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Abstract Purpose Early detection of lifestyle factors, skin and hair color, circulating parameters, and metabolic comorbidities is crucial for personalized prevention and treatment of early age-related macular degeneration (AMD). This study aimed to assess the relationships between genetically predicted comprehensive risk factors and early AMD. Methods and results Publicly available genome-wide association study (GWAS) data were utilized to identify genetic variants significantly associated with each trait. We applied a Bonferroni-corrected significance level of P

Abstract Background Sex as a biological variable is not a common consideration in molecular mechanistic or preclinical studies of retinal diseases. Understanding the sexual dimorphism of adult RPE and retina under physiological conditions is an important first step in improving our understanding of sex-based physio-pathological mechanisms. Methods Isobaric tags for relative and absolute quantitation (iTRAQ) were used for quantitative proteomics of male and female mouse retina and RPE (10 mice of each sex for each tissue type). Differentially expressed proteins were subjected to Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA). Results Differential expression analysis identified 21 differentially expressed proteins in the retina and 58 differentially expressed proteins in the RPE. Ingenuity pathway analysis identified the top canonical pathways differentially activated in the retina to be calcium transport I, nucleotide excision repair, molecular transport and cell death and survival. In the RPE, the top canonical pathways were calcium signaling, dilated cardiomyopathy signaling, actin cytoskeletal signaling and cellular assembly and organization. Conclusions These results provide insights into sex differences in the retina and RPE proteome of mice and begin to shed clues into the sexual dimorphism seen in retinal diseases.

Abstract Background Advance Care Planning via Group Visits (ACP-GV) is a patient-centered intervention facilitated by a clinician using a group modality to promote healthcare decision-making among veterans. Participants in the group document a “Next Step” to use in planning for their future care needs. The next step may include documentation of preferences in an advance directive, discussing plans with family, or anything else to fulfill their ACP needs. This evaluation seeks to determine whether there are identifiable subgroups of group participants with differing needs prior to delivery of the ACP-GV program and, if so, to use information about the subgroups to enhance the program offered to veterans in United States Department of Veterans Affairs (VA) healthcare settings. Methods We conducted a secondary analysis of national data from a quality improvement evaluation. Patient- and provider-level data from administrative healthcare records for VA users in all 50 states, territories, and the District of Columbia provides data on veterans attending ACP-GV during federal fiscal years 2018–2022 (N = 26,857). Latent class analysis seeks to identify the various subgroups of veterans based on their level of ACP self-efficacy before attending ACP-GV and any demographic differences across the resulting subgroups of veterans attending ACP-GV. ACP self-efficacy is derived from seven items obtained from a participant worksheet used during the group. Results Analysis revealed two distinct groups of veterans, distinguishable by their pre-ACP-GV levels of one aspect of ACP self-efficacy: prior knowledge of ACP. Veterans with higher prior knowledge of ACP are associated with an identified next step focused on checking their current AD status and updating it, and veterans with lower ACP prior knowledge are associated with identifying a next step to discuss ACP more fully with family. Differences in age, sex, race, ethnicity, and marital status exist across subgroups of veterans. Conclusion Greater attention must be paid to ACP and veterans’ prior knowledge of ACP to consistently encourage annual review and status updates.

Abstract Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.

Abstract Muscle stem cells (MuSCs) are effective in treating inflammatory diseases driven by overactive innate immune responses, such as colitis and acute lung injury, due to their immunomodulatory properties. However, their potential in treating diseases driven by adaptive immune responses is still uncertain. When primed with inflammatory cytokines, MuSCs strongly suppressed T cell activation and proliferation in vitro in co-culture with activated splenocytes or peripheral blood mononuclear cells. Systemic administration of MuSCs from both mice and humans alleviated pathologies in mice with concanavalin A-induced acute liver injury, characterized by hyperactivated T lymphocytes. Importantly, MuSCs showed significant species-specific differences in their immunoregulatory functions. In mouse MuSCs (mMuSCs), deletion or inhibition of inducible nitric oxide synthase (iNOS) reduced their immunosuppressive activity, and absence of iNOS negated their therapeutic effects in liver injury. Conversely, in human MuSCs (hMuSCs), knockdown or inhibition of indoleamine 2,3-dioxygenase (IDO) eliminated their immunosuppressive effects, and loss of IDO function rendered hMuSCs ineffective in treating liver injury in mice. These results reveal significant species-specific differences in the mechanisms by which MuSCs mediate T cell immunosuppression. Mouse MuSCs rely on iNOS, while human MuSCs depend on IDO expression. This highlights the need to consider species-specific responses when evaluating MuSCs’ therapeutic potential in immune-related disorders.

Abstract Healthcare data accessibility for machine learning (ML) is encumbered by a range of stringent regulations and limitations. Using synthetic data that mirrors the underlying properties in the real data is emerging as a promising solution to overcome these barriers. We propose a fully automated synthetic tabular neural generator (STNG), which comprises multiple synthetic data generators and integrates an Auto-ML module to validate and comprehensively compare the synthetic datasets generated from different approaches. An empirical study was conducted to demonstrate the performance of STNG using twelve different datasets. The results highlight STNG’s robustness and its pivotal role in enhancing the accessibility of validated synthetic healthcare data, thereby offering a promising solution to a critical barrier in ML applications in healthcare.

Abstract Background Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development and disease, how the molecular agents collectively shape the H3K36me landscape is unclear. Results We use mouse mesenchymal stem cells to perturb the H3K36me methyltransferases (K36MTs) and infer the activities of the five most prominent enzymes: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and is predominantly deposited at intergenic regions by NSD1, and partly by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 deposits most H3K36me3, it may also deposit H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting other (K36MTs) prime gene bodies with lower methylation states ahead of transcription. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks on active promoters and enhancers. Meanwhile, the activity of ASH1L is restricted to the regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. Conclusions Within genes, SETD2 primarily deposits H3K36me3, while the other K36MTs deposit H3K36me1/2 independently of SETD2 activity. For the deposition of H3K36me1/2, we find a hierarchy of K36MT activities where NSD1 > NSD2 > NSD3 > ASH1L. While NSD1 and NSD2 are responsible for most genome-wide propagation of H3K36me2, the activities of NSD3 and ASH1L are confined to active regulatory elements.

Abstract Second‐life batteries (SLBs), which are batteries retired from electric vehicles (EVs), can be used as energy storage systems to enhance the performance of distribution networks. Two issues should be addressed particularly for the optimal sizing of SLBs. Compared with fresh batteries, the failure rate of SLBs is relatively high, and timely and preventive replacement is needed. In addition, the flexibility introduced by EVs and installed SLBs should be coordinated to achieve optimal economic benefits. This paper focuses on the efficient utilization of SLBs by highlighting reliability‐flexibility concerns in optimal sizing. The model is formulated as a bi‐level model. On the upper‐level, considering the operational reliability constraints of SLBs, decisions regarding the investment and replacement of SLBs are optimized. Distribution network operations are improved on the lowerlevel, with an effective spatiotemporal flexible dispatch strategy for EVs. Finally, a linearized process for the optimal sizing of SLBs is presented and efficiently implemented. The Sioux Falls network and IEEE 69‐node distribution network are coupled as the test system. According to the simulation results, when the state of health of the SLBs decreased to 70%, the conditions were unreliable. The differences in the optimal SLB size and costs considering reliability and flexibility are highlighted.

Abstract Green hydrogen, the cleanest energy carrier, is receiving increased attention in recent years. Transporting hydrogen through a natural gas system (NGS) will significantly promote the use of hydrogen, moreover, hydrogen‐enriched compressed natural gas (HCNG) has great potential for renewable energy accommodation. To solve the problem of altered gas flow caused by hydrogen injection into natural gas networks, an optimized operation model of integrated electricity‐HCNG systems (IEHCNGS) with distributed hydrogen injecting is proposed in this paper. Firstly, a calculating model of hydrogen volume fraction based on minimum square summation and depth‐first search is established to describe the gas flow distribution of NGS accurately. Secondly, a quantitative method of gas supply reliability based on maximum entropy is proposed to ensure the safe operation of the system. Finally, an optimization model of IEHCNGS is established considering the coupling constraints of the integrated system and the reliability of NGS. The case study shows that the hydrogen volume fraction calculation model can correct the heat value of gas in each pipeline in real‐time, the maximum entropy model helps to improve the gas supply reliability of NGS, and the distributed hydrogen injecting mode is more capable of accommodating renewable energy.

Abstract High-intensity coal mining has induced a series of ecological and environmental problems issues, including surface subsidence, the development of ground cracks, and the deterioration of vegetation. The disruption of water circulation systems induced by mining, such as perched groundwater, groundwater of aeration zone, and phreatic water, is the root cause of vegetation withering. The aeration zone serves as a crucial nexus in the process of water cycling and exerts a significant influence on soil fertility. To explore the characteristics of soil moisture transport in subsidence areas under the mining disturbance, on-site monitoring of the size and morphology characteristics of subsidence areas and ground cracks was conducted in typical mining areas in Inner Mongolia, China. Subsequently, a typical soil moisture transport model was constructed in subsidence areas, the soil moisture transport patterns under the influence of different types of subsidence and cracks were analyzed, and the influence law of soil damage on soil moisture transport in the aerated zone was clarified. The results indicate that (1) Based on the occurrence and distribution characteristics of subsidence cracks, the subsidence area can be divided into tension zone, compression zone, and neutral zone; the ground cracks are divided into permanent tension cracks and dynamic cracks. (2) The drought stress effect of soil in the subsidence area is significant. Under the influence of soil structure variation, the water-holding capacity of the soil in the subsidence area decreases, and the soil moisture dissipation is strong. The soil moisture transport rate in the aeration zone of the subsidence area is ranked as follows: tension zone > neutral zone > compression zone. (3) Ground cracks can exacerbate the soil moisture transport rate in the aeration zone. After 15 d of crack appearance, the soil moisture transport reaches a relatively stable state, and the soil moisture transport rate in the surface layer of the crack is the fastest, and the loss of soil moisture is the most significant. The crack effect is not significant beyond 100 cm from the crack. This study provides a theoretical and data support for soil and vegetation remediation in mining subsidence areas.

ABSTRACTMaize (Zea mays L.) is the most important cereal crop in the world. Flowering period and photoperiod play important roles in the reproductive development of maize. This study, investigated ZmMADS42, a gene that is highly expressed in the shoot apical meristem. Agrobacterium infection was used to successfully obtain overexpressed ZmMADS42 plants. Fluorescence quantitative PCR revealed that the expression of the ZmMADS42 gene in the shoot apical meristem of transgenic plants was 2.8 times higher than that of the wild-type(WT). In addition, the expression of the ZmMADS42 gene in the endosperm was 2.4 times higher than that in the wild-type. The seed width of the T2 generation increased by 5.35%, whereas the seed length decreased by 7.78% compared with that of the wild-type. Dissection of the shoot tips of transgenic and wild-type plants from the 7-leaf stage to the 9-leaf stage revealed that the transgenic plants entered the differentiation stage earlier and exhibited more tassel meristems during their vegetative growth period. The mature transgenic plants were approximately 20 cm shorter in height and had a lower panicle position than the wild-type plants. Comparing the flowering period, the tasseling, powdering, and silking stages of the transgenic plants occurred 10 days earlier than those of the wild-type plants. The results showed that the ZmMADS42 gene played a significant role in regulating the flowering period and plant height of maize.

Abstract Power system unreliability tracing model allocates the system's reliability index to individual components, identifying potential weaknesses. This study expands its scope by considering the impact of storage resources. Unreliable factors leading to load shedding are categorized into two groups: objective factors inherent to the component and insufficient storage resources. The latter requires a retrospective analysis of other components that caused unreliability previously. When allocating responsibility for load shedding at a certain time, it begins by allocating it among components based on differences between fixed expected output and actual supply. Expected output insufficiency is considered as the unreliable factor. This insufficiency due to insufficient storage resources is then decomposed into segments, each caused by excessive output in earlier instances of the same component. The expected output excess is attributed to the expected output insufficiency of other components in previous times, for which responsibility has been allocated to each component. Consequently, the expected output insufficiency at a particular time can be traced back based on a temporal recursive model, with the load shedding further allocated to components before that time. Case studies based on several systems demonstrate that the proposed model's allocation results are reasonable and more accurate than the traditional model.

Abstract Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.

Abstract Background Preserved ratio impaired spirometry (PRISm) is a type of abnormal lung function. PRISm and mortality have been explored in several studies, but a comprehensive evaluation of the associations is limited. The current study aims to conduct a systematic review and meta-analysis in order to investigate the mortality and cardiovascular diseases in patients with PRISm. Methods PubMed, Embase, and Web of Science databases, as well as gray literature sources, were searched for relevant studies published up to 7 September 2023 without language restrictions. This review included all published observational cohort studies that investigated the association of PRISm with mortality in the general population, as well as subgroup analyses in smokers and pre-bronchodilation spirometry studies. The outcomes of interest were all-cause mortality, cardiovascular mortality, and respiratory-related mortality. The Newcastle–Ottawa scale assessed study quality. Sensitivity and subgroup analyses explored heterogeneity and robustness. Publication bias was assessed with Egger’s and Begg’s tests. Results Overall, eight studies were included in this meta-analysis. The pooled HR was 1.60 (95% CI, 1.48–1.74) for all-cause mortality, 1.68 (95% CI, 1.46–1.94) for CVD mortality, and 3.09 (95% CI, 1.42–6.71) for respiratory-related mortality in PRISm group compared to normal group. In the subgroup analysis, participants with PRISm had a higher effect (HR, 2.11; 95% CI, 1.74–2.54) on all-cause mortality among smokers relative to participants with normal spirometry. Furthermore, the association between PRISm and mortality risk was consistent across several sensitivity analyses. Conclusions People with PRISm were associated with an increased risk of all-cause mortality, CVD mortality, and respiratory-related mortality as compared to those with normal lung function in the general population. Systematic review registration PROSPERO CRD42023426872.

Abstract Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

Abstract Background This study aimed to estimate the prevalence of achieving the secondary prevention targets recommended in the World Health Organization (WHO) guidelines for cardiovascular disease (CVD) in 38 low-income and middle-income countries (LMICs). Methods We pooled nationally representative cross-sectional surveys from 38 LMICs between 2013 and 2020. Treatment, metabolic and lifestyle targets were assessed for individuals with a self-reported history of CVD according to WHO’s recommendations. Associations between the prevalence of guideline adherence and sociodemographic characteristics were assessed using multivariate Poisson regression models. Results The pooled sample included 126 106 participants, of whom 9821 (6.8% [95% CI 6.4–7.2]) reported a history of CVD. Overall, the prevalence of achieving treatment targets in patients with CVD was 22.7% (95% CI, 21.0-24.5%) for antihypertensive drugs, 19.6% (17.9-21.4%) for aspirin, and 13.6% (12.0-15.44%) for statins. The prevalence of achieving metabolic targets was 54.9% (52.5-57.3%) for BMI, 39.9% (37.7-42.2%) for blood pressure, 46.1% (43.6-48.6%) for total cholesterol, and 84.9% (83.1-86.5%) for fasting blood glucose. The prevalence of achieving lifestyle targets was 83.2% (81.5-84.7%) for not smoking, 83.1% (81.2-84.9%) for not drinking, 65.5% (63.1-67.7%) for sufficient physical activity and 16.2% (14.5-18.0%) for healthy diet. Only 6.1% (5.1-7.4%) achieved three treatment targets, 16.0% (14.3-17.9%) achieved four metabolic targets, and 6.9% (5.8-8.0%) achieved four lifestyle targets. Upper-middle income countries were better than low-income countries at achieving the treatment, non-drinking and dietary targets. Being younger and female were associated with poorer achievement of metabolic targets. Conclusion In LMICs, achieving the targets recommended in the guideline for treatment, metabolism and healthy lifestyles for patients with CVD is notably low. This highlights an urgent need for effective, systematic secondary prevention strategies to improve CVD management.

Abstract Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8+ T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.

Abstract Background HALE is now a regular strategic planning indicator for all levels of the Chinese government. However, HALE measurements necessitate comprehensive data collection and intricate technology. Therefore, effectively converting numerous diseases into the years lived with disability (YLD) rate is a significant challenge for HALE measurements. Our study aimed to construct a simple YLD rate measurement model with high applicability based on the current situation of actual data resources within China to address challenges in measuring HALE target values during planning. Methods First, based on the Chinese YLD rate in the Global Burden of Disease (GBD) 2019, Pearson correlation analysis, the global optimum method, etc., was utilized to screen the best predictor variables from the current Chinese data resources. Missing data for predictor variables were filled in via spline interpolation. Then, multiple linear regression models were fitted to construct the YLD rate measurement model. The Sullivan method was used to measure HALE. The Monte Carlo method was employed to generate 95% uncertainty intervals. Finally, model performances were assessed using the mean absolute error (MAE) and mean absolute percentage error (MAPE). Results A three-input-parameter model was constructed to measure the age-specific YLD rates by sex in China, directly using the incidence of infectious diseases, the incidence of chronic diseases among persons aged 15 and older, and the addition of an under-five mortality rate covariate. The total MAE and MAPE for the combined YLD rate were 0.0007 and 0.5949%, respectively. The MAE and MAPE of the combined HALE in the 0-year-old group were 0.0341 and 0.0526%, respectively. There were slightly fewer males (0.0197, 0.0311%) than females (0.0501, 0.0755%). Conclusion We constructed a high-accuracy model to measure the YLD rate in China by using three monitoring indicators from the Chinese national routine as predictor variables. The model provides a realistic and feasible solution for measuring HALE at the national and especially regional levels, considering limited data.

Abstract Magnetoelectric materials, which encompass coupled magnetic and electric polarizabilities within a single phase, hold great promises for magnetic controlled electronic components or electric-field controlled spintronics. However, the realization of ideal magnetoelectric materials remains tough due to the inborn competion between ferroelectricity and magnetism in both levels of symmetry and electronic structure. Herein, we introduce a methodology for constructing single phase paramagnetic ferroelectric molecule [TMCM][FeCl4], which shows low-magnetic-field magnetoelectricity at room temperature. By applying a low magnetic field (≤1 kOe), the halogen Cl‧‧‧Cl distance and the volume of [FeCl4]− anions could be manipulated. This structural change causes a characteristic magnetostriction hysteresis, resulting in a substantial deformation of ~10−4 along the a-axis under an in-plane magnetic field of 2 kOe. The magnetostrictive effect is further qualitatively simulated by density functional theory calculations. Furthermore, this mechanical deformation significantly dampens the ferroelectric polarization by directly influencing the overall dipole configuration. As a result, it induces a remarkable α 31 component (~89 mV Oe−1 cm−1) of the magnetoelectric tensor. And the magnetoelectric coupling, characterized by the change of polarization, reaches ~12% under 40 kOe magnetic field. Our results exemplify a design methodology that enables the creation of room-temperature magnetoelectrics by leveraging the potent effects of magnetostriction.

Abstract Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis. Graphical Abstract

Exercise prescriptions play a vital role in the prevention and treatment of chronic diseases. A consensus regarding exercise prescription is important for physical health. The “Consensus statement of Chinese experts on exercise prescription” (hereinafter referred to as “Expert Consensus”) divides exercise prescription into two categories: fitness exercise prescription and medical exercise prescription. Traditional Chinese fitness exercises, exercise risk, exercise prescription, and basic precautions for exercise prescription are explained.

Acute ischemic stroke represents a critical, life-threatening condition affecting the central nervous system. Intravenous thrombolysis with tissue plasminogen activator (tPA) remains a cornerstone for achieving vascular recanalization in such patients; however, its therapeutic utility is limited, with only approximately 10% of patients benefiting due to the narrow therapeutic window and significant risk of hemorrhagic transformation. Enhancing the efficacy of tPA thrombolysis is therefore imperative. Neutrophils have been identified as key modulators of thrombolytic outcomes, interacting with tPA post-stroke to influence treatment effectiveness. The binding of tPA to low-density lipoprotein receptor-related protein 1 (LRP-1) on neutrophil surfaces induces degranulation and formation of neutrophil extracellular traps (NETs). Conversely, neutrophils impede the thrombolytic action of tPA by obstructing its interaction with fibrin and activating platelets. These findings suggest that targeting neutrophils may hold promise for improving thrombolysis outcomes. This review explores the role of neutrophils in tPA-mediated thrombolysis following acute ischemic stroke, examines neutrophil-associated biomarkers, and outlines potential strategies for enhancing tPA efficacy.

Abstract Magnesium imbalances commonly exist in septic patients. However, the association of serum magnesium levels with mortality in septic patients remains uncertain. Herein, we elucidated the association between serum magnesium and all‐cause mortality in septic patients from American and Chinese cohorts by analyzing data from 9099 patients in the Medical Information Mart for Intensive Care‐IV (MIMIC‐IV) database and 1727 patients from a university‐affiliated hospital’ intensive care unit in China. Patients in both cohorts were categorized into five groups based on serum magnesium quintiles from the MIMIC‐IV dataset. Patients with higher serum magnesium levels exhibited an increased risk of 28‐day mortality in both cohorts. The restricted cubic spline (RCS) curves revealed a progressively elevated risk of 28‐day mortality with increasing serum magnesium in MIMIC‐IV cohort, while a J‐shaped correlation was observed in institutional cohort. Our findings have validated the association between high serum magnesium and high mortality in sepsis across different races and medical conditions. Serum magnesium levels might be useful in identifying septic patients at higher mortality risk.

Web phishing attacks have emerged as a significant threat to online security, enabling phishers to steal sensitive financial information and commit fraud. To combat this, many anti-phishing systems have been developed, focusing on detecting phishing content in online communications. This study introduces novel approaches to enhance phishing detection by employing machine learning techniques. Specifically, three different single models were analyzed: Random Forest Classifier (RFC), Adaptive Boosting Classification (ADAC), and Naïve Bayes Classification Algorithm (NBC). These models were optimized using Artificial Rabbits Optimization (ARO), resulting in hybrid models RFAR, NBAR, and ADAR. The results of the models’ analysis indicate that the RFAR hybrid model performs better than the other single models and their optimized models. The RFAR model achieved precision scores of 0.950 for phishing websites, 0.954 for suspicious websites, and 0.872 for legitimate websites, with corresponding recall values of 0.929, 0.954, and 0.990, respectively. In comparison, the ADAR model was notably effective in classifying legitimate websites with a precision score of 0.896. The study’s novelty lies in integrating ARO with traditional classifiers to create hybrid models that improve classification accuracy.

In a framework of the Standard Model (SM) simply extended by an SU(2) doublet (X,T) including a vectorlike X-quark (VLQ-X), with electric charge |QX|=5/3, we investigate the single production of the VLQ-X induced by the couplings between the VLQ-X with the first and the third generation quarks at the Large Hadron Collider (LHC) operating at s=14 TeV. The signal is searched in events including same-sign dileptons (electrons or muons), one b-tagged jet and missing energy, where the X quark is assumed to decay into a top quark and a W boson, both decaying leptonically. After a rapid simulation of signal and background events, the 95% CL exclusion limits and the 5σ discovery reach are respectively obtained at the LHC with an integrated luminosity of 300 and 3000 fb−1, respectively.

Abstract Background Hypoxia inducible factor‐1α (HIF‐1α) is a sensitive indicator of oxygen homeostasis, of which the expression elevates following hypoxia/ischemia. This study reveals the specific mechanisms underlying the effects of HIF‐1α on ischemic stroke (IS). Methods IS model was established using middle cerebral artery occlusion (MCAO)‐modeled male rats and oxygen glucose deprivation/reoxygenation (OGD/R)‐treated mice hippocampal cells HT22, followed by the silencing of HIF‐1α and the overexpression of C‐X‐C motif chemokine receptor 4 (CXCR4) and nuclear factor‐kappa B (NF‐κB). Following the surgery, Garcia's grading scale was applied for neurological evaluation. Cerebral infarcts and injuries were visualized using 2,3,5‐triphenyltetrazolium chloride and hematoxylin‐eosin staining. The levels of tumor necrosis factor‐α, Interleukin (IL)‐6, IL‐1β, malondialdehyde, and 8‐hydroxy‐2′‐deoxyguanosine, were calculated via ELISA. MTT assay and lactate dehydrogenase (LDH) assay kit were adopted to determine the viability and cytotoxicity of OGD/R‐modeled cells. Reactive oxygen species (ROS) generation was evaluated using a 2′‐7′dichlorofluorescin diacetate (DCFH‐DA) probe. The levels of HIF‐1α, CXCR4, and NF‐κB p65 were quantified via Western blot and immunofluorescence, respectively. Results HIF‐1α knockdown improved Garcia's score, attenuated the cerebral infarct, inflammation, and ROS generation, and alleviated the levels of inflammatory cytokines and CXCR4/NF‐κB p65 in MCAO‐modeled rats. Such effects were reversed following the overexpression of CXCR4 and NF‐κB. Also, in OGD/R‐treated HT22 cells, HIF‐1α silencing diminished the cytotoxicity and ROS production and reduced the expressions of CXCR4/NF‐κB p65, while promoting viability. However, CXCR4/NF‐κB p65 overexpression did the opposite. Conclusion HIF‐1α knockdown alleviates inflammation and oxidative stress in IS through the CXCR4/NF‐κB pathway.

Understanding the spatiotemporal changes in ecosystem service value (ESV) under urbanization, as well as the supply–demand relationship between different regions, can provide a consultation for ecological compensation (EC) standards. Taking Suzhou, a typical city experiencing rapid urbanization in the Yangtze River Delta, as a case study, this paper analyzes the spatiotemporal changes in land use and ESV from 2000 to 2020. To quantify the ecosystem service flow (ESF), we apply the breakpoint formula and field strength model. Additionally, an EC standard is established, taking population, area and GDP into account while specifying compensation. The findings reveal that urbanization has led to a substantial increase in built-up land in Suzhou, accompanied by continuous reductions in farmland and water bodies. As a result, ESV decreased from 153.07 billion CNY to 138.81 billion CNY. Furthermore, the research identifies a spatial pattern where ESV increases with distance from the city center but decreases with distance from the lake center. This pattern suggests a directional flow of ESV from lakes to cities. Notably, ESF mainly occurs in the southwestern and central areas of Suzhou, with areas closer to Taihu Lake experiencing greater ESV transfer. The transfer value ranges from 5.11 and 32.57 billion CNY. There is an imbalance between the supply and demand of ecosystem services. Therefore, specific county-level cities in Suzhou, namely, the Kunshan District and Industrial Park, emerge as contributors of EC and should contribute 71.94 and 80.74 billion CNY, respectively, to other cities. By formulating a novel EC policy for Suzhou, this paper provides a scientifically informed reference for promoting sustainable development.

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Background: The limited understanding of the physiology and psychology of polar expedition explorers has prompted concern over the potential cognitive impairments caused by exposure to extreme environmental conditions. Prior research has demonstrated that such stressors can negatively impact cognitive function, sleep quality, and behavioral outcomes. Nevertheless, the impact of the polar environment on neuronal activity remains largely unknown. Methods: In this study, we aimed to investigate spatiotemporal alterations in brain oscillations of 13 individuals (age range: 22–48 years) who participated in an Arctic expedition. We utilized electroencephalography (EEG) to record cortical activity before and during the Arctic journey, and employed standardized low resolution brain electromagnetic tomography to localize changes in alpha, beta, theta, and gamma activity. Results: Our results reveal a significant increase in the power of theta oscillations in specific regions of the Arctic, which differed significantly from pre-expedition measurements. Furthermore, microstate analysis demonstrated a significant reduction in the duration of microstates (MS) D and alterations in the local synchrony of the frontoparietal network. Conclusion: Overall, these findings provide novel insights into the neural mechanisms underlying adaptation to extreme environments. These findings have implications for understanding the cognitive consequences of polar exploration and may inform strategies to mitigate potential neurological risks associated with such endeavors. Further research is warranted to elucidate the long-term effects of Arctic exposure on brain function.

Abstract Ghost imaging in the time domain allows for reconstructing fast temporal objects using a slow photodetector. The technique involves correlating random or pre-programmed probing temporal intensity patterns with the integrated signal measured after modulation by the temporal object. However, the implementation of temporal ghost imaging necessitates ultrafast detectors or modulators for measuring or pre-programming the probing intensity patterns, which are not available in all spectral regions especially in the mid-infrared range. Here, we demonstrate a frequency downconversion temporal ghost imaging scheme that enables to extend the operation regime to arbitrary wavelengths regions where fast modulators and detectors are not available. The approach modulates a signal with temporal intensity patterns in the near-infrared and transfers the patterns to an idler via difference-frequency generation in a nonlinear crystal at a wavelength where the temporal object can be retrieved. As a proof-of-concept, we demonstrate computational temporal ghost imaging in the mid-infrared with operating wavelength that can be tuned from 3.2 to 4.3 μm. The scheme is flexible and can be extended to other regimes. Our results introduce new possibilities for scan-free pump-probe imaging and the study of ultrafast dynamics in spectral regions where ultrafast modulation or detection is challenging such as the mid-infrared and THz regions.

Abstract Background The animal sperm shows high diversity in morphology, components, and motility. In the lepidopteran model insect, the silkworm Bombyx mori, two types of sperm, including nucleate fertile eupyrene sperm and anucleate unfertile apyrene sperm, are generated. Apyrene sperm assists fertilization by facilitating the migration of eupyrene spermatozoa from the bursa copulatrix to the spermatheca. During spermatogenesis, eupyrene sperm bundles extrude the cytoplasm by peristaltic squeezing, while the nuclei of the apyrene sperm bundles are discarded with the same process, forming matured sperm. Results In this study, we describe that a mechanoreceptor BmPiezo, the sole Piezo ortholog in B. mori, plays key roles in larval feeding behavior and, more importantly, is essential for eupyrene spermatogenesis and male fertility. CRISPR/Cas9-mediated loss of BmPiezo function decreases larval appetite and subsequent body size and weight. Immunofluorescence analyses reveal that BmPiezo is intensely localized in the inflatable point of eupyrene sperm bundle induced by peristaltic squeezing. BmPiezo is also enriched in the middle region of apyrene sperm bundle before peristaltic squeezing. Cytological analyses of dimorphic sperm reveal developmental arrest of eupyrene sperm bundles in BmPiezo mutants, while the apyrene spermatogenesis is not affected. RNA-seq analysis and q-RT-PCR analyses demonstrate that eupyrene spermatogenic arrest is associated with the dysregulation of the actin cytoskeleton. Moreover, we show that the deformed eupyrene sperm bundles fail to migrate from the testes, resulting in male infertility due to the absence of eupyrene sperm in the bursa copulatrix and spermatheca. Conclusions In conclusion, our studies thus uncover a new role for Piezo in regulating spermatogenesis and male fertility in insects.

Abstract Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26R tdTomato mice to lethally irradiated Ackr1 −/− mice (Ackr1 −/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

Abstract Introduction The replacement intervals for infusion sets may differ among healthcare institutions, which may have an impact on the occurrence of central line-associated bloodstream infections (CLABSI). Nevertheless, there exists a limited amount of high-quality evidence available to assist clinicians in determining the most suitable replacement intervals for infusion sets. Therefore, the objective of this trial is to compare the efficacy of 24-h and 96-h replacement intervals for infusion sets on CLABSI among critically ill adults who have central venous access devices. Methods This is a multicenter, parallel-group randomized controlled trial that will investigate the effect of infusion set replacement intervals on CLABSI in adult patients admitted to intensive care units (ICUs). The study will enroll 1240 participants who meet the inclusion criteria, which includes being 18 years or older, expected to stay in the ICU for longer than 96 h, and in need of central venous access. Participants will be randomly assigned to either a control group receiving a 96-h replacement interval or a treatment group receiving a 24-h replacement interval. Planned Outcome The primary outcome of this trial is the rate of CLABSI within 28 days after randomization. Conclusion This is the first randomized controlled trial to investigate the effects of infusion set replacement at 24-h and 96-h intervals on CLABSI in ICU patients. Trial Registration ClinicalTrials.gov identifier, NCT05359601.

Abstract The current parallel ankle rehabilitation robot (ARR) suffers from the problem of difficult real-time alignment of the human-robot joint center of rotation, which may lead to secondary injuries to the patient. This study investigates type synthesis of a parallel self-alignment ankle rehabilitation robot (PSAARR) based on the kinematic characteristics of ankle joint rotation center drift from the perspective of introducing "suitable passive degrees of freedom (DOF)" with a suitable number and form. First, the self-alignment principle of parallel ARR was proposed by deriving conditions for transforming a human-robot closed chain (HRCC) formed by an ARR and human body into a kinematic suitable constrained system and introducing conditions of "decoupled" and "less limb". Second, the relationship between the self-alignment principle and actuation wrenches (twists) of PSAARR was analyzed with the velocity Jacobian matrix as a "bridge". Subsequently, the type synthesis conditions of PSAARR were proposed. Third, a PSAARR synthesis method was proposed based on the screw theory and type of PSAARR synthesis conducted. Finally, an HRCC kinematic model was established to verify the self-alignment capability of the PSAARR. In this study, 93 types of PSAARR limb structures were synthesized and the self-alignment capability of a human-robot joint axis was verified through kinematic analysis, which provides a theoretical basis for the design of such an ARR.

Objective Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). Methods With in vivo experiments, we established the steroid‐induced osteonecrosis of the femoral head (SONFH) model using Sprague–Dawley (SD) rats (8‐week‐old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low‐, medium‐ and high‐dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4‐week‐old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX‐containing serum and glucocorticoids: control group (CG); BSHX low‐, medium‐, and high‐dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low‐, medium‐, and high‐dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX‐containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co‐culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. Results BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p

Multiple symmetric lipomatosis, also known as madelung’s disease, is a rare syndrome characterized by the accumulation of multiple symmetric subcutaneous adipose tissues that significantly affect patients’ quality of life. Since the aetiology of the disease is still unclear, surgical intervention by doctors based on clinical experience is currently the main treatment. However, the recurrence rate remains high even after surgical intervention. Therefore, studying the pathogenesis of this disease is particularly important for overcoming this challenge. In this paper, we reviewed and summarized recent research results on the pathogenesis of this disease to provide possible research directions and treatment strategies for this disease, but no clear mechanism was identified.‘Level of Evidence: Level I, Review Articles’