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Abstract Background Triple‐negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%–15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood. Methods We analyzed single‐cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry. Results Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2–integrin–aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth. Conclusion Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.

Abstract This paper aims to propose a method for the design of the substation grounding grid in China Fusion Engineering Test Reactor (CFETR). In order to evaluate the safety of the grounding grid, Electrical Transient Analysis Program (ETAP) was used to simulate the fault current, contact voltage, and step voltage, and the results are compared with theoretical calculations to verify the correctness of the design. This will help reduce faults caused by the defects of grounding grid This method is special in that the designed grounding grid not only meets the requirements of relevant standards, but also reduces the number of conductors. During the design process, factors such as voltage level, fault location, and soil resistivity were fully considered to adapt to different occasions. This method can also guide the design and renovation of grounding grids for other buildings in CFETR.

Abstract PoissonERM is an R package used to conduct exposure–response (ER) analysis on binary outcomes for establishing the relationship between exposure and the occurrence of adverse events (AE). While Poisson regression could be implemented with glm(), PoissonERM provides a simple way to semi‐automate the entire analysis and generate an abbreviated report as an R markdown (Rmd) file that includes the essential analysis details with brief conclusions. PoissonERM processes the provided data set using the information from the user's control script and generates summary tables/figures for the exposure metrics, covariates, and event counts of each endpoint (each type of AE). After checking the incidence rate of each AE, the correlation, and missing values in each covariate, an exposure–response model is developed for each endpoint based on the provided specifications. PoissonERM has the flexibility to incorporate and compare multiple scale transformations in its modeling. The best exposure metric is selected based on a univariate model's p‐value or deviance ( Δ D ) as specified. If a covariate search is specified in the control script, the final model is developed using backward elimination. PoissonERM identifies and avoids highly correlated covariates in the final model development of each endpoint. Predicting event incidence rates using external (simulated) exposure metric data is an additional functionality in PoissonERM, which is useful to understand the event occurrence associated with certain dose regimens. The summary outputs of the cleaned data, model developments, and predictions are saved in the working folder and can be compiled into a HTML report using Rmd.

Graded reading is one of the important ways of English learning. How to automatically judge and grade the difficulty of the English reading corpus is of great significance for precision teaching and personalized learning. However, the current rule-based readability assessment methods have some limitations, such as low efficiency and poor accuracy. In particular, these traditional methods usually lack semantics, which is crucial for students to understand the reading material. Meanwhile, they are difficult to be mapped to the difficulty level, which is not conducive to flexible application in actual personalized teaching. In this study, a method for grading the difficulty of the English reading corpus is proposed. This approach makes use of a pretrained language model and feature fusion embedding to make the most of multifeature data when training. First, based on linguists' evaluations of the variables influencing the difficulty of English reading corpus, three primary statistical features--sentence length, word length, and the number of prepositions--are taken into consideration. Then, the semantic features and part-of-speech features of the text are learned by a pretrained language model and long short-term memory, respectively, to capture polysemy features and fine-grained semantic representations that are difficult to represent with traditional models. Finally, multifeature embedding extractions are fused to grade the difficulty of the English reading corpus. Extensive experimental comparisons on a self-built dataset and two datasets that are freely accessible with various models indicate that our method outperforms the others in the task of grading the difficulty of English reading corpora.

Abstract Background Acute respiratory distress syndrome (ARDS) after cardiac surgery is a severe respiratory complication with high mortality and morbidity. Traditional clinical approaches may lead to under recognition of this heterogeneous syndrome, potentially resulting in diagnosis delay. This study aims to develop and external validate seven machine learning (ML) models, trained on electronic health records data, for predicting ARDS after cardiac surgery. Methods This multicenter, observational cohort study included patients who underwent cardiac surgery in the training and testing cohorts (data from Nanjing First Hospital), as well as those patients who had cardiac surgery in a validation cohort (data from Shanghai General Hospital). The number of important features was determined using the sliding windows sequential forward feature selection method (SWSFS). We developed a set of tree-based ML models, including Decision Tree, GBDT, AdaBoost, XGBoost, LightGBM, Random Forest, and Deep Forest. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and Brier score. The SHapley Additive exPlanation (SHAP) techinque was employed to interpret the ML model. Furthermore, a comparison was made between the ML models and traditional scoring systems. ARDS is defined according to the Berlin definition. Results A total of 1996 patients who had cardiac surgery were included in the study. The top five important features identified by the SWSFS were chronic obstructive pulmonary disease, preoperative albumin, central venous pressure_T4, cardiopulmonary bypass time, and left ventricular ejection fraction. Among the seven ML models, Deep Forest demonstrated the best performance, with an AUC of 0.882 and a Brier score of 0.809 in the validation cohort. Notably, the SHAP values effectively illustrated the contribution of the 13 features attributed to the model output and the individual feature's effect on model prediction. In addition, the ensemble ML models demonstrated better performance than the other six traditional scoring systems. Conclusions Our study identified 13 important features and provided multiple ML models to enhance the risk stratification for ARDS after cardiac surgery. Using these predictors and ML models might provide a basis for early diagnostic and preventive strategies in the perioperative management of ARDS patients.

Facing the continuous improvement of war complexity under the trend of system-of-systems confrontation,this paper introduces MBSE to the modeling design of complex system-of-systems combat. Adopting Unified Architecture Framework, a modeling method based on scenes is proposed by sorting out the modeling needs and internal mechanisms of system operations. Taking the task that searching and attacking multiple target as an example,various kinds of view is constructed including strategic, operating, resources and services. Then, logic verification is carried out based on the model. This method can provide a reference for system-of-system combat design and UAF application.

The number of day surgeries in hernia and abdominal wall surgery has grown rapidly, and basic requirements need to be put forward for organizational structure, institutional norms, operational management, quality control, and all under the supervision of health administrative departments to ensure quality and safety. Currently, the Expert Committee on Day Surgery for Abdominal Wall Surgery, in collaboration with multiple departments, has developed and updated the expert consensus on standards for hernia and abdominal wall day surgery. The development of day surgery services in this field faces both opportunities and challenges. Opportunities include advancements in medical technology, the spread of minimally invasive surgery, and the growing demand for rapid recovery. Challenges involve the rational allocation of medical resources, the cultivation of professional talents, and the establishment of technical standards. Ensuring medical quality and safety while improving service efficiency remains a significant challenge.

Abstract Due to rapid technological advancements, remote patient monitoring (RPM) technology has gained traction in recent years. While the effects of specific RPM interventions are known, few published reviews examine RPM in the context of care transitions from an inpatient hospital setting to a home environment. In this systematic review, we addressed this gap by examining the impacts of RPM interventions on patient safety, adherence, clinical and quality of life outcomes and cost-related outcomes during care transition from inpatient care to a home setting. We searched five academic databases (PubMed, CINAHL, PsycINFO, Embase and SCOPUS), screened 2606 articles, and included 29 studies from 16 countries. These studies examined seven types of RPM interventions (communication tools, computer-based systems, smartphone applications, web portals, augmented clinical devices with monitoring capabilities, wearables and standard clinical tools for intermittent monitoring). RPM interventions demonstrated positive outcomes in patient safety and adherence. RPM interventions also improved patients’ mobility and functional statuses, but the impact on other clinical and quality-of-life measures, such as physical and mental health symptoms, remains inconclusive. In terms of cost-related outcomes, there was a clear downward trend in the risks of hospital admission/readmission, length of stay, number of outpatient visits and non-hospitalisation costs. Future research should explore whether incorporating intervention components with a strong human element alongside the deployment of technology enhances the effectiveness of RPM. The review highlights the need for more economic evaluations and implementation studies that shed light on the facilitators and barriers to adopting RPM interventions in different care settings.

Field monitoring was conducted to investigate and quantify the long-term effects of peanut shell biochar on soil-grass interaction over three years. Three 10 m × 5 m grassed plots were constructed in completely decomposed granitic soil. Two of them were amended, respectively, with 5% and 10% biochar contents (m3/m3) for grass growth, while the third was without biochar amendment. During the three-year monitoring, plant characteristics, saturated water permeability (ks) of grassed soil and soil suction were measured. The monitored results show that the grass leaf area index (LAI) and root length density (RLD) with biochar amendment were improved by 38% and 200%, respectively. In the grassed plot without biochar, a threshold RLD existed with a value of 1.7 cm/cm3, beyond which ks raised pronouncedly. The threshold RLD increased by 52% when biochar content increased from 0% to 10%. This implies that biochar may restrict the increase in ks of grassed soil due to the rise in the threshold RLD. The presence of biochar and grass can retain over 100% higher suction after heavy rainfalls, while 54% lower peak suction under evapotranspiration (ET) compared with the non-amended plot. Biochar can alleviate the negative effects on hydraulic properties caused by plant growth and reduce ET-induced excessive water loss. A 5% peanut shell biochar content is recommended for the long-term management of vegetated earthen infrastructures.

Hazel leaves, a by-product of hazelnut, have been consumed for health care in some countries and regions for hundreds of years. Based on our previous results, this study further investigated the protective effects of hazel leaf polyphenols (HP) on renal fibrosis induced by hyperuricemia in mice. Results showed that they significantly reduced serum UA, BUN and CRE contents, inhibited liver XOD activity. Histological examination and Western blot analysis revealed that they renal pathological changes and fibrosis were obviously improved after HP administration. Additionally, combined with TEM, they attenuated oxidative stress and mitochondrial damage, and inhibited ferroptosis by regulating the expression of related proteins. Molecular docking predicted that chlorogenic acid, p-coumaric acid, luteolin, myricetin and kaempferol may be the key active ingredients. In conclusion, HP ameliorated hyperuricemia-induced renal fibrosis through regulating uric acid production, reabsorption and excretion, and inhibiting ferroptosis through Nrf2/GPX4 signaling axis. It provides a valuable basis for the utilization of hazel leaf polyphenols as health agents in the future.

Background Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by GRHPR mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment.Methods We report a case of PH2 with a three-generational pedigree. The GRHPR genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization.Results The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (p

Fabry disease, a lysosomal storage disease, is an uncommon X-linked recessive genetic disorder stemming from abnormalities in the alpha-galactosidase gene (GLA) that codes human alpha-Galactosidase A (α-Gal A). To date, over 800 GLA mutations have been found to cause Fabry disease (FD). Continued enhancement of the GLA mutation spectrum will contribute to a deeper recognition and underlying mechanisms of FD. In this study, a 27-year-old male proband exhibited a typical phenotype of Fabry disease. Subsequently, family screening for Fabry disease was conducted, and high-throughput sequencing was employed to identify the mutated gene. The three-level structure of the mutated protein was analyzed, and its subcellular localization and enzymatic activity were determined. Apoptosis was assessed in GLA mutant cell lines to confirm the functional effects. As a result, a new mutation, c.777_778del (p. Gly261Leufs*3), in the GLA gene was identified. The mutation caused a frameshift during translation and the premature appearance of a termination codon, which led to a partial deletion of the domain in C-terminal region and altered the protein’s tertiary structure. In vitro experiments revealed a significant reduction of the enzymatic activity in mutant cells. The expression was noticeably decreased at the mRNA and protein levels in mutant cell lines. Additionally, the subcellular localization of α-Gal A changed from a homogeneous distribution to punctate aggregation in the cytoplasm. GLA mutant cells exhibited significantly higher levels of apoptosis compared to wild-type cells.

Background: Nonsmall cell lung cancer is a leading cause of cancer-related death worldwide. The long noncoding RNA MIR4435-2HG has been shown to play a carcinogenic role in various cancers. The purpose of this study was to explore the role and regulatory mechanism of MIR4435-2HG in non-small cell lung cancer. Methods: Quantitative real-time polymerase chain reaction was used to detect MIR4435-2HG and SRY-box transcription factor 2 in nonsmall cell lung cancer cells. Gain- or loss-of-function assays of MIR4435-2HG and SRY-box transcription factor 2 were subsequently conducted. Cell proliferation, apoptosis, migration, glycolysis, and invasion were tested. A nude mouse tumor model was constructed to determine the role of MIR4435-2HG and SRY-box transcription factor 2 in the growth of tumor cells in vivo. Furthermore, the interactions between MIR4435-2HG, miR-371a-5p and SRY-box transcription factor 2 were analyzed via a dual-luciferase reporter gene assay. Results: Quantitative real-time polymerase chain reaction revealed that MIR4435-2HG and SRY-box transcription factor 2 were upregulated in nonsmall cell lung cancer cells. Forced MIR4435-2HG overexpression led to increased cell proliferation, migration, invasion, and glycolysis and repressed cell apoptosis. Overexpressing MIR4435-2HG promoted SRY-box transcription factor 2 expression and PI3K/Akt/mTOR pathway activation. Downregulating MIR4435-2HG had antitumor effects both in vitro and in vivo. SRY-box transcription factor 2 overexpression mostly reversed the suppressive effects of MIR4435-2HG downregulation. Mechanistic studies revealed that MIR4435-2HG, a competitive endogenous RNA, directly targeted and inhibited miR-371a-5p. Rescue assays revealed that miR-371a-5p overexpression or SRY-box transcription factor 2 downregulation significantly inhibited MIR4435-2HG-mediated oncogenic effects. Conclusion: MIR4435-2HG promotes nonsmall cell lung cancer cell malignant behaviors and glycolysis by regulating the miR-371a-5p/SOX2 axis.

Purpose To quantify changes in colour vision immediately after exposure to different altitudes of low-pressure hypoxia.Methods The study involved 35 healthy participants (ages 20–26). Colour vision was assessed using the Farnsworth-Munsell 100-Hue test at eight different altitudes (condition 1: ground, condition 2: 3500 m, condition 3: 3500 m after 40 min, condition 4: 4000 m, condition 5: 4000 m after 40 min, condition 6: 4500 m, condition 7: 4500 m after 40 min, condition 8: back to the ground). Data were analysed using Analysis of Variance (ANOVA), paired t-test, and χ2 test .Results Total Error Score (TES) increased with altitude and hypoxia duration, with higher TES in condition 8 than in condition 1. There were significant TES differences between conditions 3 and 7, as well as 4 and 7. Friedman and repeated ANOVA tests revealed significant sector differences, with Blue-Yellow Partial Error Score (PES) greater than Red-Green PES, particularly on conditions 4, 5 and 8. Significant Red-Green PES differences were found between conditions 4 and 7, and Blue-Yellow PES between conditions 3 and 5, 7, 8. Tritan (Blue-Yellow) shift was most pronounced at high altitudes.Conclusions This experiment investigated acute low-pressure hypoxia’s effects on colour vision, supplementing chronic hypoxia research. Increased altitudes and exposure duration worsen colour vision, with effects persisting post-recovery. Tritan axis loss is most significant under hypoxia.

Phthalates are endocrine disruptors of increasing concern for human health; however, previous studies have only assessed the association between internal exposure and human health. We aimed to assess the non-carcinogenic and carcinogenic risks of non-dietary exposure to phthalates in indoor environments among primary school children and their correlations with health indicators. A study involving 54 children was conducted in Jinan, Shandong Province, China. Questionnaires and health examinations were conducted, dust in hard-to-clean corners of students’ classrooms and homes was collected, and airborne phthalates in the middle of classrooms and family living rooms were sampled. The gas-phase phthalate concentrations, individual exposure, and non-carcinogenic and carcinogenic risks were calculated. Associations were estimated using linear mixed models. The findings revealed that phthalates posed a non-carcinogenic risk to 7.4 % of the children and a moderate carcinogenic risk to 27.8 % of the children, with higher non-carcinogenic and carcinogenic risks to girls than to boys. Five phthalates were negatively correlated with body mass index, dimethyl phthalate and diethyl phthalate (DEP) were significantly correlated with waist circumference, and di-iso-butyl phthalate (DiBP) was negatively correlated with hip circumference. DiBP, di-n-butyl phthalate, and DEP, were significantly correlated with cardiovascular disease, DEP and di (2-n-butoxyethyl) phthalate were correlated with decreased lung function, and di-n-octyl phthalate influenced airway inflammation. The findings indicated that phthalate exposure may negatively impact children's health, thereby warranting further comprehensive research on the health effects of these chemicals.

Abstract The typical metal chloride‐graphite intercalation compounds (MC‐GICs) inherit intercalation capacity, high charge conductivity, and high tap density from graphite, and these are considered as one of the promising alternatives of graphite anode in rechargeable metal‐ion batteries (MIBs). Notably, the special interlayer decoupling effects and the introduction of extra conversion capacity by metal chloride could greatly break the capacity limitation of graphite anodes and achieve higher energy density in MIBs. The optimization of both graphite host and metal chloride species with specific structures endows MC‐GICs with design feasibility for different application requirements of different MIBs, such as several times the actual capacity compared to graphite anodes, rapid migration of large carriers, and other properties. Herein, a brief review has been provided with the latest understanding of conductivity characteristics and energy storage mechanisms of MC‐GICs and their interesting performance features of full potential application in rechargeable MIBs. Based on the existing research of MC‐GICs, necessary improvements and prospects in the near future have been put forward.

Abstract Background Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non‐coding RNAs (lncRNAs) and N6‐methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A‐modified lncRNAs in ESCC radioresistance remain unclear. Methods Bioinformatics analysis was conducted to identify m6A‐modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification‐mass spectrometry, RNA immunoprecipitation, and co‐immunoprecipitation experiments were performed to explore the mechanism of m6A‐mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models. Results Herein, we identified LNCAROD as a novel METTL3‐mediated lncRNA that enhanced radioresistance in ESCC cells and was post‐transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin‐proteasome degradation of PARP1 protein by facilitating PARP1‐NPM1 interaction, thereby contributing to homologous recombination‐mediated DNA double‐strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity. Conclusion Our findings enhance the understanding of m6A‐modified lncRNA‐driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.

BackgroundThe co-design of health technology enables patient-centeredness and can help reduce barriers to technology use. ObjectiveThe study objectives were to identify what remote patient monitoring (RPM) technology has been co-designed for inpatients and how effective it is, to identify and describe the co-design approaches used to develop RPM technologies and in which contexts they emerge, and to identify and describe barriers and facilitators of the co-design process. MethodsWe conducted a systematic review of co-designed RPM technologies for inpatients or for the immediate postdischarge period and assessed (1) their effectiveness in improving health outcomes, (2) the co-design approaches used, and (3) barriers and facilitators to the co-design process. Eligible records included those involving stakeholders co-designing RPM technology for use in the inpatient setting or during the immediate postdischarge period. Searches were limited to the English language within the last 10 years. We searched MEDLINE, Embase, CINAHL, PsycInfo, and Science Citation Index (Web of Science) in April 2023. We used the Joanna Briggs Institute critical appraisal checklist for quasi-experimental studies and qualitative research. Findings are presented narratively. ResultsWe screened 3334 reports, and 17 projects met the eligibility criteria. Interventions were designed for pre- and postsurgical monitoring (n=6), intensive care monitoring (n=2), posttransplant monitoring (n=3), rehabilitation (n=4), acute inpatients (n=1), and postpartum care (n=1). No projects evaluated the efficacy of their co-designed RPM technology. Three pilot studies reported clinical outcomes; their risk of bias was low to moderate. Pilot evaluations (11/17) also focused on nonclinical outcomes such as usability, usefulness, feasibility, and satisfaction. Common co-design approaches included needs assessment or ideation (16/17), prototyping (15/17), and pilot testing (11/17). The most commonly reported challenge to the co-design process was the generalizability of findings, closely followed by time and resource constraints and participant bias. Stakeholders’ perceived value was the most frequently reported enabler of co-design. Other enablers included continued stakeholder engagement and methodological factors (ie, the use of flexible mixed method approaches and prototyping). ConclusionsCo-design methods can help enhance interventions’ relevance, usability, and adoption. While included studies measured usability, satisfaction, and acceptability—critical factors for successful implementation and uptake—we could not determine the clinical effectiveness of co-designed RPM technologies. A stronger commitment to clinical evaluation is needed. Studies’ use of diverse co-design approaches can foster stakeholder inclusivity, but greater standardization in co-design terminology is needed to improve the quality and consistency of co-design research.

Abstract Background Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have shown great therapeutic potential in plastic and reconstructive surgery. However, the limited production and functional molecule loading of EVs hinder their clinical translation. Traditional two-dimensional culture of hADSCs results in stemness loss and cellular senescence, which is unfavorable for the production and functional molecule loading of EVs. Recent advances in regenerative medicine advocate for the use of three-dimensional culture of hADSCs to produce EVs, as it more accurately simulates their physiological state. Moreover, the successful application of EVs in tissue engineering relies on the targeted delivery of EVs to cells within biomaterial scaffolds. Methods and Results The hADSCs spheroids and hADSCs gelatin methacrylate (GelMA) microspheres are utilized to produce three-dimensional cultured EVs, corresponding to hADSCs spheroids-EVs and hADSCs microspheres-EVs respectively. hADSCs spheroids-EVs demonstrate excellent production and functional molecule loading compared with hADSCs microspheres-EVs. The upregulation of eight miRNAs (i.e. hsa-miR-486-5p, hsa-miR-423-5p, hsa-miR-92a-3p, hsa-miR-122-5p, hsa-miR-223-3p, hsa-miR-320a, hsa-miR-126-3p, and hsa-miR-25-3p) and the downregulation of hsa-miR-146b-5p within hADSCs spheroids-EVs show the potential of improving the fate of remaining ear chondrocytes and promoting cartilage formation probably through integrated regulatory mechanisms. Additionally, a quick and innovative pipeline is developed for isolating chondrocyte homing peptide-modified EVs (CHP-EVs) from three-dimensional dynamic cultures of hADSCs spheroids. CHP-EVs are produced by genetically fusing a CHP at the N-terminus of the exosomal surface protein LAMP2B. The CHP + LAMP2B-transfected hADSCs spheroids were cultured with wave motion to promote the secretion of CHP-EVs. A harvesting method is used to enable the time-dependent collection of CHP-EVs. The pipeline is easy to set up and quick to use for the isolation of CHP-EVs. Compared with nontagged EVs, CHP-EVs penetrate the biomaterial scaffolds and specifically deliver the therapeutic miRNAs to the remaining ear chondrocytes. Functionally, CHP-EVs show a major effect on promoting cell proliferation, reducing cell apoptosis and enhancing cartilage formation in remaining ear chondrocytes in the M1 macrophage-infiltrated microenvironment. Conclusions In summary, an innovative pipeline is developed to obtain CHP-EVs from three-dimensional dynamic culture of hADSCs spheroids. This pipeline can be customized to increase EVs production and functional molecule loading, which meets the requirements for regulating remaining ear chondrocyte fate in the M1 macrophage-infiltrated microenvironment. Graphical Abstract

ObjectiveObservational studies have suggested a potential association between constipation and several cancers. However, the causal relationship between constipation and cancer remains unclear. The purpose of this study is to explore the potential causal relationship between constipation and pan-cancer using Mendelian Randomization (MR) methods.MethodsWe performed a bidirectional MR analysis using publicly available summary data from Genome-Wide Association Studies (GWAS) statistics. The Inverse Variance Weighted (IVW) method was used as the main analysis method. We also used four MR methods: MR-Egger, Weighted Median, MR-PRESSO and MR.RAPS. Simultaneously, MR-Egger regression, Cochran’s Q test and MR-PRESSO Global test were used to estimate the pleiotropy and heterogeneity of SNPs. In addition, we performed “leave-one-out” analyses” to avoid bias caused by horizontal pleiotropy of individual SNPs.ResultsMR analysis revealed a potential causal association between constipation and the risk of colorectal cancer (CRC) [IVW (OR= 1.0021 (1.0003, 1.0039), P= 0.0234)], lung cancer (LC) [IVW (OR=1.0955 (1.0134, 1.1843), P=0.0218)], Oral cavity and pharyngeal cancer (OPC) [IVW (OR=1.4068 (1.0070, 1.9652), P=0.0454)], and Pancreatic cancer (PC) [IVW (OR=1.5580 (1.0659, 2.2773), P=0.0221)]. In addition, we explored causal relationships between constipation and 12 other types of cancers, including gastric cancer, esophageal cancer, skin melanoma and so on. All five methods yielded no evidence of a causal association between constipation and the risk of these cancer types. In the reverse MR analysis, there was no evidence of a causal association between cancer and the risk of constipation for all five methods.ConclusionOur bidirectional MR study suggests a potential relationship between constipation and an increased risk of CRC, LC OPC and PC. The underlying mechanisms behind these associations will need to be explored in future experimental studies.

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatory mechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)-induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1 mRNA levels were dramatically decreased and P53 mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by up-regulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1 mediated P53 expression might be identified as potential targets for the early treatment of septic AKI.

Introduction Esophageal cancer presents significant challenges due to limited treatment options and poor prognosis, particularly in advanced stages. Dysregulated long non-coding RNAs (lncRNAs) are implicated in cancer progression and treatment resistance. This study investigated the roles of dysregulated lncRNA NONHSAT227443.1, identified through lncRNA-seq, and its downstream target gene MRTFB in esophageal squamous cell carcinoma (ESCC). Methods Dysregulated lncRNAs were identified through lncRNA-seq in esophageal cancer tissues with varying chemotherapy response. The regulatory interaction of overexpressed NONHSAT227443.1 was assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Functional assays, including cell viability, cell proliferation, and flow cytometry analyses, were performed to comprehensively investigate the influence of NONHSAT227443.1 and its downstream molecules on ESCC. Results NONHSAT227443.1 was significantly overexpressed in paclitaxel plus platinum chemotherapy non-responders and esophageal cancer cell lines. Chemotherapy exposure led to diminished NONHSAT227443.1 expression. NONHSAT227443.1 negatively regulated MRTFB expression, and their combined dysregulation correlated with increased cancer activity, proliferation, and suppressed apoptosis. Diminished MRTFB expression was associated with PI3K/AKT pathway activation. Conclusion Our study provides insights into NONHSAT227443.1 and MRTFB roles in esophageal cancer, contributing to aggressive traits and treatment resistance. NONHSAT227443.1 and MRTFB may serve as potential therapeutic targets to enhance the response to paclitaxel plus platinum chemotherapy in non-responsive cases.

BackgroundTo quantify the changes in dynamic visual acuity (DVA) and explain the hidden reasons after acute exposure to hypobaric hypoxia status.MethodsThe study group comprised 18 healthy male and 15 healthy female participants aged 20–24 years old. DVA was measured with the self-developed software of Meidixin (Tianjin) Co., Ltd. Measurements were taken at eight altitudes. Data analysis was performed using the Kolmogorov–Smirnov test, paired sample T-test, and two-way repeated measures analysis of variance (ANOVA) for repeated measurements.ResultsAt constant altitude, DVA showed an overall decreasing trend with increasing angular velocity and a fluctuating decrease at the vast majority of altitudes. At constant angular velocities, DVA gradually increased with altitude, with the most pronounced increase in DVA at altitude 5, and thereafter a gradual decrease in DVA as altitude increased. Finally, as altitude decreased, DVA increased again and reached a higher level at the end of the experiment, which was superior to the DVA in the initial state.ConclusionUnder a hypobaric hypoxic environment at high altitude, DVA was affected by the angular velocity and the degree of hypoxia, manifesting as an increase or decrease in DVA, which affects the pilot's observation of the display and control interfaces during the driving process, acquisition of information, and decision-making ability, which in turn may potentially jeopardize the safety of the flight.