fg) were the two major causal agents of FHB, with high virulence and more frequent isolates. Fungicide resistance analysis showed that four isolates had developed the resistance to carbendazim, and four isolates had developed the resistance to tebuconazole. Of note, two point-mutation variants (F200Y and E198Q) occurred in the β2-tubulin gene, leading to the carbendazim resistance. The landscape of genomic diversity was analyzed through whole-genome sequencing, revealing a total of 182,811 and 430,733 variants (including: single nucleotide polymorphisms, SNP, insertion and deletion, Indel, and structure variation, SV) among the Fa and Fg isolates, respectively. In addition, potential alterations in gene function (15.22%) were predicted among Fg variants. These alterations offer potential helps for the Fusarium species to adapt to various managements of FHB, which may increase risks in developing fungicide-resistant isolates. However, these annotated genetic variants are valuable resources for further genetic and genomic studies, as well as potential markers to assist disease risk assessment.

Abstract Depression is a severe mental disorder among public health issues. Researchers in the field of mental health and clinical psychiatrists have long been faced with difficulties in slow treatment cycles, high recurrence rates, and lagging efficacy. These obstacles have forced us to seek more advanced and effective treatments. Research has shown that novel drug delivery strategies for natural medicinal plants can effectively improve the utilization efficiency of the active molecules in these plants and therefore improve their efficacy. Currently, with the development of treatment technologies and the constant updating of novel drug delivery strategies, the addition of natural medicinal antidepressant therapy has given new significance to the study of depression treatment against the background of novel drug delivery systems. Based on this, this review comprehensively evaluates and analyses the research progress in novel drug delivery systems, including nanodrug delivery technology, in intervention research strategies for neurological diseases from the perspective of natural medicines for depression treatment. This provided a new theoretical foundation for the development and application of novel drug delivery strategies and drug delivery technologies in basic and clinical drug research fields. Graphical Abstract