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Abstract Introduction Adolescent idiopathic scoliosis (AIS), a prevalent condition among teenagers, is often accompanied by osteopenia. However, the impact of brace treatment on bone density in AIS patients remains a matter of debate. The Vertebral bone quality (VBQ) score, derived from MRI signal intensity, has been shown to correlate with bone mineral density (BMD). Yet, no studies to date have drawn comparisons between VBQ scores in preoperative AIS patients who had brace treatment history and those who have not received brace treatment. Objective This study aims to elucidate the influence of brace treatment on bone density in AIS patients using VBQ score. Methods A retrospective analysis was conducted on 243 AIS patients, each with Cobb angles ranging from 50–70°, who had undergone preoperative MRI scans. The patients were segregated into two cohorts: those who received brace treatment (n = 174) and those who did not (n = 69). Through propensity score matching, a total of 53 matched pairs were selected for further analysis. VBQ scores were extracted from T1-weighted MRI scans. Results Post-matching, no significant baseline discrepancies were observed between the two groups. Interestingly, brace-treated patients exhibited lower average VBQ scores than their non-brace-treated counterparts (2.43 ± 0.11 vs. 2.55 ± 0.12, p

Abstract Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

Abstract Background Job burnout is a prevalent and emerging challenge in the primary medical system, causing mass turnover, especially of primary medical staff. Little attention has been paid to the different dimensions of job burnout (emotional exhaustion, personality disintegration, and reduced sense of achievement), which may hinder efforts to tackle high turnover intention among primary medical staff. From the perspective of conservation of resources theory, social support and psychological capital are basic resources with potential to diminish job burnout and thus lower turnover intention. However, there is insufficient research evidence on the relationships between social support, psychological capital, and the three dimensions of job burnout within the primary medical system. Objectives Focusing on primary medical staff, this study conducts a path analysis to examine the correlations between two types of resources (social support and psychological capital) and the three dimensions of job burnout, and to test the impact of the latter on turnover intention. Based on the results, effective management strategies to improve the work stability of primary medical staff are proposed. Methods Multi-stage cluster random sampling was used to select participants in Anhui Province, China. Data were collected using a self-administered questionnaire containing measures of the main variables and demographic questions. In total, 1132 valid questionnaires were returned by primary medical staff. Structural equation modeling was used for path analysis of the data. Results Social support was negatively associated with emotional exhaustion (β = − 0.088, P = 0.020), personality disintegration (β = − 0.235, P

Abstract Tuberculosis (TB) remains a significant global health threat, necessitating effective strategies for diagnosis, prognosis, and treatment. This study employs a multi-cohort analysis approach to unravel the immune microenvironment of TB and delineate distinct subtypes within pulmonary TB (PTB) patients. Leveraging functional gene expression signatures (Fges), we identified three PTB subtypes (C1, C2, and C3) characterized by differential immune-inflammatory activity. These subtypes exhibited unique molecular features, functional disparities, and cell infiltration patterns, suggesting varying disease trajectories and treatment responses. A neural network model was developed to predict PTB progression based on a set of biomarker genes, achieving promising accuracy. Notably, despite both genders being affected by PTB, females exhibited a relatively higher risk of deterioration. Additionally, single-cell analysis provided insights into enhanced major histocompatibility complex (MHC) signaling in the rapid clearance of early pathogens in the C3 subgroup. This comprehensive approach offers valuable insights into PTB pathogenesis, facilitating personalized treatment strategies and precision medicine interventions.

Abstract In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-β1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV–HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-β1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-β1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.

Abstract Falls can cause serious health problems in the elderly. China is gradually entering a moderately aging society. In rural areas of China, the elderly are at a higher risk of falling. This study aims to explore and analyze the factors affecting the fall risk of elderly people in rural areas of China, and provide theoretical basis for reducing the fall risk of elderly people. M County, Anhui Province, China was selected as the survey site by the typical field sampling method, and the elderly people in rural areas were selected as the research objects. A total of 1187 people were investigated. Mann–Whitney U test and Kruskal–Wallis H test were used for univariate analysis, and multiple linear regression was used for multivariate analysis. Chronic diseases, multimorbidity, daily living ability, mental health, working status and family doctors are the factors that influence falls among elderly people in rural areas of China (P

BackgroundThis study explored the epidemiological trends in pelvic fracture (PF) in China from 1992 to 2021, analyze their relationships with age–period–cohort (APC) factors, and predict the trends of PF from 2022 to 2046.MethodsIncidence and years lived with disabilities (YLDs) of PF among sexes in China from 1992 to 2021 were obtained through the 2021 Global Burden of Disease (GBD) database. Trends in the incidence and YLDs were described, and a joinpoint regression model was used. The APC model was used to explore the effects of age, period, and cohort on the incidence and YLDs. Nordpred forecasted the incidence and YLDs in China from 2022 to 2046.ResultsIn 2021, there were an estimated 0.63 million incidence cases and 0.33 million of YLDs, respectively. The number and age-standardized rate (ASR) of incidence and YLDs were both gradually increased. The average annual percent change (AAPC) in incidence and YLDs for men were 0.26% and −0.17%, respectively. For women, the AAPC values for incidence and YLDs were −0.03% and −0.57% (p 95 years for incidence and aged 90–94 years for YLDs. The period effect showed a totally increase in the risk across the general, male, and female populations. Cohort effects indicated a totally significant decline for both incidence and YLDs. The predicted incidence and YLDs of PF in China from 2022 to 2046 showed an initial rise, followed by a decline, with 2029 and 2034 being the turning point for incidence and YLDs, respectively.ConclusionThe characteristics of pelvic fracture incidence and YLDs in China are complex. Thus, primary prevention measures must be strengthened. Raising awareness about osteoporosis prevention, enhancing public health education, and promoting good dietary and hygiene habits are appropriate preventive measures for PF in China.

Abstract Objective This study aimed to investigate the association between the triglyceride-glucose (TyG) index in early pregnancy and the development of gestational diabetes mellitus (GDM) in the second trimester. The primary objectives were to evaluate the predictive potential of the TyG index for GDM, determine the optimal threshold value of the TyG index for GDM assessment, and compare the predictive performance of the TyG index alone versus its combination with maternal age and pre-pregnancy body mass index on GDM. Moreover, the study explored the association between the TyG index in early pregnancy and the risk of other pregnancy-related complications (PRCs), such as placental abruption and gestational hypertension. Patients and methods This prospective cohort study recruited 1,624 pregnant women who underwent early pregnancy antenatal counseling and comprehensive assessments with continuous monitoring until delivery. To calculate the TyG index, health indicators, including maternal triglycerides and fasting plasma glucose, were measured in early pregnancy (

Lane detection is fundamental to autonomous driving, yet remains challenging in complex environments with occlusions, ambiguous markings, and varied lighting. We introduce the Global Semantic Enhancement Network (GSENet), a groundbreaking framework that significantly advances lane detection accuracy and robustness. GSENet’s core innovations include the Global feature Extraction Module (GEM) and the Top Layer Auxiliary Module (TLAM). GEM revolutionizes the extraction of fine-grained global features, overcoming limitations of traditional deep convolutional approaches without compromising inference speed. TLAM leverages self-attention mechanisms to capture rich contextual information and learn task-specific representations, dramatically enhancing the network’s performance in complex scenarios. We further propose the Generalized Line Intersection over Union (GLIoU) Loss, a novel optimization approach that considers spatial relationships between lane points and introduces a geometric penalty term. This loss function promotes globally coherent and smooth lane predictions, addressing key limitations in existing methods. Our comprehensive mathematical analyses, including gradient derivations and complexity assessments, provide theoretical foundations for the effectiveness of these innovations. Extensive experiments on challenging benchmarks demonstrate GSENet’s superior accuracy and robustness, significantly outperforming state-of-the-art methods. Notably, our framework’s modular design extends its applicability beyond lane detection to various computer vision tasks involving elongated or curved structures, opening new avenues for research and practical applications in autonomous systems and beyond.

Background Arteriovenous fistula (AVF) dysfunction is a common complication in patients undergoing maintenance hemodialysis (MHD). Elevated serum levels of fibroblast growth factor 21 (FGF21) are associated with atherosclerosis and cardiovascular mortality. However, its association with vascular access outcomes remains elusive. The present study evaluated the relationship of serum FGF21 levels with AVF dysfunction and all-cause mortality in patients undergoing MHD.Methods We included patients undergoing MHD using AVF from January 2018 to December 2019. FGF21 concentration was detected using enzyme-linked immunosorbent assay. Patients were followed up to record two clinical outcomes, AVF functional patency loss and all-cause mortality. The follow-up period ended on April 30, 2022.Results Among 147 patients, the mean age was 58.49 ± 14.41 years, and the median serum level of FGF21 was 150.15 (70.57–318.01) pg/mL. During the median follow-up period of 40.83 months, the serum level of FGF21 was an independent risk factor for AVF functional patency loss (per 1 pg/mL increase, HR 1.002 [95% CI: 1.001–1.003, p = 0.003]). Patients with higher serum levels of FGF21 were more likely to suffer from all-cause mortality (per 1 pg/mL increase, HR 1.002 [95% CI: 1.000–1.003, p = 0.014]). The optimal cutoffs for FGF21 to predict AVF functional patency loss and all-cause mortality in patients undergoing MHD were 149.98 pg/mL and 146.43 pg/mL, with AUCs of 0.701 (95% CI: 0.606–0.796, p

ABSTRACT: Taihang chickens is precious genetic resource with excellent adaptability and disease resistance, as well as high-quality eggs and meat. However, the genetic mechanism underlying important economic traits remain largely unknown. To address this gap, we conducted whole-genome resequencing of 66 Taihang and 15 White Plymouth rock chicken (Baiyu). The population structure analysis revealed that Taihang chickens and Baiyu are 2 independent populations. The genomic regions with strong selection signals and some candidate genes related to economic and appearance traits were identified. Additionally, we found a continuously selected 1.2 Mb region on chromosome 2 that is closely related to disease resistance. Therefore, our findings were helpful in further understanding the genetic architecture of the Taihang chickens and provided a worthy theoretical basis and technological support to improve high-quality Taihang chickens.

Subtropical Moso bamboo (Phyllostachys edulis) forests have become hot spots for nitrogen (N) deposition in China. However, the effect of long-term N deposition on the structure of soil microbial communities in different horizons of these forests remains unclear. To investigate the influence of extended N deposition on soil bacteria and fungi, a simulated N deposition field study was conducted in Fujian Province with four N deposition levels (0, 20, 40 and 80 kg N hm−2 a−1). The absolute abundances, diversity, community structure, and potential functions of soil bacteria and fungi were investigated after 10 years of simulated N deposition. The results indicated that there was no significant effect of N deposition on the abundance or diversity of soil microbes in either the organic or mineral horizons of Moso bamboo forests. However, under rates of 40 and 80 kg N hm−2 a−1, long-term N deposition altered the structure of the soil bacterial community in the organic horizon. Specifically, there was a 27.75∼36.40 % increase in the relative abundance of Actinobacteria, while that of Acidobacteria decreased by 24.40∼27.52 %. Redundancy analysis (RDA) demonstrated that soil total carbon (TC) was the key variable influencing the bacterial community structure in the organic horizon. Analysis of potential microbial functions showed that in the organic horizon, the rates of chemoheterotrophy significantly decreased under 80 kg N hm−2 a−1. However, N deposition did not noticeably impact the fungal community structure in either soil horizon. Our study suggested that under 10 years of N deposition, only the bacterial community composition and function in the organic horizon was affected, indicating that soil bacteria are more sensitive to N deposition than fungi in subtropical Moso bamboo forests. Therefore, further research is necessary to fully understand the impact of N deposition on fungal community composition in the soil organic horizon and on the microbial community in the mineral horizon of subtropical bamboo forests. This study provides valuable insights for informing future environmental management and conservation strategies.

Abstract Purpose This study aimed to describe a peripherally inserted central catheterisation (PICC) for paediatric patients with inaccessible access and a high risk of general anaesthesia (GA). Methods: This was a retrospective observational study involving all paediatric inpatients who performed the PICC via an EJV approach without GA between September 2014 and September 2021 in a provincial key clinical speciality. Results: A total of 290 EJV line placement attempts were performed, and 29 were excluded due to missing placement results, resulting in a sample size of 261. The anatomical localisation, punctures, and catheterisation success rates for this practice were 100%, 100%, and 90.04%, respectively. The placement success rate in children younger than one year was 93.75% (45/48). The median line duration of use was 19 days, with a median length of catheter insertion of 13 cm. The most common complications were catheter malposition (n = 20) and dislodgement (n = 7). Conclusion: The PICC via an EJV approach without GA is a feasible and safe practice with acceptable success and complication rates, and low costs. It might be an attractive alternative for obtaining central vascular access for paediatric patients.

Purpose The relationship between contrast-enhanced ultrasound (CEUS) hemodynamics and the molecular biomarkers of adult-type diffuse gliomas, particularly isocitrate dehydrogenase (IDH), remains unclear. This study was conducted to provide a comprehensive description of the vascularization of adult-type diffuse gliomas using quantitative indicators. Additionally, it was designed to identify any variables with the potential to intraoperatively predict IDH mutation status. Methods This prospective study enrolled patients with adult-type diffuse gliomas between November 2021 and September 2022. Intraoperative CEUS was performed, and CEUS videos were recorded for 90-second periods. Hemodynamic parameters, including the peak enhancement (PE) difference, were calculated based on the time-intensity curve of the region of interest. A differential analysis was performed on the CEUS parameters with respect to molecular biomarkers and grades. Receiver operating characteristic curves for various parameters were analyzed to evaluate the ability of those parameters to predict IDH mutation status. Results Sixty patients with adult-type diffuse gliomas were evaluated. All hemodynamic parameters, apart from rising time, demonstrated significant differences between IDH-mutant and IDH-wildtype adult-type diffuse gliomas. The PE difference emerged as the optimal indicator for differentiating between IDH-wildtype and IDH-mutant gliomas, with an area under the curve of 0.958 (95% confidence interval, 0.406 to 0.785). Additionally, the hemodynamic parameters revealed significant differences across both grades and types of adult-type diffuse gliomas. Conclusion Hemodynamic parameters can be used intraoperatively to effectively distinguish between IDH-wildtype and IDH-mutant adult-type diffuse gliomas. Additionally, quantitative CEUS equips neurosurgeons with dynamic perfusion information for various types and grades of adult-type diffuse gliomas.

Abstract Due to the specific advantages of ultrasound (US) in therapeutic disease treatments, the unique therapeutic US technology has emerged. In addition to featuring a low‐invasive targeted cancer‐cell killing effect, the therapeutic US technology has been demonstrated to modulate the tumor immune landscape, amplify the therapeutic effect of other antitumor therapies, and induce immunosensitization of tumors to immunotherapy, shedding new light on the cancer treatment. Tremendous advances in nanotechnology are also expected to bring unprecedented benefits to enhancing the antitumor efficiency and immunological effects of therapeutic US, as well as therapeutic US‐derived bimodal and multimodal synergistic therapies. This comprehensive review summarizes the immunological effects induced by different therapeutic US technologies, including ultrasound‐mediated micro‐/nanobubble destruction (UTMD/UTND), sonodynamic therapy (SDT), and focused ultrasound (FUS), as well as the main underlying mechanisms involved. It is also discussed that the recent research progress of engineering intelligent nanoplatform in improving the antitumor efficiency of therapeutic US technologies. Finally, focusing on clinical translation, the key issues and challenges currently faced are summarized, and the prospects for promoting the clinical translation of these emerging nanomaterials and ultrasonic immunotherapy in the future are proposed.

Due to the influence of the groundwater system, mountain rock layers, climate rainfall, and tunnel length and depth, underground tunnels (UT) are prone to water inrush (WI) disasters, thus leading to delays and obstacles in construction projects. This paper takes the Yonglian Tunnel as the research objective and explores the water and mud inrush disasters that occurred from July to August 2012. The Yonglian Tunnel is a control project of the Jilian Expressway in Jiangxi Province. This paper aims to study and analyze the WI disaster management of the UT using artificial intelligence technology, and to deepen the understanding of its causes. It will affect the factors, hazards, and related disaster management engineering methods of the UT WI disaster. By establishing a back-propagation neural network model and a radial basis function neural network model, the risk of WI disasters in tunnels, the degree of harm caused by WI, and the ability to control them were predicted and analyzed, and the stability and error values of the models were compared. HIGHLIGHTS This paper aims to use artificial intelligence technology to study and analyze the water inrush disaster management of underground tunnels, and to deepen the understanding of its causes.; Through the establishment of a back-propagation neural network model and radial basis function neural network model, this paper predicts and analyzes the risk of tunnel flood disaster, the degree of damage caused by flood and the control ability.;

The rapid development of supply chain finance (SCF) has significantly alleviated the financing difficulties of small and medium-sized enterprises (SMEs). However, it is important to recognize that within the accounts receivable financing segment of the SCF credit market, the credit risk associated with SMEs poses a serious challenge and potential threat to the stability, health, and sustainable development of the SCF system. This paper pays special attention to the stability of the two-party evolutionary game between SMEs and financial institutions (FIs) within the context of the Chinese SCF credit market. To identify a pathway to reduce credit risks for SMEs while simultaneously enhancing system stability, this paper adopts the stochastic evolutionary game (SEG) model and combines the fixed-point method to determine the conditions that satisfy the stability of the system’s index p mean square of the system. This study has made attempts in various aspects, such as the innovative construction and investigation of a nonlinear SEG model, the endeavor to study the stability of SEG systems using fixed-point methods, and the innovative construction of a more realistic two-player SEG system. The data and simulation results generated from hypothetical scenarios show that the conclusions of the article are credible and feasible. Through the study, we conclude that the higher credit ratio from FI and the higher penalty intensity from core enterprises (CEs) will accelerate the stability of the system. Based on solid data and modeling analysis, insights into the regulation of FI are provided.

Abstract Background Multiparametric magnetic resonance imaging (MP-MRI) has high sensitivity for diagnosing breast cancers but cannot always be used as a routine diagnostic tool. The present study aimed to evaluate whether the diagnostic performance of perfluorobutane (PFB) contrast-enhanced ultrasound (CEUS) is similar to that of MP-MRI in breast cancer and whether combining the two methods would enhance diagnostic efficiency. Patients and methods This was a head-to-head, prospective, multicenter study. Patients with breast lesions diagnosed by US as Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 underwent both PFB-CEUS and MP-MRI scans. On-site operators and three reviewers categorized the BI-RADS of all lesions on two images. Logistic-bootstrap 1000-sample analysis and cross-validation were used to construct PFB-CEUS, MP-MRI, and hybrid (PFB-CEUS + MP-MRI) models to distinguish breast lesions. Results In total, 179 women with 186 breast lesions were evaluated from 17 centers in China. The area under the receiver operating characteristic curve (AUC) for the PFB-CEUS model to diagnose breast cancer (0.89; 95% confidence interval [CI] 0.74, 0.97) was similar to that of the MP-MRI model (0.89; 95% CI 0.73, 0.97) (P = 0.85). The AUC of the hybrid model (0.92, 95% CI 0.77, 0.98) did not show a statistical advantage over the PFB-CEUS and MP-MRI models (P = 0.29 and 0.40, respectively). However, 90.3% false-positive and 66.7% false-negative results of PFB-CEUS radiologists and 90.5% false-positive and 42.8% false-negative results of MP-MRI radiologists could be corrected by the hybrid model. Three dynamic nomograms of PFB-CEUS, MP-MRI and hybrid models to diagnose breast cancer are freely available online. Conclusions PFB-CEUS can be used in the differential diagnosis of breast cancer with comparable performance to MP-MRI and with less time consumption. Using PFB-CEUS and MP-MRI as joint diagnostics could further strengthen the diagnostic ability. Trial registration Clinicaltrials.gov; NCT04657328. Registered 26 September 2020. IRB number 2020-300 was approved in Chinese PLA General Hospital. Every patient signed a written informed consent form in each center.

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6−/−) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.

Summary: Background: Molecular diagnosis is crucial for biomarker-assisted glioma resection and management. However, some limitations of current molecular diagnostic techniques prevent their widespread use intraoperatively. With the unique advantages of ultrasound, this study developed a rapid intraoperative molecular diagnostic method based on ultrasound radio-frequency signals. Methods: We built a brain tumor ultrasound bank with 169 cases enrolled since July 2020, of which 43483 RF signal patches from 67 cases with a pathological diagnosis of glioma were a retrospective cohort for model training and validation. IDH1 and TERT promoter (TERTp) mutations and 1p/19q co-deletion were detected by next-generation sequencing. We designed a spatial–temporal integration model (STIM) to diagnose the three molecular biomarkers, thus establishing a rapid intraoperative molecular diagnostic system for glioma, and further analysed its consistency with the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5). We tested STIM in 16-case prospective cohorts, which contained a total of 10384 RF signal patches. Two other RF-based classical models were used for comparison. Further, we included 20 cases additional prospective data for robustness test (ClinicalTrials.gov NCT05656053). Findings: In the retrospective cohort, STIM achieved a mean accuracy and AUC of 0.9190 and 0.9650 (95% CI, 0.94–0.99) respectively for the three molecular biomarkers, with a total time of 3 s and a 96% match to WHO CNS5. In the prospective cohort, the diagnostic accuracy of STIM is 0.85 ± 0.04 (mean ± SD) for IDH1, 0.84 ± 0.05 for TERTp, and 0.88 ± 0.04 for 1p/19q. The AUC is 0.89 ± 0.02 (95% CI, 0.84–0.94) for IDH1, 0.80 ± 0.04 (95% CI, 0.71–0.89) for TERTp, and 0.85 ± 0.06 (95% CI, 0.73–0.98) for 1p/19q. Compared to the second best available method based on RF signal, the diagnostic accuracy of STIM is improved by 16.70% and the AUC is improved by 19.23% on average. Interpretation: STIM is a rapid, cost-effective, and easy-to-manipulate AI method to perform real-time intraoperative molecular diagnosis. In the future, it may help neurosurgeons designate personalized surgical plans and predict survival outcomes. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Purpose: This study aimed to determine the feasibility of using intraoperative contrast-enhanced ultrasound (CEUS) to assess subcortical hemodynamic changes in moyamoya disease patients who had undergone combined revascularization. It also aimed to investigate the correlation between quantitative CEUS parameters and post-operative neural functional recovery. Methods: This study included seventeen patients diagnosed with moyamoya disease, confirmed through cerebral angiography, who underwent combined revascularization. Intraoperative subcortical hemodynamics were assessed using CEUS before and immediately after cerebrovascular bypass. Hemodynamic parameters were calculated by analyzing the time-intensity curve generated from a defined region of interest in each CEUS video. Post-operative neurological symptoms, computed tomography records, and short-term modified Rankin Scale (mRS) scores were also recorded. Results: During the post-operative follow-up, 29.4 % of the patients experienced new neurological symptoms, including epilepsy, dyskinesia, and language impairment. Overall, CEUS quantitative parameters suggested that blood supply improved after surgery. And certain hemodynamic parameters exhibited a stronger correlation with the mRS scores, with correlation coefficients ranging up to 0.73 (p

AbstractObjective Coronary artery calcification (CAC) is positively and independently associated with cardiovascular disease (CVD) in patients undergoing maintenance hemodialysis (MHD). Insulin resistance is independently associated with CAC and is an important risk factor for CVD. The triglyceride–glucose (TyG) index is a reliable biomarker of insulin resistance. This cross-sectional, observational study aimed to investigate the relationship between the TyG index and CAC in asymptomatic non-diabetic patients undergoing MHD.Methods The quantitative coronary artery calcification score (CACS) was calculated and expressed using the Agatston score. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multiple Poisson regression analysis, Spearman correlation analysis, and receiver operating characteristic (ROC) curves were used to investigate the relationship between the TyG index and CAC.Results The 151 patients were divided into three groups according to the tertiles of the TyG index. With an increase in the TyG index, the CACS significantly increased (Spearman’s rho = 0.414, p

Intervertebral disc degeneration (IDD) is a major contributing factor to both lower back and neck pain. As IDD progresses, the intervertebral disc (IVD) loses its ability to maintain its disc height when subjected to axial loading. This failure in the weight-bearing capacity of the IVD is a characteristic feature of degeneration. Natural polymer-based hydrogel, derived from biological polymers, possesses biocompatibility and is able to mimic the structure of extracellular matrix, enabling them to support cellular behavior. However, their mechanical performance is relatively poor, thus limiting their application in IVD regeneration. In this study, we developed an injectable composite hydrogel, namely, Mel-MBG/SA, which is similar to natural weight-bearing IVD. Mesoporous bioactive glasses not only enhance hydrogels, but also act as carriers for melatonin (Mel) to suppress inflammation during IDD. The Mel-MBG/SA hydrogel further provides a mixed system with sustained Mel release to alleviate IL-1β-induced oxidative stress and relieve inflammation associated with IDD pathology. Furthermore, our study shows that this delivery system can effectively suppress inflammation in the rat tail model, which is expected to further promote IVD regeneration. This approach presents a novel strategy for promoting tissue regeneration by effectively modulating the inflammatory environment while harnessing the mechanical properties of the material.

Abstract Background and objective Mental health imbalance are the main cause of anxiety, depression and happiness reduction in the older. Self-assessment living standard and sleep quality are both influencing factors of mental health. Meantime, self-assessment living standard has an impact on sleep quality. But there’s no research on the relationship between the three, we conducted this study to explore the relationship between self-assessment living standard and mental health and the mediating role of sleep quality among the older in rural areas of China. Methods Using typical field sampling method, M County, Anhui Province was selected as the investigation site, and a total of 1223 respondents were selected. With the help of questionnaires enclosing respondents’ sociodemographics information, 12 Items General Health Questionnaire (GHQ-12) and Pittsburgh Sleep Quality Scale (PSQI), face-to-face interviews were used to collect data. Bootstrap test was used for data analysis. Results The results showed that the age of the respondents ranged from 60 to 99 years, with an average age of (66.53 ± 6.77) years, the proportion of the older with a tendency to mental health problems was 24.7%. Most of the older people’s self-assessment living standard was normal (average score was 2.89 ± 0.726), accounting for 59.3% of the total. The average sleep quality score was (6.97 ± 4.066), and 2.5% of the respondents reported serious sleep problems. older with low self- assessment living standards were more likely to report a higher propensity for psychological problems (β = 0.420, P

Abstract Background Green manure (GM) is a crop commonly grown during fallow periods, which has been applied in agriculture as a strategy to regulate nutrient cycling, improve organic matter, and enhance soil microbial biodiversity, but to date, few studies have examined the effects of GM treatments on rhizosphere soil bacterial community and soil metabolites from continuous cropping peanut field. Results: In this study, we found that the abundances of several functionally significant bacterial groups containing Actinobacteria, Acidobacteria, and genus Sphingomonas, which are associated with nitrogen cycling, were dramatically increased in GM-applied soils. Consistent with the bacterial community results, metabolomics analysis revealed a strong perturbation of nitrogen- or carbon-related metabolisms in GM-applied soils. The substantially up-regulated beneficial metabolites including sucrose, adenine, lysophosphatidylcholine (LPC), malic acid, and betaines in GM-applied soils may contribute to overcome continuous cropping obstacle. In contrast to peanut continuous cropping, planting winter wheat and oilseed rape in winter fallow period under continuous spring peanut production systems evidently improved the soil quality, concomitantly with raised peanut pod yield by 32.93% and 25.20%, in the 2020 season, respectively. Conclusions: GMs application is an effective strategy to overcome continuous cropping obstacle under continuous peanut production systems by improving nutrient cycling, soil metabolites, and rhizobacterial properties.

At present, there are many methods to construct a vehicle driving cycle, such as the micro-trip-based method and the Markov chain method. Different methods have different advantages and disadvantages. To compare these methods, this paper uses the micro-trip-based method, the Markov chain method, and the method combining micro-trips and Markov chains to construct the representative driving cycle of a Xi’an urban bus based on the driving data of the Xi’an No.2 bus. Firstly, the driving data is collected and preprocessed. Then, representative driving cycles are constructed based on different methods. Finally, different driving cycles based on different methods are compared. By calculating and comparing characteristic parameters, velocity distributions, acceleration distributions, and vehicle-specific power distributions between different representative driving cycles, this paper shows the advantages and disadvantages of different construction methods.

Herbicide residues in farmland soils have attracted a great deal of attention in recent decades. Their accumulation potentially decreases the activity of microbes and related enzymes, as well as disturbs the nitrogen cycle in farmland soils. In previous studies, the influence of natural factors or nitrogen fertilization on the soil nitrogen cycle have frequently been examined, but the role of herbicides has been ignored. This study was conducted to examine the effects of herbicides on NH3 volatilization- and denitrification-related nitrogen loss through three rotation cycles from 2013 to 2016. The four treatments included no urea fertilizer (CK), urea (CN), urea+acetochlor-fenoxaprop-ethyl (AC-FE), and urea+2,4D-dicamba (2,4D-DI) approaches. The results showed that the application of nitrogen fertilizer significantly increased the nitrogen losses from ammonia volatilization and denitrification in the soil. Ammonia volatilization was the main reason for the gaseous loss of urea nitrogen in a wheat–maize rotation system in the North China Plain (NCP), which was significantly higher than the denitrification loss. In the CK treatment, the cumulative nitrogen losses from ammonia volatilization and denitrification during the three crop rotation cycles were 66.64 kg N hm−2 and 8.07 kg N hm−2, respectively. Compared with CK, the nitrogen losses from ammonia volatilization and denitrification under the CN treatment increased 52.62% and 152.88%, respectively. The application of AC-FE and 2,4D-DI significantly reduced the nitrogen gas losses from the ammonia volatilization and denitrification in the soil. Ammonia volatilization reduction mainly occurred during the maize season, and the inhibition rates of AC-FE and 2,4D-DI were 7.72% and 11.80%, respectively, when compared with CN. From the perspective of the entire wheat–maize rotation cycle, the inhibition rates were 5.41% and 7.23% over three years, respectively. Denitrification reduction also mainly occurred in the maize season, with the inhibition rates of AC-FE and 2,4D-DI being 34.12% and 30.94%, respectively, when compared with CN. From the perspective of the entire wheat–maize rotation cycle, the inhibition rates were 28.39% and 28.58% over three years, respectively. Overall, this study demonstrates that herbicides could impact the nitrogen cycle of farmland soil ecosystems via the suppression of ammonia volatilization and denitrification rates, thus reducing gaseous N losses and mitigating global climate change.

Summary: Current biochemical approaches have only identified the most well-characterized kinases for a tiny fraction of the phosphoproteome, and the functional assignments of phosphosites are almost negligible. Herein, we analyze the substrate preference catalyzed by a specific kinase and present a novel integrated deep neural network model named FuncPhos-SEQ for functional assignment of human proteome-level phosphosites. FuncPhos-SEQ incorporates phosphosite motif information from a protein sequence using multiple convolutional neural network (CNN) channels and network features from protein-protein interactions (PPIs) using network embedding and deep neural network (DNN) channels. These concatenated features are jointly fed into a heterogeneous feature network to prioritize functional phosphosites. Combined with a series of in vitro and cellular biochemical assays, we confirm that NADK-S48/50 phosphorylation could activate its enzymatic activity. In addition, ERK1/2 are discovered as the primary kinases responsible for NADK-S48/50 phosphorylation. Moreover, FuncPhos-SEQ is developed as an online server.

Summary: Tubulointerstitial abnormalities contribute to the progression of diabetic kidney disease (DKD). However, the underlying mechanism of the pathobiology of tubulointerstitial disease is largely unknown. Here, we showed that MYCT1 expression was downregulated in in vitro and in vivo DKD models. Adeno-associated virus (AAV)-Myct1 significantly attenuated renal dysfunction and tubulointerstitial fibrosis in diabetic db/db mice and downregulated Sp1 transcription and TGF-β1/SMAD3 pathway activation. In human proximal tubular epithelial cells, high glucose-induced high expression of SP1 and TGF-β1/SMAD3 pathway activation as well as overaccumulation of extracellular matrix (ECM) were abrogated by MYCT1 overexpression. Mechanistically, the binding of VDR to the MYCT1 promoter was predicted and confirmed using dual-luciferase reporter and ChIP analysis. VDR transcriptionally upregulates MYCT1. Our data reveal MYCT1 as a new and potential therapeutic target in treating DKD.

In recent years, electroconductive hydrogels (ECHs) have shown great potential in promoting nerve regeneration and motor function recovery following diabetic peripheral nerve injury (PNI), attributed to their similar electrical and mechanical characteristics to innate nervous tissue. It is well-established that PNI causes motor deficits and pain, especially in diabetics. Current evidence suggests that ropivacaine (ROP) encapsulated in poly lactic-co-glycolic acid (PLGA) microspheres (MSs) yield a sustained analgesic effect. In this study, an ECH electroconductive network loaded with MS/ROP (ECH-MS/ROP) was designed as a promising therapeutic approach for diabetic PNI to exert lasting analgesia and functional recovery. This dual delivery system allowed ROP's slow and sequential release, achieving sustained analgesia as demonstrated by our in vivo experiments. Meanwhile, this system was designed like a lamellar dressing, with desirable adhesive and self-curling properties, convenient for treating injured nerve tissues via automatically wrapping tube-like structures, facilitating the process of implantation. Our in vitro assays verified that ECH-MS/ROP was able to enhance the adhesion and motility of Schwann cells. Besides, both in vitro and in vivo studies substantiated that ECH-MS/ROP stimulated myelinated axon regeneration through the MEK/ERK signaling pathway, thereby improving muscular denervation atrophy and facilitating functional recovery. Therefore, this study suggests that the ECH-MS/ROP dressing provides a promising strategy for treating diabetic PNI to facilitate nerve regeneration, functional recovery and pain relief.

The authors present a wearable photoacoustic patch, which integrates laser diodes and piezoelectric transducers for three-dimensional imaging of hemoglobin and temperature in deep tissues.

Abstract Objective The use of cement or cementless femoral stem prosthesis for hip arthroplasty in elderly patients has been controversial. This study investigated the efficacy and safety of cementless femoral stem in elderly patients (age ≥ 65 years). Methods The short-term efficacy of primary hip arthroplasty with cementless femoral stem in our hospital from January 2014 to June 2021 was retrospectively analyzed. Patients were divided into two groups according to age: young group (

Abstract This paper analyzes the effectiveness of government subsidies in promoting product diversity when a downstream firm has buyer power. Using an extension of the Dixit‐Stiglitz model of monopolistic competition, we compare the effects of subsidies on the equilibrium number of differentiated products and social welfare in the case where products are sold directly to consumers versus the case where they are distributed through a monopoly retailer with buyer power. We find that a production subsidy promotes product diversity in both cases, but the mechanisms through which a subsidy raises the number of products are different. Compared with the case where products are distributed directly to consumers, retailer buyer power reduces product diversity and social welfare. Furthermore, it weakens the effectiveness of the subsidy in promoting product diversity. At any given subsidy rate the equilibrium number of products is smaller, and a rise in the subsidy rate leads to a smaller increase in the number of products.

Wetlands have powerful runoff regulation functions, which can effectively store and retain surface runoff. The runoff regulation function of wetlands is affected by wetland areas, which affect the capacity of flood control. To explore the law of the area change of the main wetlands of the Naolihe River Basin (MWNRB), the visual interpretation method was used to extract wetlands. To identify the reasons for area changes in the MWNRB, the maximum likelihood method, minimum distance method, and neural network method were used to classify land use types from remote sensing images; the M-K variation point test and Theil-Sen trend analysis were used to test the variation point and calculate the trend of precipitation and temperature series. To clarify the influence of wetland areas on runoff, the Gini coefficient and SRI of runoff were used to calculate runoff temporal inhomogeneity. The results showed that the area of the MWNRB obviously decreased, with 74.5 × 106 m2/year from 1993 to 2008, and increased slowly from 2008 to 2015, with 27.7 × 106 m2/year. From 1993 to 2008, 50.74% and 38.87% of wetlands were transformed into paddy fields and dry fields, respectively. From 2008 to 2015, 61.69% and 7.76% of wetlands were transformed from paddy fields and dry fields, respectively. The temperature of the MWNRB increased slowly by 0.04 °C/year from 1993 to 2008 and increased obviously by 0.16 °C/year from 2008 to 2015. The precipitation decreased by 5.6–8.1 mm/year and increased by 16.6–41.2 mm/year in 1993–2008 and 2008–2015, respectively. Compared with precipitation and temperature, land use change caused by human activities is the main cause of wetland area change. The area change of the MWNRB has a certain influence on the runoff regulation and storage capacity. The Gini coefficient and SRI index increased from 0.002/year (0.008) to 0.023/year from 1993 to 2008 and decreased from 0.046/year (0.045) to 0.161/year from 2008 to 2015, respectively.

The Mott insulator provides an excellent foundation for exploring a wide range of strongly correlated physical phenomena, such as high-temperature superconductivity, quantum spin liquid, and colossal magnetoresistance. A Mott insulator with the simplest degree of freedom is an ideal and highly desirable system for studying the fundamental physics of Mottness. In this study, we have unambiguously identified such an anticipated Mott insulator in a van der Waals layered compound Nb_{3}Cl_{8}. In the high-temperature phase, where interlayer coupling is negligible, density functional theory calculations for the monolayer of Nb_{3}Cl_{8} suggest a half-filled flat band at the Fermi level, whereas angle-resolved photoemission spectroscopy experiments observe a large gap. This observation is perfectly reproduced by dynamical mean-field theory calculations considering strong electron correlations, indicating a correlation-driven Mott insulator state. Since this half-filled band derived from a single 2a_{1} orbital is isolated from all other bands, the monolayer of Nb_{3}Cl_{8} is an ideal realization of the celebrated single-band Hubbard model. Upon decreasing the temperature, the bulk system undergoes a phase transition, where structural changes significantly enhance the interlayer coupling. This results in a bonding-antibonding splitting in the Hubbard bands, while the Mott gap remains dominant. Our discovery provides a simple and seminal model system for investigating Mott physics and other emerging correlated states.

Cellular senescence (CS), classically considered a stable cell cycle withdrawal, is hallmarked by a progressive decrease in cell growth, differentiation, and biological activities. Senescent cells (SNCs) display a complicated senescence-associated secretory phenotype (SASP), encompassing a variety of pro-inflammatory factors that exert influence on the biology of both the cell and surrounding tissue. Among global mortality causes, cardiovascular diseases (CVDs) stand out, significantly impacting the living quality and functional abilities of patients. Recent data suggest the accumulation of SNCs in aged or diseased cardiovascular systems, suggesting their potential role in impairing cardiovascular function. CS operates as a double-edged sword: while it can stimulate the restoration of organs under physiological conditions, it can also participate in organ and tissue dysfunction and pave the way for multiple chronic diseases under pathological states. This review explores the mechanisms that underlie CS and delves into the distinctive features that characterize SNCs. Furthermore, we describe the involvement of SNCs in the progression of CVDs. Finally, the study provides a summary of emerging interventions that either promote or suppress senescence and discusses their therapeutic potential in CVDs.

Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.

Abstract Background Sonodynamic therapy (SDT) is a burgeoning modality for cancer therapy owing to its high tissue-penetrating capability, controllability and safety. Whereas, the undesirable reactive oxygen species (ROS) yield of sonosensitizers and tumor hypoxia are two vulnerable spots of SDT. Therefore, it is an advisable strategy to augment ROS level and simultaneously relieve hypoxia for SDT to arrive its full potential in cancer treatment. Results In this work, the defected two-dimensional (2D) Pd/H-TiO2 nanosheets (NSs) with triple antineoplastic properties were dexterously elaborated and engineered using a facile one-pot Pd-catalyzed hydrogenation tactic by loading a tiny amount of Pd and then inletting hydrogen flow at atmospheric pressure and temperature. The 2D black Pd/H-TiO2 NSs with oxygen defects exerted eximious SDT effect based on the decreased bandgap that made it easier for the separation of electrons and holes when triggered by ultrasound as theoretically guided by density functional theory calculations. Additionally, Pd/H-TiO2 NSs could serve as Fenton-like agents because of the presence of oxygen defects, facilitating the conversion of hydrogen peroxide into hydroxyl radicals for exerting the chemodynamic therapy (CDT). Simultaneously, the introduced tiny Pd component possessed catalase-like activity responsible for oxygen production to ameliorate hypoxic condition and thus contributed to improving SDT and CDT efficacies. Both in vitro and in vivo results provided compelling evidences of high ROS yield and aggrandized sono-chemodynamic effect of Pd/H-TiO2 nanosonosensitizers with the detailed underlying mechanism investigation by RNA sequencing. Conclusion This work delves the profound potential of Pd-catalyzed hydrogenated TiO2 on oncotherapy, and the effective antineoplastic performance and ignorable therapeutic toxicity make it a powerful competitor among a cornucopia of nanosonosensitizers. Graphical Abstract

SignificanceCardiovascular diseases are seen to be a primary cause of death, and their prevalence has significantly increased across the globe in the past few years. Several studies have shown that cell death is closely linked to the pathogenesis of cardiovascular diseases. Furthermore, many molecular and cellular mechanisms are involved in the pathogenesis of the cardiac cell death mechanism. One of the factors that played a vital role in the pathogenesis of cardiac cell death mechanisms included the early growth response-1 (Egr-1) factor.Recent AdvancesStudies have shown that abnormal Egr-1 expression is linked to different animal and human disorders like heart failure and myocardial infarction. The biosynthesis of Egr-1 regulates its activity. Egr-1 can be triggered by many factors such as serum, cytokines, hormones, growth factors, endotoxins, mechanical injury, hypoxia, and shear stress. It also displays a pro-apoptotic effect on cardiac cells, under varying stress conditions. EGR1 mediates a broad range of biological responses to oxidative stress and cell death by combining the acute changes occurring in the cellular environment with sustained changes in gene expression.Future DirectionsThe primary regulatory role played by the Egr-1-targeting DNAzymes, microRNAs, and oligonucleotide decoy strategies in cardiovascular diseases were identified to provide a reference to identify novel therapeutic targets for cardiovascular diseases.

Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD.Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis.Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis.Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments.

IntroductionMost women of reproductive age suffered from the primary dysmenorrhea (PD). Up to date, most studies on the etiology of dysmenorrhea focused on endocrine factors while ignored the effect of spino-pelvic bony anatomy on uterus. In this study, we innovatively shed light on the relationship between primary dysmenorrhea and sagittal spino-pelvic alignment.Materials and Methods120 patients diagnosed with primary dysmenorrhea and a control group of 118 healthy volunteers were enrolled into this study. All subjects received the standing full-length posteroanterior plain radiography to evaluate the sagittal spino-pelvic parameters. The visual analog scale (VAS) was used to assess pain rating of primary dysmenorrhea patients. Analysis of variance (ANOVA) or Student's t test was performed to measure statistical significance between differences.ResultsThere was a significant difference in pelvic incidence (PI), sacral slope (SS), lumbar lordosis (LL) and thoracic kyphosis (TK) between PD group and Normal group (P

BackgroundAlkaptonuria is a rare autosomal genetic disorder with an incidence of about 1 in 1 million per year. Spinal involvement often manifests in the later stages of the disease. However, this is the first report of the presentation of thoracolumbar spinal stenosis.Case presentationWe report the case of a 61-year-old female patient with significant thoracolumbar stenosis symptoms. The patient had obvious kyphosis with preoperative lower extremity muscle strength grade 2/5. Symptoms and imaging signs initially suggested ankylosing spondylitis. This patient was classified into motor incomplete injury (ASIA C). However, the patient was found to have melanin deposits on the sclera and skin, and the urine was darkened at rest. CT and MRI both suggested no bone bridge connection between vertebrae, which was the key difference between ankylosing spondylitis and alkaptonuria in imaging. Most importantly, urine specimen testing and intraoperative pathology demonstrated alkaptonuria. The patient underwent spinal decompression and vertebral body fixation. Postoperative recovery was good: the patient had significantly relieved pain and could stand and walk.ConclusionThis case is the first report of thoracolumbar spinal stenosis associated with alkaptonuria involving the spine.

Lower back pain is a significant contributor to disability and incapacity in adults. Up to 40 % of lower back pain is considered to be caused primarily by disc degeneration. The pH value in the intervertebral disc (IVD) usually decreases with the progression of degeneration, which can act as an initiator to trigger the release of drugs precisely for inhibiting the intervertebral disc degeneration (IDD). Herein, we fabricated a pH-responsive metal organic framework (MOF) to load anti-inflammatory protocatechuic acid (PCA), followed by the encapsulation of hyaluronic acid (HA), the final product was abbreviated as MOF@PH. The results showed that the acidic microenvironment could trigger drug release from MOF@PH featured by an increasing release proportion with pH decreasing. The cell assessment indicated that MOF@PH could suppress the inflammatory response of the nucleus pulposus significantly, downregulate the expression of related inflammatory markers (IL-6, ROS, NLRP-3 etc.) and promote the expression of nucleus pulposus specific markers. The administration of MOF@PH in rat disc degeneration model was proven able to effectively delay the degeneration process. The pH-sensitive MOF@PH may offer an effective strategy to precisely treat the IDD with desired therapeutic effects.

Abstract Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.

Abstract Objective We aimed to explore the correlation between functional disability and quality of life (QoL). And exploring the interaction of functional disability, basic demographic characteristics and health-related information on QoL among the rural elderly in Anhui Province. Methods This study used multi-stage stratified cluster sampling in rural Anhui Province from January to July 2018 to conduct a cross-sectional survey of older adults who met the inclusion criteria. The Five-Dimensional European Quality Of Health Scale (EQ-5D) and the WHO Disability Assessment Schedule (WHODAS2.0) scale were used to evaluate the QoL and functional disability, and the basic demographic characteristics of the survey subjects were also collected. Using binary logistic and Classification and regression tree model (CART) models to analyze the data, explore the relationship between functional disability and QoL in the elderly. Results A total of 3491 older adults were included in the survey, and 3336 completed the entire survey, with an effective response rate of 95.56%. After adjusting for covariables, those who had limited in dimension of mobility (AOR=2.243, 95%CI: 1.743-2.885), getting along (AOR=1.615, 95%CI: 1.173-2.226), life activities (AOR=2.494, 95%CI:1.928-3.226), and social participation (AOR=2.218, 95%CI: 1.656-2.971) had a lower QoL. However, the dimension of cognition (AOR=0.477, 95%CI: 0.372-0.613) is a protective factor for QoL. Additionally, we also observe that 96.3% of those who were unemployed and limited in both mobility and life activities dimensions had a lower QoL, but among those who were robust in both mobility and social participation dimensions and not suffer from chronic diseases, 56.3% had a higher QoL. Conclusions Our findings indicate that special attention should be paid to the elderly who are unemployed, have limited in cognition, getting along, social participation, mobility, life activities and cognition robust to improve their QoL. This research is of great significance for formulating targeted strategies and measures to improve the QoL for rural elderly.

Sirtuins belong to the class III histone deacetylases and possess nicotinamide adenine dinucleotide-dependent deacetylase activity. They are involved in the regulation of multiple signaling pathways implicated in cardiovascular diseases. Autophagy is a crucial adaptive cellular response to stress stimuli. Mounting evidence suggests a strong correlation between Sirtuins and autophagy, potentially involving cross-regulation and crosstalk. Sirtuin-mediated autophagy plays a crucial regulatory role in some cardiovascular diseases, including atherosclerosis, ischemia/reperfusion injury, hypertension, heart failure, diabetic cardiomyopathy, and drug-induced myocardial damage. In this context, we summarize the research advancements pertaining to various Sirtuins involved in autophagy and the molecular mechanisms regulating autophagy. We also elucidate the biological function of Sirtuins across diverse cardiovascular diseases and further discuss the development of novel drugs that regulate Sirtuin-mediated autophagy.

The glucose-lowering drug metformin has been reported to have anticancer properties through unknown mechanisms. Other unknown factors that may influence its anticancer potential include the glycemic status of the patient. Therefore, the objective of this study is to determine the effect of different glucose environments on the antiproliferative potency and the cellular mechanism of action of metformin. Human breast cancer cells, MCF-7, were incubated in low, normal, elevated, and high glucose environments and treated with metformin. The antiproliferative potential of metformin and its effect on protein expression as well as its ability to induce cellular apoptosis and autophagy under different glucose environments, were determined using different molecular techniques. Metformin significantly inhibited cellular proliferation in a time- and glucose-concentration-dependent manner. In comparison to elevated glucose, low normal glucose alone induced a significant level of autophagy that was further increased in the presence of metformin. While glucose concentration did not appear to have an effect on the antiproliferative potency of metformin, the cellular basis of action was shown to be glucose-dependent. The antiproliferative mechanism of action of metformin in elevated and low normal glucose environments is mTOR-dependent, whereas, in the high glucose environment, the antiproliferative mechanism is independent of mTOR. This is the first study to report that both the antiproliferative potency and the cellular mechanism of action aredependent on the concentration of glucose.

The yield and quality of peanut (Arachis hypogaea L.), an oil crop planted worldwide, are often limited by drought stress (DS) and nitrogen (N) deficiency. To investigate the molecular mechanism by which peanut counteracts DS and N deficiency, we conducted comprehensive transcriptomic and metabolomic analyses of peanut leaves. Herein, 829 known differentially accumulated metabolites, 324 differentially expressed transcription factors, and 5294 differentially expressed genes (DEGs) were identified under different water and N conditions. The transcriptome analysis demonstrated that drought-related DEGs were predominantly expressed in “glycolysis/gluconeogenesis” and “glycerolipid metabolism”, while N-deficiency-related DEGs were mainly expressed in starch and sucrose metabolism, as well as in the biosynthesis of amino acid pathways. The biosynthesis, transport, and catabolism of secondary metabolites accounted for a large proportion of the 1317 DEGs present in water and N co–limitation. Metabolomic analysis showed that the metabolic accumulation of these pathways was significantly dependent on the stress conditions. Additionally, the roles of metabolites and genes in these pathways, such as the biosynthesis of amino acids and phenylpropanoid biosynthesis under different stress conditions, were discussed. The results demonstrated that different genes, metabolic pathways, and metabolites were related to DS and N deficiency. Thus, this study elucidates the metabolic pathways and functional genes that can be used for the improvement of peanut resistance to abiotic stress.