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Abstract Neurodegenerative diseases pose a significant health burden globally, with limited treatment options available. Among the various cell types involved in the pathogenesis of these disorders, microglia, the resident immune cells of the central nervous system, play a pivotal role. Dysregulated microglial activation contributes to neuroinflammation and neuronal damage, making them an attractive target for therapeutic intervention. Adeno-associated virus (AAV) vectors have emerged as powerful tools for delivering therapeutic genes to specific cell types in the central nervous system with remarkable precision and safety. In the current review, we discuss the strategies employed to achieve selective transduction of microglia, including the use of cell-specific promoters, engineered capsids, and microRNA (miRNA) strategies. Additionally, we address the challenges and future directions in the development of AAV-based therapies targeting microglia. Overall, AAV-mediated targeting of microglia holds promise as a novel therapeutic approach for neurodegenerative diseases, offering the potential to modify disease progression and improve patient outcomes.

[Introduction] Under the vision of carbon peak and carbon neutralization, the construction of the new power system substations is imperative. [Method] To promote the transformation of traditional substations to new power system substations, a full-lifecycle green and low-carbon construction scheme for new power system substations was proposed. Focusing on electrical equipment, building structures, building equipment and integrated energy, the carbon emissions throughout the entire life cycle of substations were reduced, and the new power system substations were constructed and operated in a green and low-carbon manner. [Result] The results show that compared with conventional substations, the proposed green and low-carbon construction scheme not only improves the development and utilization of renewable energy and accelerates the low-carbon upgrade of power grids, but also promotes energy saving and consumption reduction of power grid equipment, reduces carbon emissions and O&M costs of substations, and improves the utilization level of basic resources of substations, thus improving the comprehensive economic benefits of the substations. [Conclusion] The proposed green and low-carbon construction scheme has certain universality and replicability. It can provide theoretical and practical guidance for the transformation and transition of substations, and lay the foundation for the low-carbon development of the power grid.

Tensegrity robots contain compression struts and tension tendons, allowing them to change their shape by controlling the lengths of members. Due to their excellent locomotion ability, they can play well when exploring complex environments. To protect the internal devices and meanwhile provide a base layer for thin film solar cells, membranes are proposed to cover the outer surface of the locomotive tensegrity in this study. A mathematical model for locomotive tensegrity with membranes is developed. A genetic algorithm incorporated with an incremental dynamic relaxation method is used to generate rolling gaits for the locomotive tensegrity with membranes. A classical strut-actuated 6-strut tensegrity system is taken as the basic model, and eight triangular membranes are covered on its outer surface to build a typical locomotive tensegrity with membranes. The influence of the membranes on the original rolling gaits generated by a numerical model of the 6-strut locomotive tensegrity without membranes is investigated. It is found that the effect of membranes becomes negligible when the relative stiffness between membranes and tendons is equal to or less than 1.2. When the effect of membranes is not negligible, the rolling gaits of the 6-strut locomotive tensegrity with membranes should be redesigned by using a numerical model taking the membranes into account. A physical prototype for the strut-actuated 6-strut locomotive tensegrity with membranes is fabricated, and tested to verify the feasibility of the redesigned rolling gaits.

Lead (Pb) is an environmentally widespread bone toxic pollutant, contributes to the development of osteoporosis. Butyric acid, mainly produced by the fermentation of indigestible dietary fiber by gut microbiota, plays a pivotal role in the maintenance of bone homeostasis. However, the effects of butyric acids on the Pb induced osteoporosis have not yet been elucidated. In this study, our results showed that Pb exposure was negatively related to the abundance of butyric acid, in the Pb-exposed population and Pb-exposed mice. Pb exposure caused gut microbiota disorders, resulting in the decline of butyric acid-producing bacteria, such as Butyrivibrio_crossotus, Clostridium_sp._JN9, and the butyrate-producing enzymes through the acetyl-CoA pathway. Moreover, results from the NHANES data suggested that dietary intake of butyrate was associated with a reduced risk of osteoporosis in lead-burdened populations, particularly among men or participants aged 18–60 years. In addition, butyrate supplementation in mice with chronic Pb exposure improved the bone microarchitectures, repaired intestinal damage, upregulated the proportion of Treg cells. Taken together, these results demonstrated that chronic Pb exposure disturbs the gut-bone axis, which can be restored by butyric acid supplement. Our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced bone toxicity.

The evasion of carbon dioxide (CO2) from lakes significantly influences the global carbon equilibrium. Amidst global climatic transformations, the role of Qingzang Plateau (QZP) lakes as carbon (C) sources or sinks remains a subject of debate. Furthermore, accurately quantifying their contribution to the global carbon budget presents a formidable challenge. Here, spanning half a century (1970–2020), we utilize a synthesis of literature and empirical field data to assess the CO2 exchange flux of QZP lakes. We find markedly higher CO2 exchange flux in the southeast lakes than that in the northern and western regions from 1970 to 2000. During this time, both freshwater and saltwater lakes served primarily as carbon sources. The annual CO2 exchange flux was estimated at 2.04 ± 0.37 Tg (Tg) C yr−1, mainly influenced by temperature fluctuations. The CO2 exchange flux patterns underwent a geographical inversion between 2000 and 2020, with increased levels in the west and decreased levels in the east. Notably, CO2 emissions from freshwater lakes diminished, and certain saltwater lakes in the QTP transitioned from carbon sources to sinks. From 2000 to 2020, the annual CO2 exchange flux from QZP lakes is estimated at 1.34 ± 0.50 Tg C yr−1, with solar radiation playing a more pronounced role in carbon emissions. Cumulatively, over the past five decades, QZP lakes have generally functioned as carbon sources. Nevertheless, the total annual CO2 emissions have declined since the year 2000, indicating a potential shift trend from being a carbon source to a sink, mirroring broader patterns of global climate change. These findings not only augment our understanding of the carbon cycle in plateau aquatic systems but also provide crucial data for refining China's carbon budget.

Abstract The Tibetan grassland ecosystems possess significant carbon sink potential and have room for improved carbon sequestration processes. There is a need to uncover more ambitious and coherent solutions (e.g., Nature-based Solutions) to increase carbon sequestration. Here, we investigated the rationale and urgency behind the implementation of Nature-based Solutions on sequestering carbon using literature review and meta-analysis. We also project the changes in terrestrial carbon sink of Tibetan Plateau grassland ecosystems using model simulations with different future emissions scenario. The results show that the Nature-based Solution projects are expected to increase the carbon sink of Tibetan Plateau grassland ecosystems by 15 to 21 tetragrams of carbon by 2060. We defined a conceptual framework of Nature-based Solutions that integrates initiatives for the restoration of degraded grasslands and carbon sequestration. Our framework consists of four stages: theory, identification, practice, and goal. Traditional Tibetan knowledge plays an important role in reframing the proposed Nature-based Solutions framework. We also apply this framework to optimize ecological restoration techniques and projects and to evaluate the annual changes in the carbon sink under different socioeconomic pathway scenarios.

Pediatric monogenetic diseases encompass a spectrum of debilitating neurological disorders that affect infants and children, often resulting in profound cognitive and motor impairments. Gene replacement therapy holds immense promise in addressing the underlying genetic defects responsible for these conditions. Adeno-associated virus (AAV) vectors have emerged as a leading platform for delivering therapeutic genes due to their safety profile and ability to transduce various cell types, including neurons. This review highlights recent advancements in AAV-mediated gene replacement therapy for pediatric monogenetic diseases, focusing on key preclinical and clinical studies. We discuss various strategies to enhance transduction efficiency, target specificity, and safety. Furthermore, we explore challenges such as immune responses, along with innovative approaches to overcome these obstacles. Moreover, we examine the clinical outcomes and safety profiles of AAV-based gene therapies in pediatric patients, providing insights into the feasibility and efficacy of these interventions. Finally, we discuss future directions and potential avenues for further research to optimize the therapeutic potential of AAV-delivered gene replacement therapy for pediatric encephalopathies, ultimately aiming to improve the quality of life for affected individuals and their families.

Abstract Base editors (BEs) are a recent generation of genome editing tools that couple a cytidine or adenosine deaminase activity to a catalytically impaired Cas9 moiety (nCas9) to enable specific base conversions at the targeted genomic loci. Given their strong application potential, BEs are under active developments toward greater levels of efficiency and safety. Here, a previously overlooked nCas9‐centric strategy is explored for enhancement of BE. Based on a cytosine BE (CBE), 20 point mutations associated with nCas9‐target interaction are tested. Subsequently, from the initial positive X‐to‐arginine hits, combinatorial modifications are applied to establish further enhanced CBE variants (1.1–1.3). Parallel nCas9 modifications in other versions of CBEs including A3A‐Y130F‐BE4max, YEE‐BE4max, CGBE, and split‐AncBE4max, as well as in the context of two adenine BEs (ABE), likewise enhance their respective activities. The same strategy also substantially improves the efficiencies of high‐fidelity nCas9/BEs. Further evidence confirms that the stabilization of nCas9‐substrate interactions underlies the enhanced BE activities. In support of their translational potential, the engineered CBE and ABE variants respectively enable 82% and 25% higher rates of editing than the controls in primary human T‐cells. This study thus demonstrates a highly adaptable strategy for enhancing BE, and for optimizing other forms of Cas9‐derived tools.

AbstractBackground Circadian rhythm involved with physiology has been reported to affect pharmacokinetics or pharmacodynamics. We hypothesized that circadian variations in physiology disturb anesthesia and eventually affect recovery after anesthesia.Methods A retrospective cohort study initially included 107,406 patients (1 June 2016–6 June 2021). Patients were classified into morning or afternoon surgery groups. The primary outcome was daytime variation in PACU (post-anesthesia care unit) recovery time and Steward score. Inverse probability weighting (IPW) approach based on propensity score and univariable/multivariable linear regression were used to estimate this outcome.Results Of 28,074 patients, 13,418 (48%) patients underwent morning surgeries, and 14,656 (52%) patients underwent afternoon surgeries. LOWESS curves and IPW illustrated daytime variation in PACU recovery time and Steward score. Before adjustment, compared to morning surgery group, afternoon surgery group had less PACU recovery time (median [interquartile range], 57 [46, 70] vs. 54 [43, 66], p

Abstract Background Postoperative delirium (POD) is an important complication for older patients and recent randomised controlled trials have showed a conflicting result of the effect of deep and light anesthesia. Methods We included randomised controlled trials including older adults that evaluated the effect of anesthetic depth on postoperative delirium from PubMed, Embase, Web of Science and Cochrane Library. We considered deep anesthesia as observer’s assessment of the alertness/ sedation scale (OAA/S) of 0–2 or targeted bispectral (BIS) 50. The primary outcome was incidence of POD within 7 days after surgery. And the secondary outcomes were mortality and cognitive function 3 months or more after surgery. The quality of evidence was assessed via the grading of recommendations assessment, development, and evaluation approach. Results We included 6 studies represented 7736 patients aged 60 years and older. We observed that the deep anesthesia would not increase incidence of POD when compared with the light anesthesia when 4 related studies were pooled (OR, 1.40; 95% CI, 0.63–3.08, P = 0.41, I2 = 82%, low certainty). And no significant was found in mortality (OR, 1.12; 95% CI, 0.93–1.35, P = 0.23, I2 = 0%, high certainty) and cognitive function (OR, 1.13; 95% CI, 0.67–1.91, P = 0.64, I2 = 13%, high certainty) 3 months or more after surgery between deep anesthesia and light anesthesia. Conclusions Low-quality evidence suggests that light general anesthesia was not associated with lower POD incidence than deep general anesthesia. And High-quality evidence showed that anesthetic depth did not affect the long-term mortality and cognitive function. Systematic review registration CRD42022300829 (PROSPERO).

This study aims to compare the restraint performance of two child restraint systems (CRSs) used on airplanes—a rear-facing child seat (RFCS) and the child aviation restraint system (CARES)—for 1.5-year-old children, along with their compatibility with different types of aircraft seats. 16 g longitudinal dynamic tests were conducted on two types of aircraft seats with CRSs. Results indicate poor compatibility of CARES with Type A seats, significantly increasing the risk of head, neck, and abdominal injuries, with Nij exceeding the acceptable limit. In contrast, CARES exhibited good compatibility with Type B seats and effectively protected children. RFCS tests demonstrated effective injury risk reduction on both types of seats. It can be found that the performance of CARES depends on restraint status and seat dimensions; RFCSs provide adequate protection for 1.5-year-olds. Optimal protection can be achieved with smaller restrain angles of CRS and using thinner seat cushions. Compared to CARES, RFCSs better adapt to various aircraft seat structures, offering superior child protection.

Abstract Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation‐based nanomedicines in tumor therapy including calcium ion (Ca2+), ferrous ion (Fe2+), cuprous ion (Cu+), managanese ion (Mn2+), and zinc ion (Zn2+). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation‐based nanomedicines. Then the antitumor mechanisms of various ions‐based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation‐based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies.

Ongoing encroachment is driving recent alpine shrubline dynamics globally, but the role of shrub-shrub interactions in shaping shrublines and their relationships with stem density changes remain poorly understood. Here, the size and age of shrubs from 26 Salix shrubline populations along a 900-km latitudinal gradient (30°–38° N) were measured and mapped across the eastern Tibetan Plateau. Point pattern analyses were used to quantify the spatial distribution patterns of juveniles and adults, and to assess spatial associations between them. Mean intensity of univariate and bivariate spatial patterns was related to biotic and abiotic variables. Bivariate mark correlation functions with a quantitative mark (shrub height, basal stem diameter, crown width) were also employed to investigate the spatial relationships between shrub traits of juveniles and adults. Structural equation models were used to explore the relationships among conspecific interactions, patterns, shrub traits and recruitment dynamics under climate change. Most shrublines showed clustered patterns, suggesting the existence of conspecific facilitation. Clustered patterns of juveniles and conspecific interactions (potentially facilitation) tended to intensify with increasing soil moisture stress. Summer warming before 2010 triggered positive effects on population interactions and spatial patterns via increased shrub recruitment. However, summer warming after 2010 triggered negative effects on interactions through reduced shrub recruitment. Therefore, shrub recruitment shifts under rapid climate change could impact spatial patterns, alter conspecific interactions and modify the direction and degree of shrublines responses to climate. These changes would have profound implications for the stability of alpine woody ecosystems.

Biodiversity and ecosystem services are seriously threatened by human activities, and there have been calls for the expansion of protected areas (PAs) to mitigate this situation. Currently, there is an urgent need to establish new PA cost-effectively from concentrating on biodiversity to including the provision of ecosystem services. Hence, a prefectural evaluation was conducted across the Qinghai-Tibet Plateau (QTP) to quantify endangered species habitat provision and three key ecosystem services to identify conservation priority zones (CPZs), which were then combined with low human footprint zones to determine cost–effective zones (CEZs). A scenario simulation, which contains conservative, moderate, and ambitious targets, was further proposed to conserve more CEZs for PA design. We found that biodiversity, ecosystem services, and human footprints varied significantly among the different taxonomic groups. CPZs and CEZs cover 33 and 28 % of the QTP, respectively, including almost all forest areas, and near medium and high elevations (approximately 3000 ∼ 4700 m). In comparison with existing PAs systems, the new PAs system is considering cost-effective in terms of biodiversity and ecosystem services, increasing 42–60 %, 32–46 %, and 62–69 %, and 47–62 % of the important habitats that serve mammals, birds, amphibians, and plants, respectively, and promoting 48–66 % carbon service, 37–54 % soil retention, and 22–37 % water yield. More importantly, it reduces conflict with the human footprint by up to 22 %. Moreover, the conservative, moderate, and ambitious targets conserved 44, 48, and 53 % of the QTP, respectively. These three targets were set for each prefecture and prefectural–level city with spatially specific CEZs recognized, providing some implications on prefectural PAs priorities for policymakers.

Abstract Background Due to the heterogeneity of the phenotype of Hereditary spherocytosis (HS) patients, some patients may have rare clinical complications such as biliary obstruction and ultra-high bilirubinemia. Case presentation A 8-y-old boy presented to the emergency with complaints of anemia for 6 years and worsened abdominal pain and scleral yellowing of the skin for 2 days. Physical examination showed tenderness in the middle and upper abdomen and splenomegaly. Abdominal CT revealed biliary obstruction. Genetic analysis revealed a de novo mutation in the gene ANK1, HS with biliary obstruction was diagnosed. The surgery of bile duct exploration and T-tube drainage, and splenectomy were performed successively. This patient was followed up for 13 months after splenectomy, and his condition was stable. Conclusion The diagnosis of HS is not clinically difficult, and once a patient with HS is diagnosed, regular follow-up management and standardized treatment are required. Genetic testing is also needed to screen for other genetic disorders that may co-exist in patients with HS who do not have a good efficacy or who have a long-term chronic onset of jaundice.

Abstract Background Measurement of the Chinese burden of disease with disability-adjusted life-years (DALYs) requires disability weight (DW) that quantify health losses for all non-fatal consequences of disease and injury. The Global Burden of Disease (GBD) 2013 DW study indicates that it is limited by lack of geographic variation in DW data and by the current measurement methodology. We aim to estimate DW for a set of health states from major diseases in the Wuhan population. Methods We conducted the DW measurement study for 206 health states through a household survey with computer-assisted face-to-face interviews and a web-based survey. Based on GBD 2013 DW study, paired comparison (PC) and Population health equivalence (PHE) method was used and different PC/PHE questions were randomly assigned to each respondent. In statistical analysis, the PC data was analyzed by probit regression. The probit regression results will be anchored by results from the PHE data analyzed by interval regression on the DW scale units between 0 (no loss of health) and 1 (loss equivalent to death). Results A total of 2610 and 3140 individuals were included in the household and web-based survey, respectively. The results from the total pooled data showed health state “mild anemia” (DW = 0.005, 95% UI 0.000–0.027) or “allergic rhinitis (hay fever)” (0.005, 95% UI 0.000–0.029) had the lowest DW and “heroin and other opioid dependence, severe” had the highest DW (0.699, 95% UI 0.579–0.827). A high correlation coefficient (Pearson’s r = 0.876; P

Abstract Background Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. Method Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L d-glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. Results In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. Conclusions These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.

γδ T cells, a specialized subset of T lymphocytes, have garnered significant attention within the realm of cancer immunotherapy. Operating at the nexus between adaptive and innate immunological paradigms, these cells showcase a profound tumor discernment repertoire, hinting at novel immunotherapeutic strategies. Significantly, these cells possess the capability to directly identify and eliminate tumor cells without reliance on HLA-antigen presentation. Furthermore, γδ T cells have the faculty to present tumor antigens to αβ T cells, amplifying their anti-tumoral efficacy.Within the diverse and heterogeneous subpopulations of γδ T cells, distinct immune functionalities emerge, manifesting either anti-tumor or pro-tumor roles within the tumor microenvironment. Grasping and strategically harnessing these heterogeneous γδ T cell cohorts is pivotal to their integration in tumor-specific immunotherapeutic modalities. The aim of this review is to describe the heterogeneity of the γδ T cell lineage and the functional plasticity it generates in the treatment of malignant tumors. This review endeavors to elucidate the intricate heterogeneity inherent to the γδ T cell lineage, the consequential functional dynamics in combating malignancies, the latest advancements from clinical trials, and the evolving landscape of γδ T cell-based oncological interventions, while addressing the challenges impeding the field.

Stephania kwangsiensis, a vine plant of the Stephaniaceae family, is mainly spread in Guangxi, China. The medicinal part (root tuber) of S. kwangsiensis, “Jin Bu Huan” in Chinese, is often used for sedative, insecticidal, anti inflammatory, anti-tumor, antiviral and antibacterial, as well as for the treatment of Alzheimer’s disease. In order to make full use of the plant resources, clarify its chemical constituents, and find the relevant active compounds, the methanol extracts of non-medicinal parts of this plant were isolated using various chromatographic methods such as positive phase Sephadex LH-20, positive phase silica gel, positive phase polyamide, and MCI gel CHP-20P. The structures of the isolated monomer compounds were determined by MS, 1H-NMR, 13C-NMR, and other spectral data analysis, as well as comparison with relevant literatures. The activities of the isolated compounds from S. kwangsiensis against bacteria (Escherichia coli, Staphylococcus aureus, Bacillus subtilis) and fungi (Fusarium oxysporum) were evaluated using filter paper method. The results were as follows: (1) A total of 10 compounds obtained from the non-medicinal parts of this plant were identified as vomifoliol (1), grasshopper ketone (2), isocorydine(3), 2-O-β-D-glucopyranosyl-D-arabinitol(4),(9S,12S,13S)-trihydroxyoctadeca-(10E,15Z)-dienoic acid (5), magnoflorine (6), corchoionoside C (7), tormentic acid (8), corydine (9) and crebanine (10). Among them, compounds 1, 2, 4, 5, 6, 7 and 8 were isolated from this plant for the first time, compounds 1, 2, 4, 5, 7 and 8 were firstly obtained from this genus plants, and Compound 4 was found from natural products for the first time. (2) At concentration of 6 mg·mL-1, compounds 1, 2 and 5 showed weak antibacterial activities against Escherichia coli; Compound 2 exhibited weak antibacterial activities against Staphylococcus aureus; compounds 3 and 8 displayed weak antibacterial activities against Bacillus subtilis. In conclusion, the non-medicinal parts of Stephania kwangsiensis contain large numbers of active components and have the potential of development and utilization.

Step voltage regulator (SVR) has been utilized in power distribution systems for decades as the voltage regulation device. Due to the increasing integration of distributed energy resources, the conventional SVR is severely challenged by the modern power distribution pattern with high renewable energy penetration. The induced arc from the conventional SVR tap change and more frequent tap changes due to voltage instability from the renewable energy impose constraints on the conventional SVRs lifetime. Meanwhile, the conventional SVR device cannot regulate the voltage accurately since the SVR regulates the voltage step-by-step. This article proposed a hybrid voltage regulator with high-efficiency and low contact wearing, which can achieve arcless tap change and stepless voltage regulation by using a fractionally rated back-to-back power converter. The accurate load voltage regulation is guaranteed, while the tap changer mechanism remains in the system, which helps to promote the upgrade to the existing power distribution systems. The power converter capacity in the proposed topology is only 0.31% of the distribution transformer rating to achieve a stepless voltage regulation range of ±10%, significantly reducing the system cost compared with the full power electronics solutions and projects high total system efficiency. The proposed hybrid voltage regulator was simulated and experimentally validated. The experimental results demonstrate arcless tap change operation and stepless voltage regulation. Collaborative operation between the conventional mechanical tap change and the power converter operation is also demonstrated to acquire large voltage regulation with fast-acting voltage control.

Abstract Background Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. Methods Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats’ cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. Results This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the “Eat Me” complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. Conclusions These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

Abstract Purpose Previous studies showed that peroxisome proliferator-activated receptor gamma (PPARγ) and PPARγ coactivator1 family (PPARGC1A and PPARGC1B) gene single nucleotide variants (SNVs)were strongly associated with cancer susceptibility. The purpose of this study was to investigate the association of PPARγ, PPARGC1A, and PPARGC1B variants with the risk of gastric cancer (GC). Patients and methods We performed a case-control study of 490 GC cases and 1,476 healthy controls from eastern China. PPARγ rs1801282 C > G, rs3856806 C > T, PPARGC1A rs2970847 C > T, rs8192678 C > T and PPARGC1B rs7732671 G > C, rs17572019 G > A SNVs were selected to investigate the association between these SNVs and GC susceptibility. Genotypes of the SNVs were assessed by multiplex fluorescent PCR using a custom-by-design 48-Plex SNPscantm Kit. Results The PPARγ rs1801282 SNV was associated with a decreased risk for GC (GC vs. CC: odds ratio (OR) = 0.62, 95% confidence interval (95%CI) = 0.42–0.93, adjusted P = 0.019; GC + GG vs. GG: OR = 0.63 95%CI = 0.42–0.93, adjusted P = 0.019; respectively). In addition, stratified analysis revealed that the PPARγ rs1801282 SNV was correlated with the risk of GC in subgroups of age ≥ 61, no smoking, and no alcohol consuming. We also confirmed that the PPARγ rs3856806 C > T SNV promoted the risk of GC in women. The PPARGC1A rs8192678 TT genotype decreased the susceptibility of GC in men. The PPARGC1A rs2970847 C > T SNV decreased the susceptibility of GC in the subgroup of BMI ≥ 24 kg/m2. The PPARGC1B rs7732671 G > C and rs17572019 G > A SNVs promoted the risk of GC in the subgroup of BMI ≥ 24 kg/m2. Conclusion This study indicates that the PPARγ, PPARGC1A, and PPARGC1B SNVs may be associated with the susceptibility of GC in eastern Chinese population. Future studies with larger populations, detailed H. pylori infection status for subgroup analysis, and functional study are needed to further clarify the relationship between these SNVs and GC risk.

The isotropic pyrocarbon bulk materials were prepared by the fixed-bed chemical vapor deposition method, and the internal structure was composed of ribbon-like structure and spherical structure together. The friction behaviors of isotropic pyrocarbon at room temperature were studied by characterizing the microstructure and friction morphology. The frictional properties of isotropic pyrocarbon are greatly influenced by internal ribbon-like pyrocarbon. With a higher content of ribbon-like pyrocarbon, the material produces a moderately rough friction film, which improves the stability of the friction coefficient. Meanwhile, ribbon-like pyrocarbon increases the hardness of the material and reduces its wear rate. In addition, external stress can impact the friction behavior of the material. Increasing the external load causes the friction film to become more continuous and uniform, reducing the overall friction coefficient of the material. When the load is low (50 N and 100 N), the friction coefficient tends to stabilize more quickly. Nevertheless, an excessive load (200 N) will result in the creation of grooves, making it difficult to stabilize the friction coefficient of the material.

Abstract Background The cerebellum is involved in hyperactivity, fear, and anxiety disorders that could be induced by whole-brain irradiation (WBI). However, whether cerebellar irradiation alone (CIA) could induce these disorders is unknown. We investigated the effect of CIA in an animal model. Methods Eleven-day-old rat pups underwent a single 3-Gy dose of either WBI (n = 28) or CIA (n = 20), while 34 rat pups were sham-irradiated (controls). Cell death was evaluated in the subgranular zone of the hippocampus by counting pyknotic cells after haematoxylin/eosin staining at 6 h after irradiation for 10, 8, and 9 pups, respectively. Behavioural changes were evaluated via open-field test at 6 weeks for 18, 12, and 25 pups, respectively. Unpaired two-tailed t-test and one-way and two-way repeated ANOVA were used. Results Massive cell death in cerebellar external granular layer was detected at 6 h after CIA (1,419 ± 211 mm, mean ± S.E.M. versus controls (68 ± 12 mm) (p < 0.001)), while no significant difference between CIA (1,419 ± 211 mm) versus WBI (1,433 ± 107 mm) (p = 0.955) was found. At open-field behavioural test, running distance, activity, wall distance, middle zone visit times, and duration were higher for WBI versus controls (p < 0.010), but no difference between CIA and controls was found (p > 0.05). Conclusions Although the cerebellum is involved in hyperactivity, fear, and anxiety disorders, CIA did not induce these disorders, indicating that WBI-induced cerebellar injury does not directly cause these behavioural abnormalities after WBI. Thus, targeting the cerebellum alone may not be enough to rescue or reduce these behavioural abnormalities after WBI.

Abstract Background Branchio-Oto-Renal (BOR) Syndrome is a rare autosomal disorder with a wide variety of clinical manifestations and a high degree of heterogeneity. Typical clinical manifestations of BOR syndrome include deafness, preauricular fistula, abnormal gill slits, and renal malformations. However, atypical phenotypes such as congenital hip dysplasia, congenital heart anomaly or facial nerve paresis are rare in BOR syndrome, and this might be easily misdiagnosed with other congenital disorders. Case presentation We report a 5-month-old boy of BOR syndrome with "congenital heart defects and proteinuria" as clinical features. Initially, as this case mainly presented with symptoms of recurrent respiratory infections and was found to be with congenital heart disease and proteinuria at the local hospital, but he only was diagnosed with congenital heart disease combined with pulmonary infection and anti-infective and supportive treatment was given. Subsequently, during the physical examination at our hospital, left side preauricular pit and branchial fistulae on the right neck were found. Subsequent evaluation of auditory brainstem response and distortion product otoacoustic emission were revealed sensorineural hearing impairment. Results of renal ultrasonography showed small kidneys. Genetic analysis revealed a microdeletion at chromosome 8q13.2-q13.3 encompassing EYA1 gene, this patient was finally diagnosed with BOR syndrome. Then, this patient received transcatheter patent ductus arteriosus closure and hearing aid treatment. Proteinuria, renal function and hearing ability are monitoring by nephrologist and otologist. The patient is currently being followed up until 3 months after discharge and his condition is stable. Conclusion Careful physical examination, detailed history and the implementation of diagnostic laboratory tests can reduce the incidence of misdiagnosis. Genetic sequencing analysis of patients is a key guide to the differential diagnosis of BOR syndrome.

Abstract Background Clinical and animal studies demonstrated that neuroinflammation from anesthesia (sevoflurane) is the main contributor to cause perioperative neurocognitive disorders (PND). Recently, it was reported that microglia respond to hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which was the target of sevoflurane. Whether HCN channels are involved in the induction of neuroinflammation after sevoflurane exposure is still unclear. Results Sevoflurane exposure had increased cognitive dysfunction and anxiety-like behaviors in rats. Rats inhaled with sevoflurane had activated microglia and increased neuroinflammation (IL-1β, IL-6, and TNF-α) in the hippocampus. RNA sequencing identified 132 DEGs (86 up-regulated and 46 down-regulated DEGs [differentially expressed genes]) in the hippocampus of PND rats. RNA-sequencing also uncovered that sevoflurane exposure down-regulates HCN2 expression. Pathway and process enrichment analysis suggests DEGs are mainly enriched in regulation of system process, positive regulation of glutamate secretion, secretion, regulation of synaptic transmission, regulation of nervous system process, behavior, negative regulation of sodium ion transport, and learning or memory. We validated that sevoflurane exposure can down-regulate the levels of PEX5R/Trip8b (an interaction partner and auxiliary subunit of HCN channels) and HCN1-4 channels in the hippocampus of PND rats. We used immunofluorescence staining to identify that HCN2 co-labels with neurons (Neun), astrocytes (GFAP), and microglia (iba1). We observed that the co-labeling of HCN2 with neurons or microglia decreased in the hippocampus and cortex after sevoflurane exposure. Blocking HCN2 by ZD7288 treatment further activated microglia and aggravated sevoflurane exposure-induced anxiety-like behavior, cognitive impairment, and neuroinflammation. Conclusions We concluded that sevoflurane exposure can induce an increased level of neuroinflammation, microglial activation, cognitive dysfunction, and anxiety-like behaviors in rats. HCN2 channel, as the target of sevoflurane action, mediates this process. HCN2 might be a target for the treatment and prevention of sevoflurane-induced PND.

Soil erosion, one of the most serious environmental concerns, might remove topsoil and essential element from terrestrial land. However, few attentions have been given to investigating how soil erosion regimes affect soil carbon and nitrogen loss. Therefore, this study investigated the effects of surface coverage rates (83%, 67%, 50%, 33%, 17% and 0%) and two positions (up- and downslope) on erosion regimes and its associated soil nitrogen and carbon loss under a sequence of six rainfalls (R1-R6). These results showed that the sediment concentrations with 33% (R4) and 17% (R5) coverage downslope were significantly lower than those with coverage upslope, whereas there was no significant difference between the runoff rates of the two slopes. Thus, surface coverage at different positions induced two soil erosion regimes (deposition- and transport-dominated processes). Dynamics of the DON and DIN concentrations indicated different release processes of soil nitrogen into runoff. The DON contributed to a substantial amount of soil nitrogen loss, which accounted approximately 81% of the organic form. The SBOC is significantly correlated with sediment-enriched clay particles from the deposition-dominated processes and is higher than that from the transport-dominated processes. The DOC is significantly correlated with Rr for transport-dominated processes. These results illustrated the critical role of erosion regimes in soil organic carbon loss in dissolved or sediment-bound form. It is concluded that erosion/covered zones altered by surface coverage could produce transport- and deposition-dominated erosion regimes and consequently affect soil carbon and nitrogen loss. In addition, these results demonstrated that surface coverage pattern may efficiently control soil erosion and soil carbon and nitrogen loss.

Abstract Background This study aims to estimate the amount of axillary lymph node (ALN) involvement in early-stage breast cancer utilizing a field of view (FOV) optimized and constrained undistorted single-shot (FOCUS) diffusion-weighted imaging (DWI) approach, as well as a whole-lesion histogram analysis. Methods This retrospective analysis involved 81 individuals with invasive breast cancer. The patients were divided into three groups: N0 (negative ALN metastasis), N1–2 (low metastatic burden with 1–2 ALNs), and N≥3 (heavy metastatic burden with ≥ 3 ALNs) based on their sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Histogram parameters of apparent diffusion coefficient (ADC) depending basically on FOCUS DWI were performed using 3D-Slicer software for whole lesions. The typical histogram characteristics for N0, N1–2, and N≥ 3 were compared to identify the significantly different parameters. To determine the diagnostic efficacy of significantly different factors, the area under their receiver operating characteristic (ROC) curves was examined. Results There were significant differences in the energy, maximum, 90 percentile, range, and lesion size among N0, N1–2, and N≥ 3 groups (P

Introduction: Dexmedetomidine (DXM) is widely used as an adjuvant to anesthesia or a sedative medicine, and differences in individual sensitivity to the drug exist. This study aimed to investigate the effect of genetic polymorphisms on these differences.Methods: A total of 112 patients undergoing hand surgery were recruited. DXM 0.5 μg/kg was administered within 10 min and then continuously injected (0.4 μg/kg/h). Narcotrend index, effective dose and onset time of sedation, MAP, and HR were measured. Forty-five single nucleotide polymorphisms (SNPs) were selected for genotype.Results: We observed individual differences in the sedation and hemodynamics induced by DXM. ABCG2 rs2231142, CYP2D6 rs16947, WBP2NL rs5758550, KATP rs141294036, KCNMB1 rs11739136, KCNMA1 rs16934182, ABCC9 rs11046209, ADRA2A rs1800544, and ADRB2 rs1042713 were shown to cause statistically significant (p < 0.05) influence on the individual variation of DXM on sedation and hemodynamics. Moreover, the multiple linear regression analysis indicated sex, BMI, and ADRA2A rs1800544 are statistically related to the effective dose of DXM sedation.Discussion: The evidence suggests that the nine SNPs involved in transport proteins, metabolic enzymes, and target proteins of DXM could explain the individual variability in the sedative and hemodynamic effects of DXM. Therefore, with SNP genotyping, these results could guide personalized medication and promote clinical and surgical management.

Abstract Background Humane treatment requires the provision of appropriate sedation and analgesia during medical diagnosis and treatment. However, limited information is available about the status of procedural analgesic interventions in Chinese hospitals. Therefore, a nationwide survey was established to identify challenges and propose potential improvement strategies. Methods Forty-three members of the Pain Group of Chinese Society of Anesthesiology established and reviewed the questionnaire, which included (1) general information on the hospitals, (2) the sedation/analgesia rate in gastrointestinal endoscopy, labor, flexible bronchoscopy, hysteroscopy in China, (3) staff assignments, (4) drug use for procedural analgesic interventions, and (5) difficulties in procedural analgesic interventions. The data were obtained using an online questionnaire sent to the chief anesthesiologists of Chinese hospitals above Grade II or members of the Pain Group of Chinese Society of Anesthesiology. Results Valid and complete questionnaires were received from 2198 (44.0%) hospitals, of which 64.5% were Grade III. The overall sedation/analgesia rates were as follows: gastroscopy (50.6%), colonoscopy (53.7%), ERCP (65.9%), induced abortion (67.5%), labor (42.3%), hysteroscopy (67.0%) and fiber bronchoscopy (52.6%). Compared with Grade II hospitals, Grade III hospitals had a higher proportion of procedural analgesic interventions services except for induced abortion. On average (median [IQR]), each anesthesiologist performed 5.7 [2.3—11.4] cases per day, with 7.3 [3.2—13.6] performed in Grade III hospitals and 3.4 [1.8—6.8] performed in Grade II hospitals (z = -7.065, p

Abstract Background Self-efficacy, as the vital determinant of behavior, influencing clinicians’ situation awareness, work performance, and medical decision-making, might affect the incidence of anesthesia-related adverse events (ARAEs). This study was employed to evaluate the association between perceived self-efficacy level and ARAEs. Methods A cross-sectional study was performed in the form of an online self-completion questionnaire-based survey. Self-efficacy was evaluated via validated 4-point Likert scales. Internal reliability and validity of both scales were also estimated via Cronbach’s alpha and validity analysis. According to the total self-efficacy score, respondents were divided into two groups: normal level group and high level group. Propensity score matching and multivariable logistic regression were employed to identify the relationship between self-efficacy level and ARAEs. Results The response rate of this study was 34%. Of the 1011 qualified respondents, 38% were women. The mean (SD) age was 35.30 (8.19) years. The Cronbach’s alpha of self-efficacy was 0.92. The KMO (KMO and Bartlett's test) value of the scale was 0.92. ARAEs occurred in 178 (33.0%) of normal level self-efficacy group and 118 (25.0%) of high level self-efficacy group. Before adjustment, high level self-efficacy was associated with a decreased incidence of ARAEs (RR [relative risk], 0.76; 95% CI [confidence interval], 0.62–0.92). After adjustment, high level self-efficacy was also associated with a decreased incidence of ARAEs (aRR [adjusted relative risk], 0.63, 95% CI, 0.51–0.77). In multivariable logistic regression, when other covariates including years of experience, drinking, and the hospital ranking were controlled, self-efficacy level (OR [odds ratio], 0.62; 95% CI, 0.46–0.82; P = 0.001) was significantly correlated with ARAEs. Conclusions Our results found a clinically meaningful and statistically significant correlation between self-efficacy and ARAEs. These findings partly support medical educators and governors in enhancing self-efficacy construction in clinical practice and training.

Studies on the neuroprotective effects of anesthetics were carried out more than half a century ago. Subsequently, many cell and animal experiments attempted to verify the findings. However, in clinical trials, the neuroprotective effects of anesthetics were not observed. These contradictory results suggest a mismatch between basic research and clinical trials. The Stroke Therapy Academic Industry Roundtable X (STAIR) proposed that the emergence of endovascular thrombectomy (EVT) would provide a proper platform to verify the neuroprotective effects of anesthetics because the haemodynamics of patients undergoing EVT is very close to the ischaemia–reperfusion model in basic research. With the widespread use of EVT, it is necessary for us to re-examine the neuroprotective effects of anesthetics to guide the use of anesthetics during EVT because the choice of anesthesia is still based on team experience without definite guidelines. In this paper, we describe the research status of anesthesia in EVT and summarize the neuroprotective mechanisms of some anesthetics. Then, we focus on the contradictory results between clinical trials and basic research and discuss the causes. Finally, we provide an outlook on the neuroprotective effects of anesthetics in the era of endovascular therapy.

Introduction: Preterm brain injury often leads to lifelong disabilities affecting both cognitive and motor functions, and effective therapies are limited. Alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteinases with anti-inflammatory, anti-apoptotic, and cytoprotective properties, might be beneficial in treating preterm brain injury. The aim of this study was to investigate whether AAT has neuroprotective effects in a mouse preterm brain injury model.Methods: Preterm brain injury was induced on postnatal day 5, and mouse pups’ right common carotid arteries were cut between two ligations followed by hypoxia induction. Brain injury was evaluated through immunohistochemistry staining and magnetic resonance imaging. Fluoro-Jade B and immunohistochemistry staining were performed to investigate the neuronal cell death and blood-brain barrier (BBB) permeability. The motor function and anxiety-like behaviors were revealed by CatWalk gait analysis and the open field test.Results: After hypoxia-ischemia (HI) insult, brain injury was alleviated by AAT treatment, and this was accompanied by reduced BBB permeability, reduced neuronal cell death and caspase-3 activation, and inhibition of microglia activation. In addition, AAT administration significantly improved HI-induced motor function deficiencies in mice. The neuroprotective effect of AAT was more pronounced in male mice.Conclusion: AAT treatment is neuroprotective against preterm brain injury in neonatal mice, and the effect is more pronounced in males.

At present, China is in the wave of new infrastructure construction.It had become an industry consensus to accelerate the construction of new information infrastructure resources such as 5G and computing resources, and then it was integrated with advanced technologies such as AI and big data to promote the high-quality development of China’s digital economy.As the main force of the digital economy, the banking industry urgently need to vigorously develop financial technology and explore intelligent transformation.Based on the industry pain points of the banking industry, combined with the urgent needs of customers in the banking industry, five business scenarios were sorted out including AI passenger flow insight and 5G+XR immersive marketing, and the key issues of planning and networking in the banking industry based on the above five business scenarios were summarized.It will help to construct of the industry’s 5G private network and successfully realize the digital and intelligent transformation of China’s banks.

Abstract Background A diagnosis of chronic kidney disease has been strongly associated with cardiovascular disease and mortality in a number of studies, but the association with specific causes of death has not been assessed in detail. We analysed the association between chronic kidney disease and all-cause mortality and 54 causes of death in the National Health Interview Survey, a prospective study of 210,748 US adults. Methods We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality associated with self-reported chronic kidney disease. Men and women aged 18–84 years were recruited between 1997 and 2004 and followed up for mortality through December 31, 2006. Results During an average of 6 years follow-up, 9564 deaths occurred. A history of chronic kidney disease vs. no chronic kidney disease was associated with increased risk of all-cause mortality (HR = 2.69, 95% CI: 2.38–3.04), and mortality from septicemia (5.65, 2.84–11.25), viral hepatitis (10.67, 2.43–46.95), other infectious parasitic diseases (10.58, 3.59–31.21), total cancer (1.48, 1.05–2.09), lung cancer (1.94, 1.10–3.44), kidney cancer (4.74, 1.81–12.41), diabetes mellitus (8.57, 5.60–13.11), circulatory disease overall (3.36, 2.70–4.18) and 11 specific circulatory diseases with the strongest associations observed for primary hypertension/renal disease (13.60, 6.42–28.84), hypertensive heart/renal disease (10.72, 2.47–46.49), and other diseases of circulatory system (7.36, 3.22–16.81). Elevated risk was also observed for alcoholic liver disease (5.63, 1.90–16.66), other chronic liver disease (4.41, 1.74–11.17), kidney failure (13.07, 8.23–20.77), and five other causes of death. Conclusions A history of chronic kidney disease was associated with increased risk of all-cause mortality and 27 out of 54 causes of death. Further studies are needed to clarify associations with less common causes of death.

“Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Here the authors present an adaptable gene circuit to harness the CRISPRa for tumorlocalized immune activation.”

Objective To evaluate the safety and effectiveness of Perioperative Transfusion Trigger Score (POTTS) in guiding surgical patients blood transfusion intraoperatively and postoperatively. Methods A total of 900 patients(perioperative Hb 60~100 g/L) from December 2017 to March 2021 were collected, including 251 males and 649 females, with ASA grading Ⅰ~Ⅳ, and randomly divided into experimental group and controls. In the experimental group, the allogeneic RBC transfusion trigger(Hb threshold) and transfusion units in anemia patients was determined by POTTS. While those in the controls were decided by physicians according to current guidelines concerning transfusion. The proportion and units of allogeneic RBC transfusion, the incidence of postoperative complications, the mortality of hospitalization and discharge for 4 weeks, Hb value, healing of surgical incision, ICU admission rate and ICU length of stay, length of hospitalization, etc were recorded. Results The proportion of allogeneic RBC transfusion in the experimental group(35.3%)were less than the controls(42.2%)(P

In present work, a novel γ′′-strengthened Nb-alloyed medium-entropy alloy (MEA) was successfully fabricated and systematically investigated. Our results evidence that the γ′′ phase brings out significant precipitation hardening effect (∼10.2 %volume fraction contributes ∼ 685 MPa strength enhancement). The metastable γ′′ phase could abnormally transform to ε phase, and the morphology and distribution of ε phase shows great impacts on mechanical properties. A hetero-lamellae grain coupling with dual-precipitation (HLG + dual-P) structure was successfully constructed in this Nb-alloyed MEA, which could effectively combine precipitation hardening and hetero-deformation induced (HDI) hardening effects. Deformation characters investigations reveals that the absence of mechanical twinning in γ′′-strengthened MEA originates from the improved critical twinning stress related to the fine dislocation source size and the difficulty of high-energy complex SFs reordering. The combination of massive stacking-faults, Lomer-Cottrell locks and dynamically reinforced HDI hardening contribute to the excellent ductility and work-hardening capacity at high-level strength in the HLG + dual-P structural alloy. Our work provides a useful insight and helpful guidance for developing high-performance precipitation-hardened multi-principal element alloys.

Abstract Background Association between blood pressure (BP) and kidney function among the middle and old aged general population without hypertension remains unclear. Methods Participants aged ≥ 45 years, with complete data in 2011 and 2015 interviews of the China Health and Retirement Longitudinal Study(CHARLS), and without pre-existing hypertension were included. Systolic BP (SBP) was categorized as low (

Type 2 diabetes mellitus (T2DM) is considered as a metabolic disease with hyperglycemia. Accumulating investigations have explored the important role of hereditary factors for T2DM occurrence. Some functional microRNA (miR) polymorphisms m ay affect their interactions with target mRNAs and result in an aberrant expression. Thus, miR variants might be considered as a biomarker of the susceptibility of T2DM. In this study, we recruited 502 T2DM cases and 782 healthy subjects. We selected miR-146a rs2910164 C>G, miR-196a2 rs11614913 T>C and miR-499 rs3746444 A>G loci and carried out an investigation to identify whether these miR loci could influence T2DM occurrence. In this investigation, a Bonferroni correction was harnessed. After adjustment, we found that rs2910164 SNP was a protective factor for T2DM (GG vs CC/CG: adjusted P = 0.010), especially in never drinking (GG vs CC/CG: adjusted P = 0.001) and BMI ≥24 kg/m2 (GG vs CC/CG: adjusted P = 0.002) subgroups. We also identified that rs11614913 SNP was a protective factor for T2DM in smoking subjects (CC/TC vs TT: adjusted P = 0.002). When we analyzed an interaction of SNP–SNP with the susceptibility tof T2DM, rs11614913/ rs3746444, rs2910164/rs3746444 and rs11614913/rs2910164 combinations were not associated with the risk of T2DM. In summary, this study highlights that rs2910164 SNP decreases the susceptibility of T2DM, especially in BMI ≥24 kg/m2 and never drinking subgroups. In addition, we also identify that rs11614913 C allele decreases the susceptibility of T2DM significantly in smoking subgroup.

Gene therapy is a powerful tool to treat various central nervous system (CNS) diseases ranging from monogenetic diseases to neurodegenerative disorders. Adeno-associated viruses (AAVs) have been widely used as the delivery vehicles for CNS gene therapies due to their safety, CNS tropism, and long-term therapeutic effect. However, several factors, including their ability to cross the blood–brain barrier, the efficiency of transduction, their immunotoxicity, loading capacity, the choice of serotype, and peripheral off-target effects should be carefully considered when designing an optimal AAV delivery strategy for a specific disease. In addition, distinct routes of administration may affect the efficiency and safety of AAV-delivered gene therapies. In this review, we summarize different administration routes of gene therapies delivered by AAVs to the brain in mice and rats. Updated knowledge regarding AAV-delivered gene therapies may facilitate the selection from various administration routes for specific disease models in future research.

ObjectiveEstablishing a risk model of the survival situation of appendix cancer for accurately identifying high-risk patients and developing individualized treatment plans.MethodsA total of 4,691 patients who were diagnosed with primary appendix cancer from 2010 to 2016 were extracted using Surveillance, Epidemiology, and End Results (SEER) * Stat software. The total sample size was divided into 3,283 cases in the modeling set and 1,408 cases in the validation set at a ratio of 7:3. A nomogram model based on independent risk factors that affect the prognosis of appendix cancer was established. Single-factor Cox risk regression, Lasso regression, and multifactor Cox risk regression were used for analyzing the risk factors that affect overall survival (OS) in appendectomy patients. A nomogram model was established based on the independent risk factors that affect appendix cancer prognosis, and the receiver operating characteristic curve (ROC) curve and calibration curve were used for evaluating the model. Survival differences between the high- and low-risk groups were analyzed through Kaplan–Meier survival analysis and the log-rank test. Single-factor Cox risk regression analysis found age, ethnicity, pathological type, pathological stage, surgery, radiotherapy, chemotherapy, number of lymph nodes removed, T stage, N stage, M stage, tumor size, and CEA all to be risk factors for appendiceal OS. At the same time, multifactor Cox risk regression analysis found age, tumor stage, surgery, lymph node removal, T stage, N stage, M stage, and CEA to be independent risk factors for appendiceal OS. A nomogram model was established for the multifactor statistically significant indicators. Further stratified with corresponding probability values based on multifactorial Cox risk regression, Kaplan–Meier survival analysis found the low-risk group of the modeling and validation sets to have a significantly better prognosis than the high-risk group (p < 0.001).ConclusionThe established appendix cancer survival model can be used for the prediction of 1-, 3-, and 5-year OS and for the development of personalized treatment options through the identification of high-risk patients.

Summary: Background: The disability weight (DW) quantifies the severity of health states from disease sequela and is a pivotal parameter for disease burden calculation. We conducted a national and subnational DW measurement in China. Methods: In 2020–2021, we conducted a web-based survey to assess DWs for 206 health states in 31 Chinese provinces targeting health workers via professional networks. We fielded questions of paired comparison (PC) and population health equivalence (PHE). The PC data were analysed by probit regression analysis, and the regression results were anchored by results from the PHE responses on the DW scale between 0 (no loss of health) and 1 (health loss equivalent to death). Findings: We used PC responses from 468,541 respondents to estimate DWs of health states. Eight of 11 domains of health had significantly negative coefficients in the regression of the difference between Chinese and Global Burden of Disease (GBD) DWs, suggesting lower DW values for health states with mention of these domains in their lay description. We noted considerable heterogeneity within domains, however. After applying these Chinese DWs to the 2019 GBD estimates for China, total years lived with disability (YLDs) increased by 14·9% to 177 million despite lower estimates for musculoskeletal disorders, cardiovascular diseases, mental disorders, diabetes and chronic kidney disease. The lower estimates of YLDs for these conditions were more than offset by higher estimates of common, low-severity conditions. Interpretation: The differences between the GBD and Chinese DWs suggest that there might be some contextual factors influencing the valuation of health states. While the reduced estimates for mental disorders, alcohol use disorder, and dementia could hint at a culturally different valuation of these conditions in China, the much greater shifts in YLDs from low-severity conditions more likely reflects methodological difficulty to distinguish between health states that vary a little in absolute DW value but a lot in relative terms. Funding: This work was supported by the National Natural Science Foundation of China [grant number 82173626], the National Key Research and Development Program of China [grant numbers 2018YFC1315302], Wuhan Medical Research Program of Joint Fund of Hubei Health Committee [grant number WJ2019H304], and Ningxia Natural Science Foundation Project [grant number 2020AAC03436].

Purpose: Etomidate is widely used in general anesthesia and sedation, and significant individual differences are observed during anesthesia induction. This study aimed to explore the molecular mechanisms of different etomidate susceptibility at the genetic level.Methods: 128 patients were enrolled in the study. The bispectral index (BIS), mean arterial pressure (MAP) and heart rate (HR) were recorded when the patients entered the operating room for 5 min, before the administration of etomidate, 30 s, 60 s, 90 s, 120 s and 150 s after the administration of etomidate, and the corresponding single nucleotide polymorphisms (SNPs) were analyzed.Results: Significant individual differences were observed in etomidate anesthesia. The results of two-way ANOVA showed that CYP2C9 rs1559, GABRB2 rs2561, GABRA2 rs279858, GABRA2 rs279863 were associated with the BIS value during etomidate anesthesia; UGT1A9 rs11692021 was associated with the Extended Observer’s Assessment of Alertness and Sedation (EOAA/S) score during etomidate anesthesia; GABRB2 rs2561 was associated with MAP. Multiple linear stepwise regression model results showed that CYP2C9 rs1559, GABRA2 rs279858 and GABRB2 rs2561 were associated with the BIS value and UGT1A9 rs11692021 was associated with the EOAA/S score; GABRB2 rs2561 was associated with MAP.Conclusion: GABRA2 rs279858, GABRB2 rs2561, CYP2C9 rs1559 and UGT1A9 rs11692021 are the SNPs with individual differences during etomidate anesthesia. This is the first to study the SNPs of etomidate, which can provide certain evidence for the future use of etomidate anesthesia and theoretical basis for precision anesthesia.

Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) proteins constitute a subfamily of receptor-like kinases (RLKs) that play diverse roles during fertilization, vegetative development and plant pathogen interactions. CrRLK1Ls possess a unique malectin-like domain at N-terminal that bind to oligo- or polysaccharides from cell wall polymers, byproducts of cell wall degradation, or membrane-associated or secreted glycosylated proteins. CrRLK1L members have been identified in many organisms, however, the study of this gene family in resurrection plant species has not been reported to date. Resurrection plants are a kind of extremophiles that can survive extreme drought stress (desiccation) and recover rapidly after rehydration, and display specific and reversible cell wall structure and component changes during dehydration and rehydration. Here, we identified 18 CrRLK1L protein members in the resurrection plant Boea hygrometrica genome and classified them into 9 clades based on the conserved amino acid sequences. Phylogenetic analysis reveals the expansion of FER clade, the absence of MEDOS and CVY clades and the emergence of a new Bh-specific clade in BhCrRLK1L protein family. Analysis of cis-regulatory elements has predicted several types of drought induced elements and/or drought related hormone responsiveness elements in the promoter regions of all BhCrRLK1Ls. In agreement, we found 15 members of BhCrRLK1Ls change their expression pattern in response to drought stress, based on a previous transcriptome survey. Subsequent qRT-PCR validation of selected 7 BhCrRLK1L genes confirmed that BhFER1, BhCrRLK1L14 and BhCrRLK1L15 are induced by desiccation, and BhFER3, BhCrRLK1L17 and BhCrRLK1L18 are repressed by desiccation. Our study systematically identified the CrRLK1L members in B. hygrometrica, and analyzed the gene expression profiles in response to desiccation stresses, which lays a foundation for exploring the function of BhCrRLK1Ls in desiccation signal transduction in B. hygrometrica.

The International Thermonuclear Experiment Reactor (ITER) Thermal shield (TS) serves as a cryogenic heat exchanger to maintain the thermal stability of the ITER superconducting magnet coil, which is critical to the control of the plasma during the operation of the ITER device. The TS is composed of long-length 316L stainless steel (SS) and copper as brazed joints. In this case, a feasible fabrication design for the CCS TS is presented, accomplished by three kinds of joining processes (vacuum brazing, friction stir weld, and TIG weld). In the reliable fabrication design, the brazing quality of the as-brazed long-distance 316L SS and copper joints plays a critical role in the thermal conductivity performance of the ITER thermal shield. Therefore, a high-quality vacuum brazing process of long-length SS/Cu joints applied in a low-temperature superconductor magnet system was first studied. The macro metallography analysis demonstrates the braze ratio of the samples is 100%, and no crack or defect is observed in the samples. The microstructural characterization reveals the brazing seams are composed of silver-based Ag-rich eutectic. The micro-shear test indicates that the shear strength of the 316L tube and copper joint is 205 MPa, with the fracture position located on the copper side; this zone will be the most vulnerable zone of the joints. In addition, the SEM results illustrated that the shear fracture morphology displayed a ductile fracture feature. The test results demonstrated that the highly precise depth drilling employed in this paper ensured a good control of the brazing clearance, resulting in a 100% braze ratio for the long-length SS/Cu joints. Therefore, it can be concluded that the brazing process can be applied in the ITER TS for the good thermal conductivity performance of long-length SS/Cu-brazing joints.

Abstract Higher mortality in asthmatics has been shown previously. However, evidence on different asthma phenotypes on long-term mortality risk is limited. The aim was to evaluate the impact of asthma phenotypes on mortality in general population. Data from the National Health and Nutrition Examination Survey from 2001–2002 to 2013–2014 linked mortality files through December 31, 2015, were used (N = 37,015). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. During the mean follow-up time of 7.5 years, 4326 participants died from a variety of causes. Current asthma, but not former asthma was associated with increased all-cause mortality (current asthma: HR = 1.37; 95% CI 1.20–1.58; Former asthma: HR = 0.93; 95% CI 0.73–1.18); as well as mortality from cardiovascular disease (HRCurrent = 1.41; 95% CI 1.08–1.85) and chronic lower respiratory diseases (HRCurrent = 3.17; 95% CI 1.96–5.14). In addition, we found that the HR for cardiovascular disease (CVD) mortality was slightly greater in people with childhood-onset asthma than those with adult-onset asthma. The HR for chronic lower respiratory diseases (CLRD) mortality was greater in people with adult-onset asthma than those with childhood-onset asthma. However, the differences were not statistically significant. Our study suggested that current asthma but not former asthma was associated with increased all-cause, CLRD and CVD mortality. Future well-designed studies with larger sample are required to demonstrate the association and clarify the potential mechanisms involved.