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Abstract This survey aimed to investigate the availability of drugs for stable chronic obstructive pulmonary disease (COPD) treatment in Chinese hospitals and to determine whether drug availability significantly varied among hospitals with different characteristics. A well-constructed questionnaire was designed according to the Chinese Guidelines for the Diagnosis and Management of COPD (revised version 2021). Both inhaled drugs (monotherapy, double therapy and triple therapy) and oral drugs (expectorants, theophylline, antibiotics, and bacterial lysates) were included in this survey. Doctors from different hospitals completed the survey via WeChat. The availability of each category and kind of drug was analyzed based on final valid responses. Subgroup analyses were also conducted to reveal drug availability in hospitals with different characteristics. A total of 1018 hospitals with different characteristics were enrolled in this survey, with 53.73% of which establishing independent respiratory departments. Insufficient supply of COPD-related drugs was observed, with only short-acting β2 agonists (80.6%), expectorants (88.2%) and antibiotics (84.3%) reaching 80%. Results of subgroup analyses suggested that primary hospitals were associated with poorer availability of all kinds of drugs than secondary and tertiary hospitals (all p

Abstract H3 lysine 4 trimethylation (H3K4me3) modification and related regulators extensively regulate various crucial transcriptional courses in health and disease. However, the regulatory relationship between H3K4me3 modification and anti-tumor immunity has not been fully elucidated. We identified 72 independent prognostic genes of lung adenocarcinoma (LUAD) whose transcriptional expression were closely correlated with known 27 H3K4me3 regulators. We constructed three H3K4me3 modification patterns utilizing the expression profiles of the 72 genes, and patients classified in each pattern exhibited unique tumor immune infiltration characteristics. Using the principal component analysis (PCA) of H3K4me3-related patterns, we constructed a H3K4me3 risk score (H3K4me3-RS) system. The deep learning analysis using 12,159 cancer samples from 26 cancer types and 725 cancer samples from 5 immunotherapy cohorts revealed that H3K4me3-RS was significantly correlated with cancer immune tolerance and sensitivity. Importantly, this risk-score system showed satisfactory predictive performance for the ICB therapy responses of patients suffering from several cancer types, and we identified that SLAMF9 was one of the immunosuppressive phenotype and immunotherapy resistance-determined genes of H3K4me3-RS. The mice melanoma model showed Slamf9 knockdown remarkably restrained cancer progression and enhanced the efficacy of anti-CTLA-4 and anti-PD-L1 therapies by elevating CD8 + T cell infiltration. This study provided a new H3K4me3-associated biomarker system to predict tumor immunotherapy response and suggested the preclinical rationale for investigating the roles of SLAMF9 in cancer immunity regulation and treatment.

Abstract Obesity is a significant public health challenge, yet the link between BMI and mortality in critical illness remains unclear. This study analyzed 19,311 patients from the MIMIC-III database, categorized into underweight, normal weight, overweight, and obese groups. Using Cox models and restricted cubic splines, we explored the complex association between BMI and mortality. Finally, multiple sensitivity analyses were performed to test the robustness of the results. The proportion of underweight patients (2.3%) was the lowest, while overweight (34.8%) and obese (34.5%) patients constituted a large proportion. Being underweight portended a greater risk, while being overweight or obese was associated with a lower risk of mortality, which is consistent with the sensitivity analysis. Moreover, we observed a typical L-shaped association between BMI and the risk of mortality with and without adjustment, with the lowest mortality occurring at approximately 32 kg/m2. The overall pattern of the nonlinear association between BMI and mortality was similar for most subgroup analyses. Underweight was associated with a greater risk of mortality, while obesity and overweight were both associated with a lower risk of mortality in critically ill patients. BMI had a typical L-shaped association with the risk of mortality.

Objective and Methods Faults are identified as one of the most threatening geological structural factors among hidden disaster-causing factors in coal mines. However, the 3D quantitative assessment of them remains challenging. Considering that existing quantitative indicators fail to fully reflect fault morphologies and there is a lack of 3D methods, this study proposed a calculational model for 3D fault complexity based on curvature analysis and fractal dimensions. This model improved the morphologies of traditional measurement volumes of fractal dimensions by employing the Delaunay tetrahedralization algorithm, thus effectively reducing the invalid values in calculating the 3D fractal dimensions of faults. Moreover, the model modified fault parameters by introducing fault plane curvatures, thereby retaining the structural characteristics of faults. To validate its effectiveness, this model was applied to the faults revealed in a coal mine in Shaanxi Province. Using this model, this study conducted a qualitative assessment of the complexity of geological structures and examined the data on the spatial distributions of the historical water inrush points in the mining face and roadways. Results and Conclusions Using this model, 75 partitioning intervals with nonzero statistics were identified in the mine field. Calculations revealed that the average 3D fractal dimension of faults and 3D fault complexity values integrated with Gaussian and mean curvatures were 0.9394, 1.1362, and 1.2199, respectively. Compared to a single fractal dimension, the fault complexity integrated with curvatures enjoyed significant advantages in revealing the differences in fault strikes and fault concentration zones. Based on the Pearson correlation coefficients calculated using the 3D fault complexity and the distance between sample points and water inrush points as two correlation indicators, water inrush points can be categorized into two types: those in the mining face and those in roadways. For water inrush points in the mining face, the average coefficients of their correlations with 3D fractal dimension of faults and 3D fault complexity integrated with Gaussian and mean curvatures were 0.7843, 0.8386, and 0.9072, respectively, while these average coefficients were 0.7718, 0.8324, and 0.8903, respectively, for water inrush points in roadways. These data indicate that fault complexity is highly correlated with water inrush points in the mining face compared to water burst points in roadways. In other words, the production activities in the mining face within the study area are more significantly affected by faults. Additionally, the Pearson correlation coefficients all exceeded 0.77 regardless of the curvature integrated, suggesting a strong correlation between the 3D fault complexity and the water hazard conditions of coal mines. The qualitative assessment reveals that the overall structural complexity of the coal mine is relatively low and is primarily affected by faults. The fault complexity values of the coal mine were determined at around 1, exceeding 2 in very few zones. This result implies the overall low fault complexity of the coal mine despite local fault concentration, aligning with the qualitative assessment results. The above methods validate the effectiveness of the proposed model, which provides a new modeling approach for the calculation of 3D fault complexity.

Abstract Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs’ activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer’s development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs’ involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies.

Abstract The occurrence of multiple primary lung cancer (MPLC) has witnessed a significant surge in recent years within the Chinese population. MPLC is distinguished by its potential genetic susceptibility and notable genetic heterogeneity. Investigating the etiology of MPLC holds substantial clinical importance.The whole genome sequencing (WGS) and genome-wide linkage analysis were performed in a family affected by a dominant form of lung abnormalities. Specifically, five family members were diagnosed with MPLC, while nine members had pulmonary nodules and one normal member. To confirm the potential pathogenic germline mutations sites, Sanger sequencing was performed in an additional 162 MPLC family patients. Furthermore, molecular biology experiments were conducted to investigate the function and the mechanism of the identified pathogenic mutation site in lung cancer A549 and H322, both in vitro and in vivo. Linkage analysis revealed the presence of shared genomic regions among affected family members. Subsequent exome sequencing identified a deleterious variant within these linkage intervals, specifically a heterozygous mutation in ETS-oncogene transcription factors 4 (ETV4). This particular variant was found in affected family members at a rate of 13 out of 15 individuals. Furthermore, ETV4 P433L mutation could be detected in an additional MPLC family patients and mutation frequency was 3.7% (6 out of 162). The ETV4 P433L mutations site was introduced into lung cancer cell lines, resulting in altered migration and stem-like properties of the cancer cells. Further investigation revealed that the activation of the Wnt/β-catenin signaling pathway, which is associated with stemness, could be attributed to the presence of the ETV4 P433L mutation, suggesting its involvement in tumor promotion. A novel pathogenic germline mutation, ETV4 P433L, was identified in a dominant MPLC family, with a mutation rate of 3.7% among MPLC family patients. The ETV4 P433L mutation was found to impact the stem-like properties and migration of tumors through Wnt/β-catenin signaling pathway.

Abstract Magnesium (Mg) plays a pivotal role as an essential component of plant chlorophyll and functions as a critical coenzyme. However, research exploring the regulatory mechanisms of magnesium ions on the synthesis of secondary metabolites is still in its early stages. Sophora tonkinensis is a widely utilized medicinal plant in China, recognized for its diverse secondary metabolites with active properties. This study investigates variations in these ingredients in tissue-cultured seedlings under varying magnesium concentrations. Simultaneously, an omics data analysis was conducted on tissue-cultured seedlings subjected to treatments with magnesium and low magnesium. These comprehensive omics analyses aimed to elucidate the mechanisms through which magnesium influences active components, growth, and development. Magnesium exerts a pervasive influence on various metabolic pathways, forming an intricate network. Research findings indicate that magnesium impacts diverse metabolic processes, including the absorption of potassium and calcium, as well as photosynthetic activity. Consequently, these influences lead to discernible changes in the levels of pharmacologically active compounds and the growth and developmental status.This study is the first to employ a multi-omics data analysis in S. tonkinensis. This methodology allows us to uncover the overarching impact of metabolic networks on the levels of various active ingredients and specific phenotypes.

Abstract Background Patients with inflammatory bowel disease (IBD) are at risk of developing dysplasia and, subsequently, colorectal cancer (CRC) owing to chronic inflammation. Patients may also experience other severe disease complications, such as hospitalization and surgery. Several biologics are available for the treatment of patients with IBD and some patients require multiple lines of treatment owing to loss of response or tolerability to their prescribed biologic. Previous studies suggest that the choice of initial biologic treatment may impact the outcomes of later treatment lines. In this study, we assessed adverse clinical outcomes in patients with Crohn’s disease (CD) or ulcerative colitis (UC) who received different biologic treatment sequences. Methods ROTARY part B was a retrospective cohort study using the Optum® Clinical Database that evaluated the incidences of IBD-related hospitalization, IBD-related surgery, dysplasia, CRC, and infections in patients with CD or UC who received two biologics successively. First-line biologics included adalimumab, infliximab, ustekinumab (CD only), and vedolizumab; second-line biologics included infliximab and adalimumab. Results In patients with CD, the treatment sequence of ustekinumab to infliximab was associated with the highest overall incidences of hospitalization (51.9%), surgery (40.7%), CRC (3.7%), and infection (37.0%). Vedolizumab followed by an anti-tumor necrosis factor alpha (anti-TNFα) treatment was associated with a significantly lower risk of experiencing an adverse medical event (hospitalization, surgery, or infection) than two successive anti-TNFα treatments (odds ratio, 1.526; 95% confidence interval, 1.004–2.320; P

Abstract Background Congenital craniovertebral deformity, including basilar invagination (BI) and atlantoaxial instability (AAI), are often associated with three-dimensional (3D) deformity, such as C1-2 rotational deformity, craniocervical kyphosis, C1 lateral inclination, among other abnormalities. Effective management of these conditions requires the restoration of the 3D alignment to achieve optimal reduction. Recently, 3D printing technology has emerged as a valuable tool in spine surgery, offering the significant advantage of allowing surgeons to customize the prosthesis design. This innovation provides an ideal solution for precise 3D reduction in the treatment of craniovertebral deformities. Objective This study aims to describe our approach to individualized computer-simulated reduction and the design of C1-2 intra-articular 3D printed porous titanium alloy cages for the quantitative correction of craniovertebral junction deformities. Methods A retrospective analysis was conducted on patients with craniovertebral deformities treated at our institution using individualized 3D-printed porous titanium alloy cages. Preoperative CT data were used to construct models for 3D realignment simulations. Cage designs were tailored to the simulated joint morphology following computer-assisted realignment. Preoperative and postoperative parameters were statistically analyzed. Results Fourteen patients were included in the study, with a total of 28 3D-printed porous titanium alloy cages implanted. There were no cases of C2 nerve root resection or vertebral artery injury. All patients experienced symptom relief and stable implant fixation achieved in all cases. No implant-related complications were reported. Conclusion The use of individualized computer-simulated reduction and the design of C1-2 intra-articular 3D printed porous titanium alloy cage facilitates precise 3D realignment in patients with craniovertebral deformities, demonstrating effectiveness in symptom relief and stability.

Abstract In this study, SiO2 coating was electrodeposited on Ti45Al8.5Nb alloy to enhance its oxidation resistance at 900 °C. The focus was on the interaction between SiO2 coating and the alloy substrate, and specifically, the role of the Nb element in this context. The formation of a SiO2/(Ti, Nb)O2/Ti5Si3 + Al2O3 three-layer oxide scale significantly inhibits the inward diffusion of oxygen. Beyond the characteristic Ti5Si3 + Al2O3 layer at the interface, the Nb2Al phase embedded within Ti5Si3 was observed. Concurrently, the presence of a (Ti, Nb)O2 layer was confirmed. The relationship between the coating thickness and oxidation resistance was also investigated. It was found that the thickness of the SiO2 coating affects the density of the oxide scale and the inward diffusion rate of oxygen. Moreover, due to the good adhesion to the substrate, the derived oxide scale exhibited good anti-peeling performance when subjected to a cyclic oxidation test.

Abstract Background Concerns have been raised regarding changes in lipid profiles among patients with chronic hepatitis B (CHB) during tenofovir alafenamide fumarate (TAF) treatment. We aimed to evaluate the effect of TAF treatment on the lipid profiles of patients with CHB. Methods A total of 430 patients with CHB from three hospitals were retrospectively included, including 158 patients treated with TAF and 272 patients treated with tenofovir disoproxil fumarate (TDF). Results In this multicenter cohort, the cumulative incidence of dyslipidemia was notably higher in the TAF group than in the TDF group (P

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of “partial cure” in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg

Predicting hepatitis B surface antigen (HBsAg) clearance is important for chronic hepatitis B (CHB) patients receiving pegylated interferon-alfa (Peg-IFN) therapy. We aimed to determine the predictive value of serum hepatitis B core antibody (anti-HBc) for HBsAg clearance. A total of 189 HBeAg-negative CHB patients who received Peg-IFN based therapy were retrospectively included and classified into two groups: nucleos(t)ide analogues (NAs) add-on Peg-IFN group (add-on group, n = 94) and Peg-IFN combined with NAs or Peg-IFN monotherapy group (combination or monotherapy group, n = 95). After 48 weeks of treatment, 27.5% (52/189) and 15.9% (30/189) of patients achieved HBsAg clearance and seroconversion, respectively. Patients in the combination or monotherapy group tended to achieve relatively higher HBsAg clearance (31.6% vs. 23.4%, p = 0.208) and seroconversion (21.1% vs. 10.6%, p = 0.050) rates than those in the add-on group. In combination or monotherapy group, anti-HBc levels at week 12 were lower in patients with HBsAg clearance (9.0 S/CO vs. 9.9 S/CO, p

Abstract Background Proper control of the lineage bias of megakaryocytic and erythroid progenitor cells (MEPs) is of significant importance, the disorder of which will lead to abnormalities in the number and function of platelets and erythrocytes. Unfortunately, the signaling pathways regulating MEP differentiation largely remain to be elucidated. This study aimed to analyze the role and the underlying molecular mechanism of miR-1915-3p in megakaryocytic and erythroid differentiation. Methods We utilized miRNA mimics and miRNA sponge to alter the expression of miR-1915-3p in megakaryocytic and/or erythroid potential cells; siRNA and overexpression plasmid to change the expression of SOCS4, a potential target of miR-1915-3p. The expression of relevant surface markers was detected by flow cytometry. We scanned for miR-1915-3p target genes by mRNA expression profiling and bioinformatic analysis, and confirmed the targeting by dual-luciferase reporter assay, western blot and gain- and lost-of-function studies. One-way ANOVA and t-test were used to analyze the statistical significance. Results In this study, overexpression or knockdown of miR-1915-3p inhibited or promoted erythroid differentiation, respectively. Accordingly, we scanned for miR-1915-3p target genes and confirmed that SOCS4 is one of the direct targets of miR-1915-3p. An attentive examination of the endogenous expression of SOCS4 during megakaryocytic and erythroid differentiation suggested the involvement of SOCS4 in erythroid/megakaryocytic lineage determination. SOCS4 knockdown lessened erythroid surface markers expression, as well as improved megakaryocytic differentiation, similar to the effects of miR-1915-3p overexpression. While SOCS4 overexpression resulted in reversed effects. SOCS4 overexpression in miR-1915-3p upregulated cells rescued the effect of miR-1915-3p. Conclusions miR-1915-3p acts as a negative regulator of erythropoiesis, and positively in thrombopoiesis. SOCS4 is one of the key mediators of miR-1915-3p during the differentiation of MEPs.

Abstract Background The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. Methods Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA

Abstract Background Hemiplegic shoulder pain (HSP) is a common complication after stroke. It severely affects the recovery of upper limb motor function. Early shoulder pain in hemiplegic patients is mainly neuropathic caused by central nerve injury or neuroplasticity. Commonly used corticosteroid injections in the shoulder joint can reduce shoulder pain; however, the side effects also include soft tissue degeneration or increased tendon fragility, and the long-term effects remain controversial. Botulinum toxin injections are relatively new and are thought to block the transmission of pain receptors in the shoulder joint cavity and inhibit the production of neuropathogenic substances to reduce neurogenic inflammation. Some studies suggest that the shoulder pain of hemiplegia after stroke is caused by changes in the central system related to shoulder joint pain, and persistent pain may induce the reorganization of the cortical sensory center or motor center. However, there is no conclusive evidence as to whether or not the amelioration of pain by botulinum toxin affects brain function. In previous studies of botulinum toxin versus glucocorticoids (triamcinolone acetonide injection) in the treatment of shoulder pain, there is a lack of observation of differences in changes in brain function. As the content of previous assessments of pain improvement was predominantly subjective, objective quantitative assessment indicators were lacking. Functional near-infrared imaging (fNIRS) can remedy this problem. Methods This study protocol is designed for a double-blind, randomized controlled clinical trial of patients with post-stroke HSP without biceps longus tenosynovitis or acromion bursitis. Seventy-eight patients will be randomly assigned to either the botulinum toxin type A or glucocorticoid group. At baseline, patients in each group will receive shoulder cavity injections of either botulinum toxin or glucocorticoids and will be followed for 1 and 4 weeks. The primary outcome is change in shoulder pain on the visual analog scale (VAS). The secondary outcome is the assessment of changes in oxyhemoglobin levels in the corresponding brain regions by fNIRS imaging, shoulder flexion, external rotation range of motion, upper extremity Fugl-Meyer, and modified Ashworth score. Discussion Ultrasound-guided botulinum toxin type A shoulder joint cavity injections may provide evidence of pain improvement in patients with HSP. The results of this trial are also help to analyze the correlation between changes in shoulder pain and changes in cerebral hemodynamics and shoulder joint motor function. Trial registration Chinese clinical Trial Registry, ChiCTR2300070132. Registered 03 April 2023, https://www.chictr.org.cn/showproj.html?proj=193722 .

ABSTRACT Background Intervertebral disc degeneration (IDD) is a major cause for low back pain. Studies showed the association between senescence and degenerative diseases. Cell senescence can promote the occurrence and development of degenerative diseases through multiple mechanisms including inflammatory stress, oxidative stress and nutritional deprivation. The roles of senescence and senescence‐associated genes (SAGs) remains unknown in IDD. Methods Four differently expressed SAGs were identified as hub SAGs using “limma“ package in R. We then calculated the immune infiltration of IDD patients, and investigated the relation between hub SAGs and immune infiltration. Enrichment analysis was performed to explore the functions of hub SAGs in IDD. Nomogram and LASSO model based on hub SAGs was constructed to predict the risk of severe degeneration (SD) for IDD patients. Subsequently, single cell analysis was conducted to describe the expression pattern of hub SAGs in intervertebral disc tissue. Results We identified ASPH, CCND1, IGFBP3 and SGK1 as hub SAGs. Further analysis demonstrated that the hub SAGs might mediate the development of IDD by regulating immune infiltration and multiple pathways. The LASSO model based on the four hub SAGs showed good performance in predicting the risk of SD. Single cell analysis revealed that ASPH, CCND1 and SGK1 mainly expressed in nucleus pulposus cells, while IGFBP3 mainly expressed in epithelial cells. Eleven candidate drugs targeting hub SAGS were predicted for IDD patients through Comparative Toxicogenomics Database (CDT). PCR and immunohistochemical analysis showed that the levels of four hub SAGs were higher in SD than MD (mild degeneration) patients. Conclusions We performed a comprehensive analysis of SAGs in IDD, which revealed their functions and expression pattern in intervertebral disc tissue. Based on hub SAGs, we established a predictive model and explored the potential drugs. These findings provide new understandings of SAG mechanism and promising therapeutic strategies for IDD.

BackgroundThis study aimed to examine the evolving trends in the global burden of low back pain (LBP) from 1990 to 2021 and predicted disease burden until 2035.Materials and methodsLBP-related data were obtained from the Global Health Data Exchange (GHDx) query tool. All estimates and their 95% uncertainty intervals (UIs) were generated using DisMod-MR 2.1, a Bayesian meta-regression tool in Global Burden of Disease, Injury, and Risk Factor Study (GBD) 2021. Data processing and visualization were conducted using The R Programming Language software version 4.3.2 and Joinpoint 4.7.ResultsIn 2021, approximately 628.8 million people worldwide were affected by LBP, with approximately 266.9 million new incident cases and age-standardized incidence rate (ASIR) of 3176.6 per 100,000. Compared with 1990, although the ASIR and age-standardized disability-adjusted life years rate (ASDALYsR) decreased, absolute numbers increased significantly. Projections for 2035 reveal a continued decline in ASIR and ASDALYsR for LBP. The LBP burden varied by the sociodemographic index quintile and GBD region, with the highest ASIR and ASDALYsR observed in Central Europe and the greatest decrease in East Asia. Globally, women bear a higher burden of LBP than men, with middle-aged populations experiencing the heaviest burden. Occupational ergonomic factors, high body mass index, and smoking remain the primary risk factors for LBP, with occupational ergonomic factors contributing the most to the overall burden.ConclusionDespite a projected decline in incidence, the global burden of LBP persists, exhibiting significant regional and gender disparities. To mitigate its future burden, precise and effective prevention and control strategies targeting high-risk factors are imperative.

To determine the effect of ignition height on indoor flame spread behavior and overpressure development, a comprehensive full-scale deflagration testing facility was established. Extensive experimental research was conducted within this facility. The findings indicate that indoor flame reignition and the occurrence of secondary explosions are most pronounced with intermediate ignition. Furthermore, the explosion overpressure generated during the reverse turn of shock wave propagation is greater than that produced by the forward turn. In comparison to the peak overpressure Pext in the master bedroom for top, middle, and bottom ignition, the peak overpressure Pext in the second bedroom increased by approximately 14.48 %, 15.04 %, and 19.20 %, respectively. When comparing middle ignition to top ignition, the propagation speed of shock waves in the kitchen balcony, restroom, second bedroom, and master bedroom was enhanced by 34.21 %, 40.85 %, 40.70 %, and 34.65 %, respectively. Furthermore, when comparing middle ignition to bottom ignition, the propagation speed of shock waves in these areas experienced a significant increase of 126.32 %, 124.39 %, 123.26 %, and 113.86 %, respectively. These research findings provide a theoretical foundation and empirical data to support the investigation and analysis of the causes of indoor gas explosion incidents.

BackgroundHypertension (HT) is a common chronic disease in older adults. It not only leads to dizziness and other symptoms affecting balance in older adults with HT but also affects the hemodynamics of the cerebral cortex. At present, potential neural mechanisms of balance control in older adults with HT are still unclear. Therefore, this study aimed to explore the differences in the center of pressure (COP) and cerebral cortex activation between older adults with HT and normotension (NT) during standing balance tasks. This study May provide guidance for the early detection of the risk of falls among older adults with HT and the development of clinical rehabilitation strategies.MethodsIn this cross-sectional study, 30 older adults with NT (NT group) and 27 older adults with HT (HT group) were subjected to three conditions: task 1, standing with eyes open on a stable surface; task 2, standing with eyes closed on a stable surface; and task 3, standing with eyes open on the surface of the foam pad. Cortical hemodynamic reactions were measured using functional near-infrared spectroscopy, and COP parameters were measured using a force plate.ResultsThe mean velocity of the COP in the medial–lateral direction in the NT group was significantly higher than that in the HT group (F = 5.955, p = 0.018) during task 3. When proprioception was disturbed, the activation of the left premotor cortex and supplementary motor cortex in the HT group was significantly lower than that in the NT group (F = 14.381, p

Abstract Background Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues. Methods To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids. Results The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation. Conclusions These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Silicon carbide (SiC) power modules play an essential role in the electric vehicle drive system. To improve their performance, reduce their size, and increase production efficiency, this paper proposes a multiple staked direct bonded copper (DBC) unit based power module packaging method to parallel more chips. This method utilizes mutual inductance cancellation effect to reduce parasitic inductance. Because the conduction area in the new package is doubled, the overall area of power module can be reduced. Entire power module is divided into smaller units to enhance manufacture yield, and improve design freedom. This paper provides a detailed design, analysis and fabrication procedure for the proposed package structure. Additionally, this paper offers several feasible solutions for the connection between power terminals and DBC untis. With the structure, 18 dies were paralleled for each phase-leg in a econodual size power module. Both simulation and double pulse test results demonstrate that, compared to conventional layouts, the proposed package method has 74.8% smaller parasitic inductance and 34.9% lower footprint.

High-performance Cu/Graphene composite wire synergistically strengthened by nano Cr 3 C 2 phase was directly synthesized via hot press sintering followed by severe cold plastic deformation, using liquid paraffin and CuCr alloy powder as the raw materials. Since graphene is in situ formed under the catalysis of copper powder during the sintering process, the problem that graphene is easy to agglomerate and difficult to disperse uniformly in the copper matrix has been solved. The nano Cr 3 C 2 -particles nailed at the interface favor to improve the interface bonding. The Cu/Graphene composite possesses high electrical conductivity, hardness, and plasticity. The composite wire exhibits high electrical conductivity of 96.93% IACS, great tensile strength of 488 MPa, and excellent resistance to softening. Even after annealing at 400°C for 1 h, the tensile strength can still reach 268 MPa with a conductivity of about 99.14% IACS. The wire's temperature coefficient of resistance (TCR) is largely reduced to 0.0035/°C due to the complex structure, which leads the wire to present low resistivity at higher temperatures. Such Cu/Graphene composite wire with excellent comprehensive performance has a good application prospect in high-power density motors.

Abstract Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.

The deep migration of soil nitrogen (N) poses a significant risk of N leaching, contributing to non-point-source pollution. This study examines the influence of microbial networks on the deep migration of chemical fertilizer N under varying irrigation management and multiple N fertilizer sources. A soil column experiment with eight treatments was conducted, utilizing 15N isotope labeling and metagenomic sequencing technology. The findings revealed that reduced irrigation significantly curbs the deep migration of chemical fertilizer N, and straw returning also mitigates this migration under conventional irrigation. Microbial network complexity and stability were markedly higher under reduced irrigation compared to conventional practices. Notably, network node count, average degree, and modularity exhibited significant negative correlations with the deep migration of chemical fertilizer N. The network topology indices, including node count, average clustering coefficient, average degree, modularity, and edge count, were found to be relatively more important for the deep migration of chemical fertilizer N. In conclusion, microbial networks play an important role in reducing the deep migration of chemical fertilizer N.

Spinal cord astrocytoma (SCA) is a rare subtype of astrocytoma, posing challenges in diagnosis and treatment. Low-grade SCA can achieve long-term survival solely through surgery, while high-grade has a disappointing prognosis even with comprehensive treatment. Diagnostic criteria and standard treatment of intracranial astrocytoma have shown obvious limitations in SCA. Research on the molecular mechanism in SCA is lagging far behind that on intracranial astrocytoma. In recent years, huge breakthroughs have been made in molecular pathology of astrocytoma, and novel techniques have emerged, including DNA methylation analysis and radiomics. These advances are now making it possible to provide a precise diagnosis and develop corresponding treatment strategies in SCA. Our aim is to review the current status of diagnosis and treatment of SCA, and summarize the latest research advancement, including tumor subtype, molecular characteristics, diagnostic technology, and potential therapy strategies, thus deepening our understanding of this uncommon tumor type and providing guidance for accurate diagnosis and treatment.

Background and Aims: Eosinophilic esophagitis (EoE) is associated with impaired health-related quality of life (HRQoL) and stigma perceptions. Therefore, we examined the real-world impact of EoE on the daily life and ability to function in adolescents (caregiver-reported) and adults with EoE in the United States of America in a noninterventional, cross-sectional, web-based survey. Methods: HRQoL was assessed using the Short Form Health Survey (domains: vitality and social functioning) and the European Health Interview Survey (domain: sleep). Scores for the survey responses were on a scale of 0 to 100; higher scores indicated better performance in the HRQoL domain. Anxiety and depression were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. Higher PROMIS scores indicated higher levels of anxiety and depression; a mean score of 50.0 was representative of the general population (individuals without EoE). The sources and impact of EoE-associated perceived stigma were also examined. Results: Overall, 211 caregivers and 184 adults completed the survey. HRQoL scores were slightly higher for adolescents than adults with EoE (adolescent and adult scores, respectively: vitality, 50.3 and 36.1; social functioning, 64.0 and 62.4; and sleep, 55.7 and 52.0). Anxiety scores (adolescent and adult scores, respectively: 54.8 and 59.7) and depression scores (54.5 and 56.3) were higher in those with EoE than in the general population. Most participants reported experiencing perceived stigma, which was most commonly from family, friends, classmates, or health-care professionals. Conclusion: Patients with EoE had poor HRQoL, which was demonstrated by the high EoE-associated emotional and psychological burdens and perceived stigma they experience.

Adaptive compliance control is critical for rehabilitation robots to cope with the varying rehabilitation needs and enhance training safety. This article presents a trajectory deformation-based multi-modal adaptive compliance control strategy (TD-MACCS) for a wearable lower limb rehabilitation robot (WLLRR), which includes a high-level trajectory planner and a low-level position controller. Dynamic motion primitives (DMPs) and a trajectory deformation algorithm (TDA) are integrated into the high-level trajectory planner, generating multi-joint synchronized desired trajectories through physical human-robot interaction (pHRI). In particular, the amplitude modulation factor of DMPs and the deformation factor of TDA are adapted by a multi-modal adaptive regulator, achieving smooth switching of human-dominant mode, robot-dominant mode, and soft-stop mode. Besides, a linear active disturbance rejection controller is designed as the low-level position controller. Four healthy participants and two stroke survivors are recruited to conduct robot-assisted walking experiments using the TD-MACCS. The results show that the TD-MACCS can smoothly switch three control modes while guaranteeing trajectory tracking accuracy. Moreover, we find that appropriately increasing the upper bound of the deformation factor can enhance the average walking speed (AWS) and root mean square of trajectory deviation (RMSTD).

Abstract Lung squamous cell carcinoma (LUSC) is the second most common lung cancer worldwide, leading to millions of deaths annually. Although immunotherapy has expanded the therapeutic choices for LUSC and achieved considerable efficacy in a subset of patients, many patients could not benefit, and resistance was pervasive. Therefore, it is significant to investigate the mechanisms leading to patients’ poor response to immunotherapies and explore novel therapeutic targets. Using multiple public LUSC datasets, we found that Kallikrein-8 (KLK8) expression was higher in tumor samples and was correlated with inferior survival. Using a LUSC cohort (n = 190) from our center, we validated the bioinformatic findings about KLK8 and identified high KLK8 expression as an independent risk factor for LUSC. Function enrichment showed that several immune signaling pathways were upregulated in the KLK8 low-expression group and downregulated in the KLK8 high-expression group. For patients with low KLK8 expression, they were with a more active TME, which was both observed in the TCGA database and immune marker immunohistochemistry, and they had extensive positive relations with immune cells with tumor-eliminating functions. This study identified KLK8 as a risk factor in LUSC and illustrated the associations between KLK8 and cancer immunity, suggesting the potentiality of KLK8 as a novel immune target in LUSC.

Objective To evaluate the impact of H3K27M mutation in the prognosis of histological high-grade intramedullary astrocytoma. Methods A total of 78 patients who were diagnosed with high-grade spinal cord astrocytoma were included. Clinical data consisting demographic, radiological, molecular features and treatment data were recorded. Univariate and multivariate Cox analysis were performed to investigate variables associated with survival outcome of histological high-grade spinal cord astrocytoma. Results Median survival time was 21 months. Overall survival (OS) at 1 and 3 years was 65.7% and 40.7%, respectively. Sex, location, and tumor span did not present significant association with OS. Patients with H3K27M mutation showed significant shorter duration of symptom than patients with H3K27 wild-type. As respect to adjuvant treatment, adjuvant radiotherapy and chemotherapy were associated with favorable OS (both p = 0.01). Younger patients (age ≤ 18 years) had shorter OS (p = 0.008) than adult patients (age > 18 years). Of note, H3K27M mutation did not show significant impact on the survival outcome, regardless of histology grade 3 or grade 4 (p = 0.3). Conclusion Histological high-grade spinal cord astrocytoma has dismal prognosis. Our study demonstrated that H3K27M mutation did not show significant impact on survival outcome of histological high-grade spinal cord astrocytoma.