Search

Abstract Background To compare the POD rates in patients undergoing non-cardiac surgery who received remimazolam perioperatively versus placebo or other sedatives. Methods We systematically searched four major databases (Cochrane Central Register of Controlled Trials, Web of Science, Embase, and PubMed) for relevant randomized controlled trials (RCTs) up to July 11, 2024. Literature quality evaluation was used the bias risk table in Review Manager 5.4. The primary outcome of interest was POD, and secondary outcomes were the hypotension risk, bradycardia and, nausea and vomiting. Results Across 11 trials involving 1985 participants, we recorded 309 cases of POD during follow-up. In trials where the control group received saline, remimazolam decrease the risk of POD significantly by 70% (RR 0.30, 95% CI [0.19, 0.46]; p

Abstract Background Resistance to treatment is a critical factor contributing to poor prognosis in gastric cancer patients. HSP90 has emerged as a promising therapeutic target; however, its role in regulating tumor metabolic pathways, particularly glycolysis, remains poorly understood, which limits its clinical application. Methods We identified proteins that directly interact with HSP90 using immunoprecipitation (IP) followed by mass spectrometry. The relationship between HSP90 and glycolysis was further investigated through transcriptomic analyses and in vitro experiments. Mechanistic insights were obtained through mass spectrometry, co-immunoprecipitation (Co-IP) assays, drug sensitivity tests, and bioinformatics analyses. Additionally, we developed a scoring system based on transcriptomic data to evaluate its prognostic significance and association with treatment resistance in gastric cancer patients. Results Our multi-omics and in vitro studies revealed that HSP90 regulates glycolysis and influences the stemness properties of gastric cancer cells. Mechanistically, HSP90 facilitates the assembly of a glycolytic multi-enzyme complex, termed the HGEO complex, which enhances glycolytic metabolism. Mechanistically, HSP90 facilitates the formation of a multienzyme complex comprising key enzymes including PGK1, PKM2, ENO1, and LDHA, thereby facilitating the production of the final glycolytic products. We refer to this as the "HSP90-Glycolytic Output Complex" (HGEO Complex). We quantified this phenomenon with a scoring system (HGScore), finding that patients with a high HGScore exhibited more malignant signatures, increased resistance to treatment, and poorer prognoses. Furthermore, we demonstrated that the HGEO complex is localized in the nucleus, regulated by the nuclear lamina protein LMNA, which further contributes to treatment resistance and adverse outcomes. In vitro experiments indicated that inhibiting the formation of this complex sensitizes gastric cancer cells to chemotherapy. Conclusion Our findings suggest that HSP90 and LMNA mediated the formation and nuclear localization of the HGEO complex, thereby enhancing the malignant traits and resistance mechanisms in gastric cancer. Targeting this pathway may offer a novel therapeutic strategy to improve treatment outcomes. Graphical Abstract

Abstract Background Complex health interventions (CHIs) are increasingly used in public health, clinical research and education to reduce the burden of disease worldwide. Numerous theories, models and frameworks (TMFs) have been developed to support implementation of CHIs. This systematic review aims to identify and critique theoretical frameworks concerned with three features of implementation; adaptability, scalability and sustainability (ASaS). By dismantling the constituent theories, analysing their component concepts and then exploring factors that influence each theory the review team hopes to offer an enhanced understanding of considerations when implementing CHIs. Methods This review searched PubMed MEDLINE, CINAHL, Web of Science, and Google Scholar for research investigating the TMFs of complex health interventions. Narrative synthesis was employed to examine factors that may influence the adaptability, scalability and sustainability of complex health interventions. Results A total of 9763 studies were retrieved from the five databases (PubMed, MEDLINE, CINAHL, Web of Science, and Google Scholar). Following removal of duplicates and application of the eligibility criteria, 35 papers were eligible for inclusion. Influencing factors can be grouped within outer context (socio-political context; leadership funding, inter-organisational networks), inner context; (client advocacy; organisational characteristics), intervention characteristics (supervision, monitoring and evaluation), and bridging factors (individual adopter or provider characteristics). Conclusion This review confirms that identified TMFS do not typically include the three components of adaptability, scalability, and sustainability. Current approaches focus on high income countries or generic “whole world” approaches with few frameworks specific to low- and middle-income countries. The review offers a starting point for further exploration of adaptability, scalability and sustainability, within a low- and middle-income context. Trial registration Not registered.

Objective We aimed to evaluate the diagnostic utility of 3.0-T magnetic resonance (MR) diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC) values in conjunction with clinical indices for prostate cancer (PCa). Methods A retrospective analysis was conducted on the clinical data of 181 patients with suspected PCa who underwent MR DWI prior to biopsy at LuHe Hospital, Beijing, between February 2022 and July 2023. Patients were placed into Malignancy and Benign groups according to the biopsy results. Univariate and multivariate analyses were performed on the ADC values and clinical indicators, and then a combination predictive model was developed. The model’s diagnostic accuracy was assessed using receiver operating characteristic (ROC) curve and decision curves analysis (DCA), and a nomogram was constructed for the assessment of individual risk. Results The ADC value and the free prostate-specific antigen and total prostate-specific antigen (tPSA) levels were found to be independent predictors of PCa. tPSA showed the best diagnostic performance, with an area under the curve (AUC) of 0.914. However, the combined model had a higher diagnostic accuracy, with an AUC of 0.959. Conclusion The combined model has superior predictive performance to other diagnostic methods and should help with the avoidance of unnecessary prostate biopsies.

With the rapid development of China's socio-economic landscape and shifts in population structure, rural empty nesters have increasingly become a focal point of social concern. Compared to their urban counterparts, rural empty nesters face more life challenges and psychological stress, making their subjective wellbeing a significant issue. This study explores the impact of learning engagement on the subjective wellbeing of rural empty nesters in China, aiming to provide theoretical support and policy recommendations to enhance their wellbeing. Using a random sampling method, the study focused on elderly learners aged 50 and above from counties within Z Province, N City, where elderly learning is relatively concentrated. Data were processed using SPSS 27.0 software. The findings indicate that there is a significant difference in subjective wellbeing between rural empty nesters and rural non-empty nesters, with rural empty nesters exhibiting lower subjective wellbeing and more passive involvement in learning activities. Learning engagement has a significant effect on improving the subjective wellbeing of rural empty nesters, with a notable positive correlation between learning engagement dimensions and subjective wellbeing. Compared to rural non-empty nesters, learning engagement has a more pronounced positive effect on the subjective wellbeing of rural empty nesters.

Abstract Mass spectrometry imaging (MSI)‐based spatially resolved metabolomics addresses the limitations inherent in traditional liquid chromatography‐tandem mass spectrometry (LC–MS)‐based metabolomics, particularly the loss of spatial context within heterogeneous tissues. MSI not only enhances our understanding of disease aetiology but also aids in the identification of biomarkers and the assessment of drug toxicity and therapeutic efficacy by converting invisible metabolites and biological networks into visually rendered image data. In this comprehensive review, we illuminate the key advancements in MSI‐driven spatially resolved metabolomics over the past few years. We first outline recent innovations in preprocessing methodologies and MSI instrumentation that improve the sensitivity and comprehensiveness of metabolite detection. We then delve into the progress made in functional visualization techniques, which enhance the precision of metabolite identification and annotation. Ultimately, we discuss the significant potential applications of spatially resolved metabolomics technology in translational medicine and drug development, offering new perspectives for future research and clinical translation. Highlights MSI‐driven spatial metabolomics preserves metabolite spatial information, enhancing disease analysis and biomarker discovery. Advances in MSI technology improve detection sensitivity and accuracy, expanding bioanalytical applications. Enhanced visualization techniques refine metabolite identification and spatial distribution analysis. Integration of MSI with AI promises to advance precision medicine and accelerate drug development.

Abstract Metal surfaces have long been known to reconstruct, significantly influencing their structural and catalytic properties. Many key mechanistic aspects of these subtle transformations remain poorly understood due to limitations of previous simulation approaches. Using active learning of Bayesian machine-learned force fields trained from ab initio calculations, we enable large-scale molecular dynamics simulations to describe the thermodynamics and time evolution of the low-index mesoscopic surface reconstructions of Au (e.g., the Au(111)-‘Herringbone,’ Au(110)-(1 × 2)-‘Missing-Row,’ and Au(100)-‘Quasi-Hexagonal’ reconstructions). This capability yields direct atomistic understanding of the dynamic emergence of these surface states from their initial facets, providing previously inaccessible information such as nucleation kinetics and a complete mechanistic interpretation of reconstruction under the effects of strain and local deviations from the original stoichiometry. We successfully reproduce previous experimental observations of reconstructions on pristine surfaces and provide quantitative predictions of the emergence of spinodal decomposition and localized reconstruction in response to strain at non-ideal stoichiometries. A unified mechanistic explanation is presented of the kinetic and thermodynamic factors driving surface reconstruction. Furthermore, we study surface reconstructions on Au nanoparticles, where characteristic (111) and (100) reconstructions spontaneously appear on a variety of high-symmetry particle morphologies.

Abstract This work examines challenges associated with the accuracy of machine-learned force fields (MLFFs) for bulk solid and liquid phases of d-block elements. In exhaustive detail, we contrast the performance of force, energy, and stress predictions across the transition metals for two leading MLFF models: a kernel-based atomic cluster expansion method implemented using sparse Gaussian processes (FLARE), and an equivariant message-passing neural network (NequIP). Early transition metals present higher relative errors and are more difficult to learn relative to late platinum- and coinage-group elements, and this trend persists across model architectures. Trends in complexity of interatomic interactions for different metals are revealed via comparison of the performance of representations with different many-body order and angular resolution. Using arguments based on perturbation theory on the occupied and unoccupied d states near the Fermi level, we determine that the large, sharp d density of states both above and below the Fermi level in early transition metals leads to a more complex, harder-to-learn potential energy surface for these metals. Increasing the fictitious electronic temperature (smearing) modifies the angular sensitivity of forces and makes the early transition metal forces easier to learn. This work illustrates challenges in capturing intricate properties of metallic bonding with current leading MLFFs and provides a reference data set for transition metals, aimed at benchmarking the accuracy and improving the development of emerging machine-learned approximations.

Abstract Heat‐shock protein 90 (Hsp90) plays a crucial role in tumorigenesis and tumor progression; however, its mechanism of action in gastric cancer (GC) remains unclear. Here, the role of Hsp90 in GC metabolism is the focus of this research. High expression of Hsp90 in GC tissues can interact with glycolysis, collectively affecting prognosis in clinical samples. Both in vitro and in vivo experiments demonstrate that Hsp90 is able to regulate the migration and stemness properties of GC cells. Metabolic phenotype analyses indicate that Hsp90 influences glycolytic metabolism. Mechanistically, Hsp90 interacts with glycolysis‐related enzymes, forming multienzyme complexes to enhance glycolysis efficiency and yield. Additionally, Hsp90 binds to cytoskeleton‐related proteins, regulating the regional distribution of glycolytic enzymes at the cell margin and lamellar pseudopods. This effect could lead to a local increase in efficient energy supply from glycolysis, further promoting epithelial‐mesenchymal transition (EMT) and metastasis. In summary, Hsp90, through its interaction with metabolic enzymes related to glycolysis, forms multi‐enzyme complexes and regulates regional distribution of glycolysis by dynamic cytoskeletal adjustments, thereby promoting the migration and stemness of GC cells. These conclusions also support the potential for a combined targeted approach involving Hsp90, glycolysis, and the cytoskeleton in clinical therapy.

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

Abstract It is difficult to distinguish other pathologies mimicking Ménière’s disease (MD) clinically. This study aims to investigate the differences of imaging findings and features between MD and other menieriform diseases via intravenous gadolinium-enhanced magnetic resonance imaging (MRI). 426 patients with menieriform symptoms, including MD, vestibular migraine (VM), and vestibular schwannoma (VS), underwent 3D-FLAIR and 3D-T2WI MRI 6 h after the intravenous gadolinium injection. MR images were analyzed for inner ear morphology, perilymphatic enhancement (PE), EH and other abnormalities. EH was observed at a higher rate in MD patients (85.71%) than patients with other menieriform diseases (VM group = 14.75%, VS group = 37.50%). The prevalence of unilateral EH as well as both cochlear and vestibular EH showed significant differences between MD and VM groups. The prevalence of cochlear EH (I and II) and vestibular EH (II and III) was different between MD and VM groups. The prevalence of PE was higher in MD than VM group. The degrees of cochlear and vestibular hydrops were higher in the definite than probable MD group (P

Abstract Background Routine data are increasingly used in randomised controlled trials evaluating healthcare interventions. They can aid participant identification, outcome assessment, and intervention delivery. Randomised implementation trials evaluate the effect of implementation strategies on implementation outcomes. Implementation strategies, such as reminders, are used to increase the uptake of evidence-based interventions into practice, while implementation outcomes, such as adoption, are key measures of the implementation process. The use of routine data in effectiveness trials has been explored; however, there are no reviews on implementation trials. We therefore aimed to describe how routine data have been used in randomised implementation trials and the design characteristics of these trials. Methods We searched MEDLINE (Ovid) and Cochrane Central Register of Controlled Trials from Jan 2000 to Dec 2021 and manually searched protocols from trial registers. We included implementation trials and type II and type III hybrid effectiveness-implementation trials conducted using routine data. We extracted quantitative and qualitative data and narratively synthesised findings. Results From 4206 titles, we included 80 trials, of which 22.5% targeted implementation of evidence-based clinical guidelines. Multicomponent implementation strategies were more commonly evaluated (70.0%) than single strategies. Most trials assessed adoption as the primary outcome (65.0%). The majority of trials extracted data from electronic health records (EHRs) (62.5%), and 91.3% used routine data for outcome ascertainment. Reported reasons for using routine data were increasing efficiency, assessing outcomes, reducing research burden, improving quality of care, identifying study samples, confirming findings, and assessing representativeness. Data quality, the EHR system, research governance, and external factors such as government policy could act either as facilitators or barriers. Conclusions Adherence to guidance on designing and reporting implementation studies, and specifically to harmonise the language used in describing implementation strategies and implementation outcomes, would aid identification of studies and data extraction. Routine healthcare data are widely used for participant identification, outcome assessment and intervention delivery. Researchers should familiarise themselves with the barriers and facilitators to using routine data, and efforts could be made to improve data quality to overcome some of the barriers. Registration PROSPERO CRD42022292321.

The optimal aging temperatures of 400–550 °C for high strength steels falls into the dangerous temperature range of temper-embrittlement. To obtain a good low-temperature toughness, temperatures above 600 °C are usually selected for aging treatments, resulting in a huge loss of strength. In this work, the effects of aging treatments at 500 and 550 °C on the impact performance of a Cu precipitation-strengthened steel at a low temperature of −80 °C were systematically investigated. The solute segregation at lath boundaries is found to be the main factor controlling the low-temperature toughness. Excellent impact performance of ∼180 J at −80 °C along with a high yield strength of ∼1050 MPa and a total elongation of 19% can be obtained by controlling the segregation of solute elements, specifically Mo and Mn at the lath boundaries. The evolutions of matrix and precipitates during aging treatments were investigated. The strengthening and toughening mechanisms are also critically discussed.

Background/Aims Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effects of bile acids on the activation of hepatic stellate cells (HSCs) remain unclear. This study investigated the effects of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms. Methods The immortalized HSCs, LX-2 and JS-1cells were used for the in vitro study. in vitro, the adeno-associated viruses adeno-associated virus-sh-S1PR2 and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSCs. Results S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during taurocholic acid (TCA) stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013 and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCA-mediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK). Conclusions TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation, which might be therapeutically relevant for targeting cholestatic liver fibrosis.

Polycrystalline FeMnAlNi-based alloys generally exhibit poor pseudoelasticity owing to grain constraint. A promising method to improve the pseudoelasticity involves increasing the grain size by directional recrystallisation (DR). To improve the efficiency of obtaining large grain size, the effect of DR parameters—hot zone temperature (HZT) and drawing velocity—on the columnar grain size and the mechanisms of grain growth were investigated. The results showed that samples of FeMnAlNiCo shape memory alloys (SMAs) with an average grain size of over 20 mm and the largest grain size exceeding 50 mm were obtained after DR. The apparent activation energy of the columnar grain growth for DR was ≈135 kJ/mol, which was much lower than that of the equiaxed grain growth for isothermal annealing (≈384 kJ/mol). The lateral growth of the columnar grains was probably because the boundaries between columnar grains tend to form random high-angle grain (HAG) boundaries. By incremental compression test, at an applied strain of 7.0%, nearly oriented single crystal exhibited a recoverable strain of ≈6.0%, while the polycrystal had a recoverable strain of only ≈3.4%. This work provides important guidance and inspires new strategies for microstructural control in FeMnAlNi-based SMAs.

Abstract Objective The relationship between the preoperative red blood cell distribution width and postoperative pneumonia in elderly patients with hip fractures remains unclear. This study investigated whether the preoperative red blood cell distribution width was associated with postoperative pneumonia in elderly patients with hip fractures. Methods Clinical data of patients with hip fractures in the Department of orthopedics of a hospital from January 2012 to December 2021 were retrospectively analyzed. A generalized additive model was used to identify both linear and nonlinear relationships between red blood cell distribution width and postoperative pneumonia. A two-piecewise linear regression model was used to calculate the saturation effect. Subgroup analyses were performed using stratified logistic regression. Results This study included a total of 1444 patients. The incidence of postoperative pneumonia was 6.30% (91/1444), the mean age of the patients was 77.55 ± 8.75 years, and 73.06% of them (1055/1444) were female. After full adjustment for covariates, the preoperative red blood cell distribution width showed a nonlinear relationship with postoperative pneumonia. The two-piecewise regression model showed an inflection point at 14.3%. On the left side of the inflection point, the incidence of postoperative pneumonia increased by 61% for every 1% increase in red blood cell distribution width (OR: 1.61, 95% CI 1.13–2.31, P = 0.0089). The effect size was not statistically significant on the right side of the inflection point (OR: 0.83, 95% CI 0.61–1.12, P = 0.2171). Conclusion The relationship between preoperative red blood cell distribution width and incidence or postoperative pneumonia was nonlinear in elderly patients with hip fractures. The incidence of postoperative pneumonia was positively correlated with red blood cell distribution width when it was

Abstract Multiple missense mutations in p150Glued are linked to Perry syndrome (PS), a rare neurodegenerative disease pathologically characterized by loss of nigral dopaminergic (DAergic) neurons. Here we generated p150Glued conditional knockout (cKO) mice by deleting p150Glued in midbrain DAergic neurons. The young cKO mice displayed impaired motor coordination, dystrophic DAergic dendrites, swollen axon terminals, reduced striatal dopamine transporter (DAT), and dysregulated dopamine transmission. The aged cKO mice showed loss of DAergic neurons and axons, somatic accumulation of α-synuclein, and astrogliosis. Further mechanistic studies revealed that p150Glued deficiency in DAergic neurons led to the reorganization of endoplasmic reticulum (ER) in dystrophic dendrites, upregulation of ER tubule-shaping protein reticulon 3, accumulation of DAT in reorganized ERs, dysfunction of COPII-mediated ER export, activation of unfolded protein response, and exacerbation of ER stress-induced cell death. Our findings demonstrate the importance of p150Glued in controlling the structure and function of ER, which is critical for the survival and function of midbrain DAergic neurons in PS.

The paper presents a method that allows scaling machine learning interatomic potentials to extremely large systems, while at the same time retaining the remarkable accuracy and learning efficiency of deep equivariant models. This is obtained with an E(3)- equivariant neural network architecture that combines the high accuracy of equivariant neural networks with the scalability of local methods.

Abstract Background The effect of preoperative oral carbohydrates (POC) on insulin resistance (IR) of laparoscopic cholecystectomy (LC) remains debatable. Enzyme-hydrolyzed rice flour (EHR) is a kind of water-soluble micromolecular carbohydrates. This study aimed to investigate the impact of preoperative oral EHR solution on gastric emptying and IR in patients undergoing LC. Methods Patients (n = 100) undergoing LC were divided into oral-water group (group C) or oral-EHR solution (group E) randomly (n = 50 each), and the patients drank 300 ml water or EHR solution 2-3 h before surgery respectively. Gastric emptying which was quantized by gastric volume (GV) from antrum ultrasonography, IR indicators, subjective comfort indicators, handgrip strength, postoperative recovery indexes, and complications were recorded. Results There were no differences in GV between the two groups before oral administration (V0), immediately after oral administration (V1) and before anesthesia induction(V2). The GV at V2 (GV2) reduced to the level of V0 (GV0) in the two groups. Fasting glucose (FG), fasting insulin (FINS) and Homa-IR in the two groups increased at postoperative day 1 (Pos 1d) compared with those at preoperative day 1(Pre 1d). Homa-IS and Homa-β in the two groups decreased at Pos 1d compared with those at Pre 1d. FG, FINS and Homa-IR in group E were lower than those in group C at Pos 1d, and Homa-IS and Homa-β were higher in group E than those in group C at Pos 1d. Subjective comfort indictors (hunger, fatigue and anxiety) in group E were lower than those in group C at preoperative 15 min (Pre 15 min) and postoperative 1 h (Pos 1 h). Handgrip strength in group E was raised compared with that in group C at Pre 15 min, Pos 1 h and Pos 1d. There was a lower incidence of nausea and earlier exhaust time in group E. Conclusion Oral 300 ml EHR solution 2-3 h before LC surgery did not increase the occurrence of reflux and aspiration during anesthesia induction with a normal gastric emptying, ameliorated postoperative IR, improved subjective comfort, and promoted postoperative gastrointestinal function recovery. Trial registration Prospectively registered at the China Clinical Trial Registry, registration number: ChiCTR2000039939, date of registration:14/11/2020.

Abstract Backround The supraclavicular plexus block (SCB) and interscalene plexus block (ISB) have the potential to pulmonary function, the duration of the potential remains uncertain. So, we compared the effect of SCB and ISB on pulmonary function, especially the duration time. Methods Ninety-six patients were finally allocated to group I and group S. The ISB and the SCB procedures were performed with ultrasound guidance before anesthesia induction. An investigator recorded the diaphragm mobility and respiratory function test indicators before the block (T0) and at 30 min (T30 min), 4 h (T4), 8 h (T8), and 12 h (T12) after the block. The diaphragmatic paralysis rate was calculated for above timepoint. The VAS, the recovery time for the sensory and motor block, and adverse reactions within 24 h of administering the block were also recorded. Results The recovery times of diaphragm mobility in group I were longer than those in group S. Compared with group I, group S had a significantly lower diaphragmatic paralysis rate during eupnea breathing at T30 min and T8 after the block. Similarly, group S had a significantly lower diaphragmatic paralysis rate at deep breathing at T30 min, T8, and T12 after the block. The recovery times of FEV1 and FVC in group I were longer than those in group S. The other results were not statistically significant. Conclusions Ultrasound-guided ISB resulted in a longer periods with a suppressive effect on pulmonary function than SCB. Trials registration 17/12/2019, ChiCTR1900028286.

The effects of Zr addition on the microstructural evolution and mechanical properties of FeCrAl alloys were investigated. Fine Fe2Zr particles with their sizes ranging from 0.5 to 1.2 μm were observed when the alloying element Zr was introduced in FeCrAl alloy. The addition of Zr led to the formation of Fe2Zr particles either within the grains or on the grain boundaries, and this was found to enhance the strength of the FeCrAl alloys. Moreover, the Fe2Zr particles stabilized the microstructures by promoting recrystallization nucleation and retarding grain growth. The critical size of the Fe2Zr particles for stimulating recrystallization nucleation and the activation energy of grain boundary migration during recrystallization were determined. The effects of Fe2Zr particles on particle-stimulated nucleation behavior and recrystallization grain growth dynamics are discussed.

BackgroundThis study aimed to investigate the differences in long-term oncological outcomes between high-risk human papillomavirus (HR-HPV) negative and HR-HPV positive early-stage cervical cancers.MethodsWe retrospectively analysed 2061 cases of early-stage cervical cancer from the Chinese cervical cancer clinical diagnosis and treatment database. Kaplan-Meier curves were used to describe the survival outcomes of different HR-HPV infections. Cox proportional hazard regression model was used to analyze and determine independent risk factors.ResultsK-M analysis revealed no significant difference in 5-year OS between HR-HPV negative and HR-HPV positive groups (OS: 95.0% vs.95.6%, P=0.900). A significant difference was observed in 5-year DFS between the HR-HPV negative and HR-HPV positive groups (DFS: 87.2% vs.91.9%, P=0.025). Cox proportional hazard regression model indicated that HR-HPV infection (negative vs. positive) was an independent factor influencing 5-year DFS after early cervical cancer surgery (DFS: hazard ratio [HR]=1.862, P=0.022). HR-HPV infection (negative vs positive) was not an independent factor influencing 5-year OS after early cervical cancer surgery (OS: P=0.813). After 1:1 PSM pairing, there was no significant difference in 5-year OS and DFS between HR-HPV negative group and HR-HPV positive group (OS: 91.6% vs.95.0%, P=0.297; DFS: 87.2% vs.85.1%, P=0.758). Cox multivariate analysis indicated that HR-HPV infection was not an independent factor influencing 5-year OS and DFS after early cervical cancer surgery (OS: P=0.806, DFS: P=0.251).ConclusionsThe tumour results of HR-HPV negative group and HR-HPV positive group were similar, after eliminating the differences in known variables that affect the oncological outcomes of cervical cancer. The treatment plan of HR-HPV positive cervical cancer is suitable for HR-HPV negative cervical cancer.

Due to social transformation, economic reform, and the advent of an aging society, the number of disadvantaged older adults in China is increasing. The living conditions of the disadvantaged older adult groups determine society’s stability to a certain extent. How to make their lives happier in their old age, promote their subjective well-being, and realize the “enjoyment of the older adults” is of great practical significance in improving social civilization and building a harmonious society.This study uses questionnaires to obtain survey data from the lower counties of Ningbo City, Zhejiang Province, where there is a high concentration of older learners, and used SPSS 27.0 software to process the data. The results indicated the following: the subjective well-being of disadvantaged and non-disadvantaged older adults differed significantly; learning engagement had a significant effect on enhancing the subjective well-being of disadvantaged older adults, and all dimensions of learning engagement had a significant positive relationship with subjective well-being (SWB). Compared to non-disadvantaged older adults, learning engagement had a more significant contribution to the SWB of disadvantaged older adults.

2- arachidonoylglycerol (2-AG), an abundant endocannabinoid in the brain, regulates diverse neural functions. Here, the authors identified four loss-of-function mutations in dicylglycerol lipase β (DAGLB) from six patients with early onset Parkinsonism. In mice, loss of DAGLB in dopamine neurons reduced neuronal activity and impaired locomotor function and augmentation of 2-AG levels boosted neuronal activity and rescued locomotor deficits.

An E(3)-equivariant deep learning interatomic potential is introduced for accelerating molecular dynamics simulations. The method obtains state-of-the-art accuracy, can faithfully describe dynamics of complex systems with remarkable sample efficiency.

Abstract Osteopontin (OPN) is a multifunctional cytokine that can impact cancer progression. Therefore, it is crucial to determine the key factors involved in the biological role of OPN for the development of treatment. Here, we investigated that OPN promoted hepatocellular carcinoma (HCC) cell proliferation and migration by increasing Reactive oxygen species (ROS) production and disclosed the underlying mechanism. Knockdown of OPN suppressed ROS production in vitro and in vivo, whereas treatment with human recombinant OPN produced the opposite effect. N-Acetyl-L-cysteine (NAC, ROS scavenger) partially blocked HCC cell proliferation and migration induced by OPN. Mechanistically, OPN induced ROS production in HCC cells by upregulating the expression of NADPH oxidase 1 (NOX1). NOX1 knockdown in HCC cells partially abrogated the cell proliferation and migration induced by OPN. Moreover, inhibition of JAK2/STAT3 phosphorylation effectively decreased the transcription of NOX1, upregulated by OPN. In addition, NOX1 overexpression increased JAK2 and STAT3 phosphorylation by increasing ROS production, creating a positive feedback loop for stimulating JAK2/STAT3 signaling induced by OPN. This study for the first time demonstrated that HCC cells utilized OPN to generate ROS for tumor progression, and disruption of OPN/NOX1 axis might be a promising therapeutic strategy for HCC.

Abstract Background Radial artery cannulation is a crucial investigative procedure for measuring patients’ blood pressure invasively and serial blood gases. However, radial artery cannulation can be challenging for medical residents, and it is necessary to establish a facile and straightforward teaching strategy. This study aimed to evaluate the efficiency of acoustic shadowing-facilitated ultrasound guidance on radial artery cannulation teaching for medical residents. Methods A total of 116 medical postgraduates who underwent standardized residency training programs in the Department of Anesthesiology were randomly divided into a new ultrasound-guided teaching group and a traditional ultrasound-guided teaching group. In the new ultrasound-guided teaching group, radial artery puncture technique was taught by acoustic shadowing-facilitated ultrasound guidance. The training included both theoretical and practical components. After the training, the success rate of the first puncture attempt, the success rate of the catheterization, the ultrasonic positioning time, and the catheterization time of the two groups were compared in a unified manner. A questionnaire on the subjective evaluation of the various aspects of the program by participants was conducted at the end of the training period. Results The study included 101 medical residents. The success rate for radial artery puncture at the first attempt in the new ultrasound-guided teaching group was 78.43%. It was significantly higher than that of the traditional ultrasound-guided group (58.00%, odds ratio = 0.380; 95% CI = 0.159 to 0.908; p = 0.027). The success rate for the first arterial catheterization in the new ultrasound-guided teaching group was significantly higher than that of the traditional ultrasound-guided group (74.51% vs. 52.00%, odds ratio = 0.371; 95% CI = 0.160 to 0.858; p = 0.019). The ultrasonic positioning time and catheterization time in minutes in the new ultrasound-guided teaching group were significantly shorter than that of the traditional ultrasound-guided group (14.36 ± 3.31 vs. 18.02 ± 4.95, p

Virtual reality (VR) technology offers a great opportunity to explore stress disorder therapies. We created a VR stress training system, which incorporates three highly interactive stressful scenes to elicit stress, and demonstrate the concurrent variations between physiological data (heart rate, electrodermal activity and eye-blink rate) and self-reported stress ratings through a self-designed customized perceived stress questionnaire (SSAI) and wearable devices. Several supervised learning models were rigorously applied to automate stress recognition. Our findings include the evaluations of the VR system by computing Cronbach’s alpha ( $\alpha =0.72$ ) and Kaiser-Meyer-Olkin (KMO) coefficient ( $\eta =0.78$ ) through a retrospective survey, which were subsequently confirmed as reliable on four aspects (sense of presence, sense of space, sense of immersion and sense of reality) via factor analysis. Additionally, we demonstrate the effectiveness of physiology-based stress level classification (no stress, low stress and high stress) and continuous SSAI score prediction, with accuracy reaching 0.742 by bagging ensemble learning model and goodness-of-fit reaching 0.44 via multivariate stepwise regression. This study provides detailed insight regarding the effect of objective physiological measures on the validation of subjective self-ratings under a novel complex VR stress training system, which stimulates the further investigations of stress disorder recognition and treatment.

Aims: Long non-coding RNAs (lncRNAs) contribute to the regulation of vital physiological processes and play a role in the pathogenesis of many diseases. Monocrotaline (MCT) can cause large-scale outbreaks of toxic liver disease in humans and animals in the form of hepatic sinusoidal obstruction syndrome (HSOS). Although many experiments have been carried out to explain the pathogenesis of Monocrotaline-induced hepatic sinusoidal obstruction syndrome and to develop treatments for it, no studies have examined the role of Long non-coding RNAs in this condition. This study aimed to investigate the Long non-coding RNAs–mRNA regulation network in Monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats.Main methods: We established a model for MCT-induced hepatic sinusoidal obstruction syndrome, and then carried out microarray for liver tissues of SD rats in a model of early hepatic sinusoidal obstruction syndrome (12 h Monocrotaline treatment vs. control group) to investigate the differentially expressed Long non-coding RNAs and mRNAs in early hepatotoxicity. This was followed by RT-PCR analysis of selected Long non-coding RNAs, which were markedly altered. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analyses were also conducted.Key findings: 176 Long non-coding RNAs (63 downregulated and 113 upregulated) and 4,221 mRNAs (2,385 downregulated and 1836 upregulated) were differentially expressed in the Monocrotaline-treated group compared to the control group. The biological processes identified in GO enrichment analysis as playing a role in hepatotoxicity were positive regulation of guanosine triphosphate phosphohydrolase, liver development, and the oxidation-reduction process. Pathway analysis revealed that the metabolism pathways, gap junction, and ribosome biogenesis in eukaryotes were closely related to Monocrotaline-induced hepatotoxicity. According to these analyses, LOC102552718 might play an essential role in hepatotoxicity mechanisms by regulating the expression of inositol 1,4,5-trisphosphate receptor-1 (Itpr-1).Significance: This study provides a basis for further research on the molecular mechanisms underlying Monocrotaline-induced hepatotoxicity and its treatment, especially in the early stage, when successful treatment is critical before irreversible liver damage occurs.

Background Icaritin (ICT) has been previously demonstrated to display protective effects against cerebral ischemic reperfusion (I/R) by inhibiting oxidative stress, but the mechanism remains unclear. This study aimed to explore the mechanism from the perspective of metabolomics. Methods A mice cerebral artery occlusion/reperfusion (MCAO/R) model was explored to mimic cerebral ischemic reperfusion and protective effect of ICT was assessed by neurologic deficit scoring, infarct volume and brain water content. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-QE-Orbitrap-MS) based metabolomic was performed to explore potential biomarkers. Brain tissue metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. The protein levels of Nrf2, HO-1 and HQO1 were assayed by western blot. The release of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were detected using corresponding assay kits. Results The results showed that after ICT treatment, the neurological deficit, cerebral infarction area, brain edema and the level of MDA in brain tissue of MCAO/R mice were significantly reduced. Meanwhile, ICT enhanced the activity of SOD, CAT and GSH-Px. Western blot results confirmed that ICT up-regulated the protein levels of antioxidant-related protein including Nrf2, HO-1 and NQO1. According to the metabolomic profiling of brain tissues, clear separations were observed among the Sham, Model and ICT groups. A total of 44 biomarkers were identified, and the identified biomarkers were mainly related to linoleic acid metabolism, arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism and purine metabolism, respectively. At the same time, the inhibitory effect of ICT on arachidonic acid and linoleic acid in brain tissue, as well as the promoting effect on taurine, GABA, NAAG, may be the key factors for the anti-neurooxidative function of mice after MCAO/R injury. Conclusion Our results demonstrate that ICT has benefits for MCAO/R injury, which are partially related to the suppression of oxidative stress via stimulating the Nrf2 signaling and regulating the production of arachidonic acid, linoleic acid, taurine, GABA, NAAG in brain tissue.

Abstract Urine is a promising resource for biomarker research. Therefore, the purpose of this study was to investigate potential urinary biomarkers to monitor the disease activity of ventilator-induced lung injury (VILI). In the discovery phase, a label-free data-dependent acquisition (DDA) quantitative proteomics method was used to profile the urinary proteomes of VILI rats. For further validation, the differential proteins were verified by parallel reaction monitoring (PRM)-targeted quantitative proteomics. In total, 727 high-confidence proteins were identified with at least 1 unique peptide (FDR ≤ 1%). Compared to the control group, 110 proteins (65 upregulated, 45 downregulated) were significantly changed in the VILI group (1.5-fold change, P

The trend of the feminization of the aging population in China is accelerating, and the differences in the subjective well-being of older adults are becoming more and more obvious. This study combines gender theory with gender differences as an entry point, based on 436 survey data, and examines effects and differences between learning engagement on the subjective well-being of older Chinese learners by gender. The study found the following: learning can enhance the subjective well-being of older people; there were significant differences in the subjective well-being of older adult learners by gender in two dimensions, namely, physical and mental health experience and adaptation satisfaction experience; and the positive effect of learning engagement on subjective well-being of female older adults was more pronounced and thus had a stronger effect on their subjective well-being. In addition, the gender equality of older adults’ learning participation and gender differences in learning needs are further explored based on the gender theory perspective, and this gives suggestions for enhancing older adult learners’ subjective well-being.

Atractylodes macrocephala Koidz. is one of the most frequently used traditional Chinese medicines for the treatment of ulcerative colitis (UC). The beneficial effect of polysaccharide from Atractylodes macrocephala Koidz. (PAMK) on UC has been reported, while the underlying mechanism and target remain unclear. In this study, we systematically investigated the therapeutic effect and the underlying mechanism of PAMK in UC based on a mouse model of dextran sodium sulfate (DSS)-induced colitis. PAMK treatment (100 mg/kg, 200 mg/kg and 400 mg/kg) significantly ameliorated DSS-induced colitis, manifested as a reduction in weight loss, disease activity index (DAI), colon shortening, spleen index and histological score. Moreover, PAMK treatment inhibited inflammation and improved the integrity of the intestinal barrier in colitis mice. Mechanistically, microarray analysis determined the critical role of the immunoregulatory effect of PAMK in alleviating UC. Flow cytometry analysis further demonstrated that PAMK treatment regulated the balance between T helper (Th) 17 and regulatory T (Treg) cells in the mesenteric lymph nodes (MLN) and spleen in mice with colitis. In addition, PAMK treatment downregulated the expression of IL-6 and suppressed the phosphorylation of STAT3. Together, these data revealed that PAMK treatment alleviated DSS-induced colitis by regulating the Th17/Treg cell balance, which may be dependent on the inhibition of the IL-6/STAT3 signaling pathway. Our study is the first to elucidate that the underlying mechanism by which PAMK treatment alleviates DSS-induced colitis is associated with an improved the Th17/Treg cell balance. Collectively, the study provides evidence for the potential of PAMK to treat UC.

This study aims to provide a brief overview of the history and development of global health education (GHE) as academic degree programs worldwide, and to identify GHE's development opportunities and obstacles in China. This is a state-of-the-art review of published and unpublished information that described and evaluated disciplinary development of global health degree programs worldwide, written in English, and published or shared between 1990 and 2020. Data were derived from official websites of leading global health institutions, like “Google Scholar”, “PubMed”, and unpublished information such as presentation files and unpublished manuscripts collected from knowledgeable leaders in the field. We retrieved and reviewed a total of 35 articles and a large amount of unpublished information or sources on the internet. Global Health emerged as a new discipline around the end of the last millennium and proliferated in the last two decades in developed nations, especially the United States and the United Kingdom. The development of China's GHE programs was built on China's increasing engagement in global health affairs and research. In 2012, Wuhan University established the first official global health department in China. Several universities such as Peking University and Duke Kunshan University subsequently set up departments or programs to offer undergraduate and postgraduate majors and degrees. The first school-level global health unit was established in Shanghai in 2019. The Consortium of Chinese Universities for Global Health (CCUGH) grew from 10 founding members in 2013 to 25 in 2020. Major desirable attributes “unique” to students majoring in global health include global-mindedness, health interests, compassion, intercultural sensitivity, and adventurous spirit. Graduates from GHE programs have a diverse set of career choices spanning research, government, not-for-profit, and private sector occupations. We identified a number of strengths, weaknesses, opportunities, and threats to the future development of GHE in China. To ensure sustainable future growth, we advocate addressing the following key aspects: (1) clearer disciplinary distinctions; (2) multidisciplinary collaborations; (3) public-sector investments; and (4) non-public sectors participation. Amidst China's increasing engagement in health affairs globally and the proliferation of GHE programs in developed nations, China has experienced fast growth in GHE degree programs since 2012 while a number of challenges remain for its future development.

This study aimed to investigate the impact of entrepreneurial educational support (NEES), entrepreneurial activities support (NEAS), and entrepreneurial commercialization support (NECS) on the nascent entrepreneurial intention (NEI) by mediating roles of entrepreneurial self-efficacy (NESE), opportunity recognition (OR), and the moderating effect of meaning in life (MLI). Data were gathered using a survey questionnaire from the 868 management, engineering, technical, and vocational institute students of China. The NEI model was analyzed using the partial least squares structural equation modeling through Smart-PLS software. The findings of the study reveal that NEES, NEAS, and NECS have a positive effect on NEI. Meanwhile, results indicate that NESE and OR partially mediate the relationship between entrepreneurship support programs and nascent entrepreneurial intention. Furthermore, the relationship between NESE and the NEI was insignificantly influenced by MLI, and the relationship between OR and the NEI was significantly moderated by MLI. Lastly, implications and limitations are also discussed in this article.

Cu alloys can be plastically deformed to reach ultra-high strength, but often at an expense of their electrical conductivity. Here we report that the introduction of hierarchical precipitations and the resultant microstructural heterogeneities at different scales could overcome the strength-conductivity tradeoff in Cu-Ag-Zr alloy. The intrinsic particle size dependent precipitation behavior, owing to the different cooling rate during powder atomization, has been inherited after hot isostatic pressing (HIP) of powders into bulk sample. The following cold rolling and aging created multi-scale structures with the sub-micron particles at grain boundaries and sub-micron-to-nano scale precipitates in the grain interior. Those introduced heterogeneous precipitate configurations also altered the evolution of deformation structures during cold rolling and aging, with partially recrystallized grains embedded in highly deformed matrix featured by high density of dislocation and substructures, which results in an excellent combination of tensile strength (704 MPa), electrical conductivity (88.7% IACS), and tensile elongation (14.9%). Besides, no significant coarsening in the micro-nano structures is observed after annealing at 450 °C for 1 h. The findings in this work proposed a novel approach for designing high-strength, high-conductivity, and high-thermal stability copper alloys based on hierarchical precipitation-stimulated structures at nano-to-micron scale.

Abstract We present a way to dramatically accelerate Gaussian process models for interatomic force fields based on many-body kernels by mapping both forces and uncertainties onto functions of low-dimensional features. This allows for automated active learning of models combining near-quantum accuracy, built-in uncertainty, and constant cost of evaluation that is comparable to classical analytical models, capable of simulating millions of atoms. Using this approach, we perform large-scale molecular dynamics simulations of the stability of the stanene monolayer. We discover an unusual phase transformation mechanism of 2D stanene, where ripples lead to nucleation of bilayer defects, densification into a disordered multilayer structure, followed by formation of bulk liquid at high temperature or nucleation and growth of the 3D bcc crystal at low temperature. The presented method opens possibilities for rapid development of fast accurate uncertainty-aware models for simulating long-time large-scale dynamics of complex materials.

Abstract Background Transforming growth factor‐β‐activated kinase 1 (TAK1) plays a key role in regulating fibroblast and myoblast proliferation and differentiation. However, the TAK1 changes associated with Duchenne muscular dystrophy (DMD) are poorly understood, and it remains unclear how TAK1 regulation could be exploited to aid the treatment of this disease. Methods Muscle biopsies were obtained from control donors or DMD patients for diagnosis (n = 6 per group, male, 2–3 years, respectively). Protein expression of phosphorylated TAK1 was measured by western blot and immunofluorescence analysis. In vivo overexpression of TAK1 was performed in skeletal muscle to assess whether TAK1 is sufficient to induce or aggravate atrophy and fibrosis. To explore whether TAK1 inhibition protects against muscle damage, mdx (loss of dystrophin) mice were treated with adeno‐associated virus (AAV)‐short hairpin TAK1 (shTAK1) or NG25 (a TAK1 inhibitor). Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Results We found that TAK1 was activated in the dystrophic muscles of DMD patients (n = 6, +72.2%, P

Abstract Objective To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. Methods This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. Results Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2–6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4–46.4%), and the DCR was 65.2% (95% CI, 56.4–74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. Conclusions For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Background Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the loss of dystrophin, which results in inflammation, fibrosis, and the inhibition of myoblast differentiation in skeletal muscle. Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle. Methods mdx (loss of dystrophin) mice (n = 18 per group) were treated with catalpol (200 mg/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand–target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor‐β–activated kinase 1 (TAK1) in skeletal muscle. Results Six weeks of catalpol treatment improved whole‐body muscle health in mdx mice, which was characterized by reduced plasma creatine kinase (n = 18, −35.1%, P

Previously, we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, the mechanisms for TP/LPS-induced hepatotoxicity remained elusive. The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation. TNF-α inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF-α by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-α to assess the function of TNF-α in TP/LPS co-treatment. Additionally, time-dependent NF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro. Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF-κB-mediated pro-survival protein, was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity. Etanercept counteracted the toxic reactions induced by TP/LPS. TP-treatment sensitized mice and hepatocytes to TNF-α, revealing the role of TNF-α in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF-κB dependent pro-survival signals, especially FLIP, induced by LPS/TNF-α. Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-α-induced apoptosis in vitro. Mice and hepatocytes treated with TP were sensitive to TNF-α, which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.

PurposeTo accurately provide evaluations on how match performance for elite skaters in short track speed skating developed, and whether geographical factors of ice rink locations should be considered apart from technical abilities. We created a dataset containing competition records from the 2013–14 to 2020–21 seasons (500 m event) on the official website.MethodsOne-way ANOVA was applied to statistically analyze whether the best performance times exhibited significant differences in varied hosting cities. Performance–time matrix and multivariate regression model were further established to quantitatively explain how geographical factors (longitude, latitude, altitude, and barometric pressure) affected performance.ResultsOur findings firstly confirmed that the fastest 500 m finishing times varied due to the hosting cities (P = 0.008) and showed that venue locations could boost or impair performance time with the maximum range of 3.6 s. Meanwhile, latitude (slightly over 46° when performance is maximized) was the most influential factor to account for the performance–time difference in different ice rink locations according to the multivariate regression model, though altitude (1,225 meters when performance is maximized) was also important.ConclusionsIn this perspective, elite skaters should check the geographical factors of the venues before they participated in the upcoming competitions, assess the real strength of their rivals, and adopt flexible tactics during training sessions.

Although β-xylosidases with xylanase activity are preferential for the hydrolysis of xylan and production of xylitol, reports on their use are scarce. In this study, a multifunctional β-xylosidase (XYL4) was identified. In addition to β-xylosidase activity, XYL4 also exhibited xylanase and low α-arabinosidase activity. The enzyme was able to hydrolyze bagasse xylan, oat spelt xylan, birchwood xylan, beechwood xylan, and corncob xylan, and showed the highest hydrolysis activity for corncob xylan. Structural modeling analysis indicated that XYL4 had an additional PA14 domain, which may play a key role in binding xylan substrates. Moreover, XYL4 was used to hydrolyze corncob xylan to produce xylose. When enzymatic hydrolysis and whole-cell catalysis were used to hydrolyze 100 g/L of corncob xylan, the xylose yields were 60.26% and 35.85%, respectively. Then, the Candida tropicalis was inoculated with the above hydrolysates for fermentation to produce xylitol. Using enzymatic hydrolysis and whole-cell catalysis, xylitol yields of 77.56% and 73.67% were obtained by C. tropicalis after the optimization of fermentation, respectively.

Ataxia telangiectasia mutated (ATM) plays an essential role in DNA damage response and the maintenance of genomic stability. However, the role of ATM in regulating the function of adult neural stem cells (NSCs) remains unclear. Here we report that ATM deficiency led to accumulated DNA damage and decreased DNA damage repair capacity in neural progenitor cells. Moreover, we observed ATM ablation lead to the short-term increase of proliferation of neural progenitor cells, resulting in the depletion of the NSC pool over time, and this loss of NSC quiescence resulted in accelerated cell senescence. We further apply RNA sequencing to unravel that ATM knockout significantly affected Notch signaling pathway, furthermore, notch activation inhibit the abnormal increased proliferation of ATM–/– NSCs. Taken together, these findings indicate that ATM can serve as a key regulator for the normal function of adult NSCs by maintaining their stemness and preventing cellular senescence primarily through Notch signaling pathway.

Purpose: Short track speed skating is a racing sport with racing tactics are equally crucial to speed and technical skating skills. Therefore, to investigate the relationship between starting and finishing positions for elite skaters and subsequently, explore pacing patterns for champions are necessary.Methods: To investigate a pattern of effective tactical positioning strategy, Kendall’s tau-b correlations between starting and finishing position were calculated, with 500 m races having the most positive correlation (0.347, P < 0.05).Results: Furthermore, starting position distributions of winners in each round, as well as the fluctuations in champion starting positions across rounds were analyzed. Our findings showed that skaters on the first track were inclined to win the rounds in 500, 1,000, and 1,500 m (28, 28, and 22%, respectively), and the differences between starting and finishing positions for champions were minimized in semi-finals. Meanwhile, the pacing patterns were gaining more fluctuations by the increase of race distances for champions, as the average standard deviation of lap rankings equaled 0.90, 1.15, and 2.21 for 500, 1,000, and 1,500 m races, respectively.Conclusion: In conclusion, elite skaters should adopt flexible tactics at the lowest cost of energy consumption. The overall variability of lap ranking in long-distance races were distinctly higher than it in short distance.

Background: There is a lack of evidence concerning the effective implementation of strategies for stroke prevention and management, particularly in resource-limited settings. A primary-care-based integrated mobile health intervention (SINEMA intervention) has been implemented and evaluated via a 1-year-long cluster-randomized controlled trial. This study reports the findings from the trial implementation and process evaluation that investigate the implementation of the intervention and inform factors that may influence the wider implementation of the intervention in the future.Methods: We developed an evaluation framework by employing both the RE-AIM framework and the MRC process evaluation framework to describe the implementation indicators, related enablers and barriers, and illustrate some potential impact pathways that may influence the effectiveness of the intervention in the trial. Quantitative data were collected from surveys and extracted from digital health monitoring systems. In addition, we conducted quarterly in-depth interviews with stakeholders in order to understand barriers and enablers of program implementation and effectiveness. Quantitative data analysis and thematic qualitative data analysis were applied, and the findings were synthesized based on the evaluation framework.Results: The SINEMA intervention was successfully implemented in 25 rural villages, reached 637 patients with stroke in rural Northern China during the 12 months of the trial. Almost 90% of the participants received all follow-up visits per protocol, and about half of the participants received daily voice messages. The majority of the intervention components were adopted by village doctors with some adaptation made. The interaction between human-delivered and technology-enabled components reinforced the program implementation and effectiveness. However, characteristics of the participants, doctor-patient relationships, and the healthcare system context attributed to the variation of program implementation and effectiveness.Conclusion: A comprehensive evaluation of program implementation demonstrates that the SINEMA program was well implemented in rural China. Findings from this research provide additional information for program adaptation, which shed light on the future program scale-up. The study also demonstrates the feasibility of combining RE-AIM and MRC process evaluation frameworks in process and implementation evaluation in trials.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03185858.

Oxygen vacancies can impart interesting properties in complex oxides, but specific architectures designed to create high-density oxygen vacancies are largely unknown. Here the authors report a fluorite-bixbyite nanobrush platform to tune interfacial oxygen and show that an atomically well-defined heterointerface can induce charge modulation.

Abstract Background Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson’s disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. Methods We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2 −/−) and control (Lrrk2 +/+) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2 +/+ and Lrrk2 −/− mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2 +/+ and Lrrk2 −/− mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. Results Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2 −/− striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2 −/− and R1441C SPNs. Conclusions Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.

The shapes of particles and their distribution in tablets, controlled by pretreatment and tableting process, determine the pharmaceutical performance of excipient like lubricant. This study aims to provide deeper insights to the relationship of the morphology and spatial distribution of stearic acid (SA) with the lubrication efficiency, as well as the resulting tablet property. Unmodified SA particles as flat sheet-like particles were firstly reprocessed by emulsification in hot water to obtain the reprocessed SA particles with spherical morphology. The three-dimensional (3D) information of SA particles in tablets was detected by a quantitative and non-invasive 3D structure elucidation technique, namely, synchrotron radiation X-ray micro-computed tomography (SR-µCT). SA particles in glipizide tablets prepared by using unmodified SA (GUT), reprocessed SA (GRT), as well as reference listed drug (RLD) of glipizide tablets were analyzed by SR-µCT. The results showed that the reprocessed SA with better flowability contributed to similarity of breaking forces between that of GRT and RLD. SA particles in GRT were very similar to those in RLD with uniform morphology and particle size, while SA particles in GUT were not evenly distributed. These findings not only demonstrated the feasibility of SR-µCT as a new method in revealing the morphology and spatial distribution of excipient in drug delivery system, but also deepened insights of solid dosage form design into a new scale by powder engineering. Keywords: Stearic acid, Morphology, Spatial distribution, SR-µCT, Glipizide tablets

Abstract Background Whether thoracic paravertebral block (PVB) is useful in patients undergoing off-pump coronary artery bypass grafting (OPCABG) remains unknown. This study aimed to investigate the feasibility of bilateral PVB combined with general anesthesia (GA) in patients undergoing OPCABG. Methods This feasibility study assessed 60 patients scheduled for OPCABG at the Qingdao Municipal Hospital in 2016–2017. Patients were randomly assigned to receive nerve stimulator-guided bilateral PVB combined with GA (PVB + GA) or GA alone (n = 30/group). Patients were asked to rate rest and cough pain hourly after the surgery. The primary endpoint was the visual analogue scale (VAS) pain score within 48 h postoperatively. Secondary endpoints were rescue analgesia and morphine consumption, fentanyl dose within 48 h postoperatively, as well as operative time, time to extubation, intensive care unit (ICU) stay, hospital stay and other postoperative adverse events. Results Both rest and cough pains were lower in the PVB + GA group at 12, 24, 36, and 48 h after surgery compared with the GA group. There were fewer patients who needed rescue analgesia in the PVB + GA group at 12 and 24 h than in the GA group. Morphine consumptions at 24 and 48 h were lower in the PVB + GA group compared with the GA group. Time to extubation (P = 0.035) and ICU stay (P = 0.028) were shorter in the PVB + GA group compared with the GA group. AEs showed no differences between the two groups. Conclusions Nerve stimulator-guided bilateral thoracic PVB combined with GA in OPCABG is associated with a reduced rescue analgesia and morphine consumption, compared to GA.