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Abstract The skin epidermis is continually influenced by a myriad of internal and external elements. At its basal layer reside epidermal stem cells, which fuels epidermal renovation and hair regeneration with powerful self-renewal ability, as well as keeping diverse signals that direct their activity under surveillance with quick response. The importance of epidermal stem cells in wound healing and immune-related skin conditions has been increasingly recognized, and their potential for clinical applications is attracting attention. In this review, we delve into recent advancements and the various physiological and psychological factors that govern distinct epidermal stem cell populations, including psychological stress, mechanical forces, chronic aging, and circadian rhythm, as well as providing an overview of current methodological approaches. Furthermore, we discuss the pathogenic role of epidermal stem cells in immune-related skin disorders and their potential clinical applications.

Abstract Roughness or texture endow the solid surface with the ability of some particular property of water repellency that has been employed in a variety of practical applications, including self-cleaning, icing-resistant, and so forth. However, the understanding of the dynamic evolution of impacting binary droplets on rough surfaces is not satisfactory, especially at the nanoscale. In this work, we investigate the impact process of the binary droplet system, a suspending droplet impacts a sessile one deposited on hydrophobic textured surfaces, via molecular dynamics (MD) simulations. Dynamic evolutions from MD simulations under various impact conditions are discussed, including coalescence, spreading, retraction and vibration, and bouncing. The free energy variation during the impacting process is calculated to reveal the mechanisms behind the impact dynamics. The effect of the surface texture on the spreading and retraction is investigated, and the corresponding maximum spreading diameter is also discussed. Finally, we investigate the effect of the surface texture on bouncing behavior, which is found to promote the droplet bouncing at low We range but suppress the bouncing behavior at high We range.

Abstract In the mechanical cutting industry, trial production is used for predicting and evaluating the quality of product processes before batch production, and it can be expressed through the qualification rate. However, it cannot objectively and comprehensively evaluate the quality of product processes. This study optimizes the analysis of outliers and stability in mathematical statistics to better apply it in the mechanical cutting industry; then, it combines them with process capability analysis. Simultaneously, considering the non-normal distribution of process parameters, a batch production-prediction model is proposed. The reliability of batch production-prediction model is verified by the diameter, roundness and roughness of structural common samples. Meanwhile, for other mechanical parts in the mechanical cutting industry, the model proposed in this paper can be used to quickly and accurately predict and evaluate batch production.

Abstract Background Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), which accounts for approximately one-fifth of all BCs, are highly invasive with a high rate of recurrence and a poor prognosis. Several studies have shown that growth factor receptor-bound protein 7 (GRB7) might be a potential therapeutic target for tumor diagnosis and prognosis. Nevertheless, the role of GRB7 in HER2+ BC and its underlying mechanisms have not been fully elucidated. The aim of this study was to investigate the biological function and regulatory mechanism of GRB7 in HER2+ BC. Methods Bioinformatics analysis was performed using the TCGA, GEO and CancerSEA databases to evaluate the clinical significance of GRB7. RT quantitative PCR, western blot and immunofluorescence were conducted to assess the expression of GRB7 in BC cell lines and tissues. MTT, EdU, colony formation, wound healing, transwell, and xenograft assays were adopted to explore the biological function of GRB7 in HER2+ BC. RNA sequencing was performed to analyze the signaling pathways associated with GRB7 in SK-BR-3 cells after the cells were transfected with GRB7 siRNA. Chromatin immunoprecipitation analysis (ChIP) and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of GRB7 in HER2+ BC. Results GRB7 was markedly upregulated and associated with poor prognosis in BC, especially in HER2+ BC. Overexpression of GRB7 increased the proliferation, migration, invasion, and colony formation of HER2+ BC cells, while depletion of GRB7 had the opposite effects in HER2+ BC cells and inhibited xenograft growth. ChIP-PCR and luciferase reporter assay revealed that TCF12 directly bound to the promoter of the GRB7 gene to promote its transcription. GRB7 facilitated HER2+ BC epithelial-mesenchymal transition (EMT) progression by interacting with Notch1 to activate Wnt/β-catenin pathways and other signaling (i.e., AKT, ERK). Moreover, forced GRB7 overexpression activated Wnt/β-catenin to promote EMT progression, and partially rescued the inhibition of HER2+ BC proliferation, migration and invasion induced by TCF12 silencing. Conclusions Our work elucidates the oncogenic role of GRB7 in HER2+ BC, which could serve as a prognostic indicator and promising therapeutic target.

Abstract Visceral adiposity index (VAI) is a reliable indicator of visceral adiposity. However, no stu-dies have evaluated the association between VAI and DKD in US adults with diabetes. Theref-ore, this study aimed to explore the relationship between them and whether VAI is a good pr-edictor of DKD in US adults with diabetes. Our cross-sectional study included 2508 participan-ts with diabetes who were eligible for the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Univariate and multivariate logistic regression were used to an-alyze the association between VAI level and DKD. Three models were used to control for pot-ential confounding factors, and subgroup analysis was performed for further verification. A tot-al of 2508 diabetic patients were enrolled, of whom 945 (37.68%) were diagnosed with DKD. Overall, the VAI was 3.36 ± 0.18 in the DKD group and 2.76 ± 0.11 in the control group. VAI was positively correlated with DKD (OR = 1.050, 95% CI 1.049, 1.050) after fully adjusting for co-nfounding factors. Compared with participants in the lowest tertile of VAI, participants in the highest tertile of VAI had a significantly increased risk of DKD by 35.9% (OR = 1.359, 95% CI 1.355, 1.362). Through subgroup analysis, we found that VAI was positively correlated with the occurrence of DKD in all age subgroups, male(OR = 1.043, 95% CI 1.010, 1.080), participants wit-hout cardiovascular disease(OR = 1.038, 95% CI 1.011, 1.069), hypertension (OR = 1.054, 95% CI 1.021, 1.090), unmarried participants (OR = 1.153, 95% CI 1.036, 1.294), PIR

Abstract The traceability of groundwater nitrate pollution is crucial for controlling and managing polluted groundwater. This study integrates hydrochemistry, nitrate isotope (δ15N-NO3 − and δ18O-NO3 −), and self-organizing map (SOM) and end-member mixing (EMMTE) models to identify the sources and quantify the contributions of nitrate pollution to groundwater in an intensive agricultural region in the Sha River Basin in southwestern Henan Province. The results indicate that the NO3 −-N concentration in 74% (n = 39) of the groundwater samples exceeded the WHO standard of 10 mg/L. According to the results of EMMTE modeling, soil nitrogen (68.4%) was the main source of nitrate in Cluster-1, followed by manure and sewage (16.5%), chemical fertilizer (11.9%) and atmospheric deposition (3.3%). In Cluster-2, soil nitrogen (60.1%) was the main source of nitrate, with a significant increase in the contribution of manure and sewage (35.5%). The considerable contributions of soil nitrogen may be attributed to the high nitrogen fertilizer usage that accumulated in the soil in this traditional agricultural area. Moreover, it is apparent that most Cluster-2 sampling sites with high contributions of manure and sewage are located around residential land. Therefore, the arbitrary discharge and leaching of domestic sewage may be responsible for these results. Therefore, this study provides useful assistance for the continuous management and pollution control of groundwater in the Sha River Basin.

Abstract. Background:. Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection on psoriasis patients. The objective of this study was to identify clinical factors associated with the prognosis of psoriasis following SARS-CoV-2 infection. Methods:. A retrospective, multicenter study was conducted between March and May 2023. Univariable and multivariable logistic regression analyses were employed to identify factors associated with coronavirus disease 2019 (COVID-19)-related psoriasis outcomes. The study included 2371 psoriasis patients from 12 clinical centers, with 2049 of them having been infected with SARS-CoV-2. Results:. Among the infected groups, lower exacerbation rates were observed in individuals treated with biologics compared to those receiving traditional systemic or nonsystemic treatments (22.3% [236/1058] vs. 39.8% [92/231] vs. 37.5% [140/373], P

Abstract The early diagnosis and treatment of foreign body aspiration (FBA) can significantly improve the overall prognosis of children. There are significant differences in the epidemiology and clinical characteristics of FBA in different regions. Therefore, we conducted a real-world study in the western region of China with over 4000 patients. The aim of this study was to improve the understanding of FBA in terms of its types, the specific months of its occurrence, and the distribution of primary caregiver characteristics in western China. We collected the clinical and epidemiological data of children who were diagnosed with FBA in our hospital over the past 20 years through a big data centre. We matched the data of healthy children who underwent routine physical examinations at the paediatric health clinic during the same period to analyse the differences in the data of actual guardians. A total of 4227 patients from five provinces were included in this study. Foreign bodies were removed by rigid bronchoscopy in 99.4% (4202/4227) of patients, with a median age of 19 months and a median surgical duration 16 min. January was the most common month of onset for 1725 patients, followed by February, with 1027 patients. The most common types of foreign objects were melon peanuts, seeds and walnuts, accounting for 47.2%, 15.3%, and 10.2%, respectively. In the FBA group, the proportion of grandparents who were primary caregivers was 70.33% (2973/4227), which was significantly greater than the 63.05% in the healthy group (2665/4227) (P

Abstract CD8+ T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8+ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8+ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8+ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8+ T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8+ T cells. Intriguingly, inhibition of ADAM17 in CD8+ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8+ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

Abstract Objective Our study aimed to determine whether there exists an association between low-grade systemic inflammation, as measured by serum C-reactive protein (CRP), and the risk of lower-extremity deep venous thrombosis (LEDVT) in patients with primary intracerebral hemorrhage (ICH). Methods This observational study was retrospectively conducted on patients with primary ICH who were presented to two tertiary medical centers between January 2021 and August 2022. The primary outcome was detecting LEDVT occurrence within 14 days from the onset of the acute ICH episode. Weighted logistic regression and restricted cubic spline models were employed to estimate the association between CRP and LEDVT following 1:1 propensity score matching (PSM). Results Of the 538 patients with primary ICH who met the inclusion criteria, 76 (14.13%) experienced LEDVT. Based on the cut-off levels of CRP measured upon admission from the receiver operating characteristic (ROC) curve, patients with primary ICH were categorized into two groups: (i) CRP

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbated IFN-I response and cytokine storm are related to the mortality of patients with SFTS. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that can block proinflammatory cytokines and inhibit the type I IFN pathway. We aimed to explore the use of ruxolitinib plus standard of care for severe SFTS. Methods We conducted a prospective, single-arm study of severe SFTS. We recruited participants aged 18 years or older who were admitted to the hospital with laboratory-confirmed severe SFTS and whose clinical score exceeded 8 points within 6 days of symptom onset. Participants received oral ruxolitinib (10 mg twice a day) for up to 10 days. The primary endpoint was 28-day overall survival. The secondary endpoints included the proportion of participants who needed intensive care unit (ICU) admission, total cost, changes in neurologic symptoms and clinical laboratory parameters, and adverse events (AEs) within 28 days. A historical control group (HC group, n = 26) who met the upper criteria for inclusion and hospitalized from April 1, 2021, to September 16, 2022, was selected and 1:1 matched for baseline characteristics by propensity score matching. Results Between Sep 16, 2022, and Sep 16, 2023, 26 participants were recruited into the ruxolitinib treatment group (RUX group). The 28-day overall mortality was 7.7% in the RUX group and 46.2% in the HC group (P = 0.0017). There was a significantly lower proportion of ICU admissions (15.4% vs 65.4%, p

Abstract. Background:. There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. Methods:. In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. Results:. At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P

Abstract This study aims to establish a rapid diagnostic method for Streptococcus agalactiae (GBS) based on recombinase polymerase amplification (RPA) and lateral flow strips (LFS). The best primer pairs designed by SIP gene were screened according to the basic RPA reaction, then the probe was designed. The reaction condition was optimized based on the color development of the LFS detection line. To ascertain the reaction specificity, 10 common clinical pathogens and 10 clinical specimens of GBS were tested. Furthermore, the reaction sensitivity was assessed by utilizing a tenfold gradient dilution of GBS genomic DNA as templates. RPA–LFS method was compared to the qPCR assay and biochemical culture method for the Kappa consistency test. The RPA–LFS technique was able to complete the amplification process within 30 min and the results were observed on lateral flow strips. The method is highly sensitive, with a minimum detection limit of 1.31 ng for GBS. The RPA–LFS method showed consistent accuracy of results compared to qPCR and the culture–biochemical method. The establishment of this method is conducive to the development of on-site immediate detection, which can provide information for the timely development of a reasonable antimicrobial treatment plan, and has a greater potential for clinical application.

Abstract The joints are existing throughout the underground rock mass. It is of great significance to investigate the shear performance of the rock mass to maintain the stability of the underground structure. In this study, we conducted orthogonal tests to determine the proportion of rock-like materials, and used JRC curves to make specimen molds and then prepare the specimens. We conducted straight shear tests and uniaxial compression tests to determine the various mechanical parameters of the rock-like materials. Next, we carried out the compression and shear tests to investigate the shear characteristics of the specimens, and study the damage pattern and shear strength of the jointed rock mass under different confining pressures and roughness levels. The mesoscopic displacements in the shear process of joints were analyzed by using ABAQUS. The test results show that the effect of the confining pressure on the shear strength of the joint plane is relatively obvious, and a larger confining pressure indicates a larger shear strength. The effects of different joint plane roughness and shear rated on the shear characteristics of the joint plane are also significant. The mesoscopic displacement difference inside the joint plane with higher roughness is relatively large, and the stress concentration phenomenon is obvious and lasts longer, which leads to the faster destruction of the specimen with higher roughness and the higher destruction degree. Therefore, we suggest that the priority should be given to the reinforcement of jointed rock mass with high roughness during the construction to prevent sudden destabilization and failure.

Background The role of phytoestrogens in asthma/wheeze and lung function remains controversial. Thus, we aimed to examine whether phytoestrogens have beneficial effects on asthma/wheeze, lung function for subgroups and mortality.Methods Participants in this study were individuals aged 20 years or older from the National Health and Nutrition Examination Survey. Multivariate logistic regression models were fitted to examine the associations of urinary phytoestrogens with the risk of asthma/wheeze and lung function in individuals with and without asthma/wheeze. Cox proportional hazards regression was used to examine the relationship between urinary phytoestrogens and all-cause mortality. Stratified analyses were conducted based on gender and smoking status.Results We included 2465 individuals in this study. Enterolactone levels in the highest quartile were associated with a lower risk of asthma than those in the lowest quartile. As compared with the lowest quartile, the highest quartile of enterodiol and enterolactone was associated with a lower risk of wheeze. Significant associations were observed between subtypes of phytoestrogens (equol and enterolactone) and lung function (forced vital capacity (FVC) and forced expiratory volume in 1 s). Besides, FVC was higher in individuals with higher levels of enterodiol. The results were consistent in subpopulations without asthma/wheeze, while the significant difference was not observed in individuals with asthma/wheeze. The stratified analyses revealed that the associations between phytoestrogens and lung function differed by gender and smoking status among subgroups. No significant association was found between urinary phytoestrogens and all-cause mortality.Conclusion In summary, subtypes of phytoestrogens were associated with lower risk of asthma/wheeze and beneficial for lung function improvement in individuals without asthma/wheeze. Furthermore, gender and smoking may interact in the relationship between phytoestrogens and asthma/wheeze, and lung function. Further researches are needed to confirm these associations and explain the results of stratified analyses.

Abstract The conservative treatment for Kohler's disease will take several months, but some patients still have flatfoot and persistent pain. From October 2013 to July 2015, 3 children with Kohler's disease underwent navicular decompression and micro-circulation reconstruction surgery in our hospital. All the patients have received conservative treatment for more than 3 months and the effect was poor. X-ray showed the bone density of navicular increased significantly. All patients were followed up over 1 year. The 3 patients recovered well. VAS score decreased from 7.0 to 2.6 at 1 month after the operation. The pain symptom disappeared completely on 3 months after surgery. The density of navicular bone recovered to normal. Navicular decompression and micro-circulation reconstruction surgery may quickly improve the ischemic status of navicular bone, alleviate pain symptom and enable patients to resume normal activity as soon as possible.

Abstract Background While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated. Methods We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P

Abstract To quickly determine the blasting block degree and conduct an accurate and objective analysis of the tunnel blasting effect, this study has enhanced and improved upon the traditional genetic algorithm and Otsu algorithm. It has combined it with the marking watershed method and utilized ground digital acquisition to capture images of blasting debris. These images are then used in our custom-developed blasting analysis software to calculate the blasting block degree distribution and provide a quantitative analysis of blasting block degree. The research results show that the optimized image segmentation algorithm effectively improves the traditional threshold segmentation method on the poor effect of segmentation of the edge of the adherent block or the direct application of the watershed segmentation of the over-segmentation problem, to improve the segmentation accuracy based on the new segmentation technology is close to the traditional technology in terms of time. Through the self-developed software, the construction personnel in the project site to quickly obtain the blasting block degree histogram, block degree cumulative curve and other important indicators of the evaluation of the effect of blasting block degree, to provide data support for on-site construction, to assist in the modification of the blasting program, and to improve the efficiency of construction. This study realizes the rapid detection and block identification of blasting blocks, provides data support for the optimization of blasting parameters, and has good application and promotion value.

Abstract Urban economic development, congestion relief, and traffic efficiency are all greatly impacted by the thoughtful planning of urban metro station layout. with the urban area of Lanzhou as an example, the suitability of the station locations of the built metro stations of the rail transit lines 1 and 2 in the study area have been evaluated using multi-source heterogeneous spatial data through data collection, feature matrix construction, the use of random forest and K-fold cross-validation, among other methods. The average Gini reduction value was used to examine the contribution rate of each feature indicator based on the examination of model truthfulness. According to the study's findings: (1) K-fold cross-validation was applied to test the random forest model that was built using the built metro stations and particular factors. The average accuracy of the tests and out-of-bag data (OOB) of tenfold cross-validation were 89.62% and 91.285%, respectively. Additionally, the AUC area under the ROC curve was 0.9823, indicating that this time, from the perspective of the natural environment, traffic location, and social factors The 19 elements selected from the views of the urban function structure, social economics, and natural environment are closely associated to the locations of the metro station in the research region, and the prediction the findings are more reliable; (2) It becomes apparent that more than half of the built station sites display excellent agreement with the predicted sites in terms of geographical location by superimposing the built metro station sites with the prediction results and tally up their cumulative prediction probability values within the 300 m buffering zone; (3) Based on the contribution rate of each indicator to the model, transport facilities, companies, population density, night lighting, science, education and culture, residential communities, and road network density are identified as the primary influential factors, each accounting for over 6.6%. Subsequently, land use, elevation, and slope are found to have relatively lower contributions. The results of the research provided important information for the local metro's best location selection and planning.

Abstract Water from hydraulic technology affects the desorption of gas from coal seams. Gas desorption behavior is critical information for gas control in coal mines. In this study, a designed coal seam water injection simulation experimental device was utilized to conduct dynamic water injection experiments on coal samples at different adsorption equilibrium pressures, analyzing the gas desorption law under dynamic water injection, as well as the role of water replacement, water imbibition and water blockage in gas desorption. The results showed that water altered the gas desorption rate in coal, causing fluctuating attenuation of the desorption rate of a water-injected coal sample (WCS). Under the same adsorption equilibrium pressure, the relationship between the desorption rate of the WCS and the non-water-injected coal samples (NCS) underwent a transition in desorption time. In contrast to the NCS desorption curves, the WCS desorption curves lacked a rapid growth phase and exhibited only a slow growth phase and a stopping phase. Water imbibition and water replacement promoted the desorption of gas in the non-wet area during the water injection process, while it inhibited the desorption of gas in the wet area. Under the effects of water imbibition, water blockage, and water replacement, the discharge rate of WCS is greater than the desorption rate of NCS, indicating that water injection increases the total amount of gas desorption. The study results have significant implications for gas extraction and the prevention and control of coal and gas outbursts.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. Methods Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. Results Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. Conclusions Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.

Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.

We aimed to investigate the species composition of a small mammal community and the prevalence of Echinococcus spp. in a typical endemic area of the Tibetan Plateau. One pika and five rodent species were identified based on the morphological characteristics of 1278 small mammal specimens collected during 2014–2019. Detection of Echinococcus DNA in tissue samples from small mammal specimens revealed that Ochotona curzoniae (pika, total prevalence: 6.02%, 26/432), Neodon fuscus (5.91%, 38/643), N. leucurus (2.50%, 3/120), and Alexandromys limnophilus (21.74%, 10/46) were infected by both E. multilocularis and E. shiquicus; Cricetulus longicaudatus (16.67%, 1/6) was infected by E. shiquicus; and no infection was detected in N. irene (0/15). Neodon fuscus and O. curzoniae were the two most abundant small mammal species. There was no significant difference in the prevalence of pika and the overall rodent species assemblage (6.26%, 53/846); however, the larger rodent populations suggested that more attention should be paid to their role in the transmission of echinococcosis in the wildlife reservoir, which has long been underestimated. Moreover, although DNA barcoding provides a more efficient method than traditional morphological methods for identifying large numbers of small mammal samples, commonly used barcodes failed to distinguish the three Neodon species in this study. The close genetic relationships between these species suggest the need to develop more powerful molecular taxonomic tools.

Objectives This study aims to present the clinical characteristics of young patients with bladder cancer (YBCa), evaluate related risk factors and construct a nomogram based on data acquired from the Surveillance, Epidemiology, and End Results (SEER) Database.Design Retrospective analysis of the SEER Database (2004–2015) for primary YBCa.Setting and participants Data for YBCa (defined as those aged 40 years or younger) were extracted from the SEER Database, which covers approximately 28% of the US population, using the SEER*Stat software (V.8.4.0.1). A total of 1233 YBCa were identified. Patients were randomly assigned to the training and validation sets. The database included clinicopathological features, demographic information and survival outcomes, such as age, gender, race, year of diagnosis, marital status at diagnosis, primary tumour site, histological type, tumour grade, tumour, node, metastases (TNM) staging, treatment regimen for the primary tumour, cause of death and survival time. A nomogram model was developed using univariate and multivariate analyses. The prediction model was validated using the consistency index (C-index), calibration curve and receiver operating characteristic curve.Primary outcome measures 3-year, 5-year and 10-year overall survival (OS).Results 1233 YBCa from 2004 to 2015 were randomly assigned to the training set (n=865) and validation set (n=368). Age, marital status, tumour grade, histological type and TNM staging were included in the nomogram. The C-index of the model was 0.876. The 3-year, 5-year and 10-year OS area under the curve values for the training and validation sets were 0.949, 0.923 and 0.856, and 0.919, 0.890 and 0.904, respectively. Calibration plots showed that the nomogram had a robust predictive accuracy.Conclusions To our knowledge, this is the first study to establish a precise nomogram predicting the 3-year, 5-year and 10-year OS in YBCa based on multivariate analyses. Our nomogram may serve as a valuable reference for future diagnostics and individualised treatments for YBCa. However, external validation is warranted to assess the accuracy and generalisability of our prognostic model.

Background Moderate-to-late preterm birth (32 to

Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still required. In this study, 1,852 differentially expressed genes (DEGs) were identified in the GSE45001 dataset for weighted gene co-expression network analysis (WGCNA), and the turquoise module was confirmed as the key module. Next, the subnetworks of the 1,009 genes in the turquoise module analyzed by MCODE, MCC, and BottleNeck algorithms identified nine overlapping genes (CAT, APOA1, APOC2, HSD17B4, EHHADH, APOA2, APOE4, ACOX1, AGXT), significantly associated with lipid metabolism pathways, such as peroxisome and cholesterol metabolism. Among them, APOE4 exhibited a potential tumor-suppressive role in ICC and high diagnostic value for ICC in both GSE45001 and GSE32879 datasets. In vitro experiments demonstrated Apolipoprotein E4 (APOE4) overexpression suppressed ICC cell proliferation, migration, and invasion, knockdown was the opposite trend. And in ICC modulated lipid metabolism, notably decreasing levels of TG, LDL-C, and HDL-C, while concurrently increasing the expressions of TC. Further, APOE4 also downregulated lipid metabolism-related genes, suggesting a key regulatory role in maintaining cellular homeostasis, and regulating the expression of the membrane protein ATP-binding cassette transporter A1 (ABCA1). These findings highlighted the coordinated regulation of lipid metabolism by APOE4 and ABCA1 in ICC progression, providing new insights into ICC mechanisms and potential therapeutic strategies.

Abstract T cell leukemia homeobox 2 (TLX2) plays an important role in some tumors. Bioinformatics and experimental validation represent a useful way to explore the mechanisms and functions of TLX2 gene in the cancer disease process from a pan cancer perspective. TLX2 was aberrantly expressed in pan cancer and cell lines and correlated with clinical stage. High TLX2 expression was significantly associated with poor overall survival in COAD, KIRC, OC, and UCS. The greatest frequency of TLX2 alterations in pan cancer was amplification. Alterations of NXF2B, MSLNL, PCGF1, INO80B-WBP1, LBX2-AS1, MRPL53, LBX2, TTC31, WDR54, and WBP1 co-occurred in the TLX2 alteration group. PFS was significantly shorter in the TLX2-altered group (n = 6) compared to the TLX2-unaltered group (n = 400). Methylation levels of TLX2 were high in 17 tumors. TLX2 expression was associated with MSI in seven tumors and TMB in five tumors. TLX2 expression was associated with immune infiltration and immune checkpoint genes. TLX2 may be associated with some pathways and chemoresistance. We constructed a possible competing endogenous RNA (ceRNA) network of LINC01010/miR-146a-5p/TLX2 in OC. TLX2 expression was significantly upregulated in ovarian cancer cell lines compared to ovarian epithelial cell lines. Aberrant expression of TLX2 in pan cancer may promote tumorigenesis and progression through different mechanisms. TLX2 may represent an important therapeutic target for human cancers.

Abstract Indoor testing are performed to explore the charge induction law during the uniaxial compression fracture process of coal samples, and the charge time and frequency domain signals of coal samples with different primary fissures are analyzed in the paper. On-site monitoring of charge in different fissures distribution areas of underground coal tunnels, and the charge signals of different drillingdepths in coal seams are analyzed. The results show that the uniaxial compressive strength and elastic modulus of multi-fissured coal samples are less than those of less fissured coal samples, and the Poisson’s ratio is greater than those of less fissured coal samples. The charge induction signal intensity during the fracture process of multi-fissured coal samples is relatively low, but it is concentrated at the low frequency of 0–50 Hz in the compacting elasticity stage. The charge signal intensity during the fracture process of coal samples with less fissure is relatively high, and the charge frequency during the reinforcement damage stage is concentrated at a low frequency of 0–50 Hz. Therefore, the sudden appearance of low-frequency charge signals is more suitable as effective precursor information for the instability and failure of less fissured coal bodies. The average charge intensity is small in the multi-fissured area with a drilling depth of 1–4 m in the coal seam, and the average charge intensity of the coal body with less fissures is larger in the 5–12 m region. The on-site charge monitoring results have good consistency with the indoor test results. This study has guiding significance in setting up a charge monitoring warning index of instability failure in different coal body fissures regions.

The highly pathogenic coronaviruses SARS-CoV-2 and SARS-CoV have led to the COVID-19 pandemic and SARS outbreak, respectively. The receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2, particularly the Omicron variant, has frequent mutations, resulting in the reduced efficiency of current COVID-19 vaccines against new variants. Here, we designed two lipid nanoparticle-encapsulated mRNA vaccines by deleting the mutant RBD of the SARS-CoV-2 Omicron variant (SARS2-S (RBD-del)) or by replacing this mutant RBD with the conserved and potent RBD of SARS-CoV (SARS2-S (SARS-RBD)). Both mRNA vaccines were stable at various temperatures for different time periods. Unlike SARS2-S (RBD-del) mRNA, SARS2-S (SARS-RBD) mRNA elicited effective T-cell responses and potent antibodies specific to both SARS-CoV-2 S and SARS-CoV RBD proteins. It induced strong neutralizing antibodies against pseudotyped SARS-CoV-2 and SARS-CoV infections and protected immunized mice from the challenge of the SARS-CoV-2 Omicron variant and SARS-CoV by significantly reducing the viral titers in the lungs after Omicron challenge and by completely preventing SARS-CoV-induced weight loss and death. SARS2-S (SARS-RBD)-immunized serum antibodies protected naïve mice from the SARS-CoV challenge, with its protective efficacy positively correlating with the neutralizing antibody titers. These findings indicate that this mRNA vaccine has the potential for development as an effective vaccine against current and future SARS-CoV-2 variants and SARS-CoV.

Herbal medicines are widely used for clinical purposes worldwide. These herbs are susceptible to phytopathogenic fungal invasion during the culturing, harvesting, storage, and processing stages. The threat of fungal and mycotoxin contamination requires the evaluation of the health risks associated with these herbal medicines. In this study, we collected 138 samples of 23 commonly used herbs from 20 regions in China, from which we isolated a total of 200 phytopathogenic fungi. Through morphological observation and ITS sequencing, 173 fungal isolates were identified and classified into 24 genera, of which the predominant genera were Fusarium (27.74%) and Alternaria (20.81%), followed by Epicoccum (11.56%), Nigrospora (7.51%), and Trichocladium (6.84%). Quantitative analysis of the abundance of both Fusarium and Alternaria in herbal medicines via RT-qPCR revealed that the most abundant fungi were found on the herb Taraxacum mongolicum, reaching 300,000 copies/μL for Fusarium and 700 copies/μL for Alternaria. The in vitro mycotoxin productivities of the isolated Fusarium and Alternaria strains were evaluated by using liquid chromatography–tandem mass spectrometry (LC-MS/MS), and it was found that the Fusarium species mainly produced the acetyl forms of deoxynivalenol, while Alternaria species mainly produced altertoxins. These findings revealed widely distributed fungal contamination in herbal medicines and thus raise concerns for the sake of the quality and safety of herbal medicines.

Abstract Objective Early intervention with neutralizing antibodies is considered to be effective in preventing disease progression in patients with mild to moderate COVID-19 infection. Elderly patients are the most susceptible and at a higher risk of COVID-19 infection. The present study aimed to assess the necessity and possible clinical benefits of the early administration of Amubarvimab/Romlusevimab (BRII-196/198) in the elderly population. Methods The present study was designed as a retrospective, multi-center cohort study conducted with 90 COVID-19 patients aged over 60, who were divided into two groups based on the timing of the administration of BRII-196/198 (administration at ≤ 3 days or > 3 days from the onset of infection symptoms). Results The ≤ 3 days group exhibited a greater positive effect (HR 5.94, 95% CI, 1.42–24.83; P 3 days group who exhibited disease progression. The multivariate Cox regression analysis revealed low flow oxygen support prior to BRII-196/198 administration (HR 3.53, 95% CI 1.42–8.77, P

Background Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown. Methods Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations. Results In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47–3.30). Conclusion Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing.

Objective(s): To explore the ability and underlying molecular mechanisms involved in the protective effects of Baicalin (BA) against L-Glutamate-induced mouse hippocampal neuron cell line HT-22.Materials and Methods: The cell injury model of HT-22 cells was induced by L-glutamate, and cell viability and damage were detected by CCK-8 and LDH assays. Generation of intracellular reactive oxygen species (ROS) was measured by DCFH-DA in situ fluorescence method. The SOD activity and MDA concentration in the supernatants were determined by WST-8 and colorimetric method, respectively. Furthermore, Western blot and real-time qPCR analysis were utilized to detect the expression levels of the Nrf2/HO-1 signaling pathway and NLRP3 inflammasome proteins and genes.Results: L-Glutamate exposure induced cell injuries in HT-22 cells, and the concentration of 5 mM L-Glutamate was chosen to be the modeling condition. Co-treatment with BA significantly promoted cell viability and reduced LDH release in a dose-dependent manner. In addition, BA attenuated the L-Glutamate-induced injuries by decreasing the ROS production and MDA concentration, while increasing the SOD activity. Moreover, we also found that BA treatment up-regulated the gene and protein expression of Nrf2 and HO-1, and then inhibited the expression of NLRP3.Conclusion: Our study found that BA could relieve oxidative stress damage of HT-22 cells induced by L-Glutamate, and the mechanism might be related to the activation of Nrf2/HO-1 and inhibition of NLRP3 inflammasome.

Non-coding RNAs: Modification by adding methyl groups The reversible addition of a chemical methyl group (CH3) to the base adenine in RNA molecules, creating N6-methyladenosine, regulates the activity of many non-coding RNAs that, unlike messenger RNAs, do not code for the formation of proteins. These RNAs can regulate gene activity. Researchers in China led by Gang Wang at Harbin Medical University, and Qiushi Tang at the Chinese Medical University, Liaoning, review the molecular mechanisms and significance of ‘m6A modification’ of non-coding RNAs. They focus on the progress of research into the role of m6A modification in cancer and its potential relevance for diagnosis and treatment. Approaches to treating cancer by interfering with m6A modification have been explored in mice. Future research will aim to translate the promise of these early animal studies into tests in human cells and clinical trials in patients.

Abstract Patients with severe fever with thrombocytopenia syndrome (SFTS) had been confirmed to have immune dysfunction and were prone to invasive pulmonary aspergillosis (IPA), which was directly related to the increased mortality. The aim of this study was to investigate the predictors for IPA in SFTS patients, and the results were expected to be helpful for early identification of IPA and initiation of anti-fungal therapy. The study was performed to review laboratory confirmed SFTS patients in two tertiary hospitals in Shandong province (Qilu Hospital of Shandong University and Shandong Public Health Clinical Center) from April 2021 to August 2022. The enrolled patients were further divided into IPA group and non-IPA group. Demographic characteristics, clinical manifestations and laboratory parameters between IPA group and non-IPA group patients were analyzed and compared to identify the independent predictors for IPA by univariate analysis and multivariable logistic regression analysis. Sensitivity and specificity of independent predictors were evaluated by receiver operating characteristic (ROC) curve analysis. In total, 67 SFTS patients were enrolled with an average age of 64.7 (± 8.4) years old. The incidence of IPA was 32.8% (22/67). Mortality of patients in IPA group was 27.3% (6/22), which was significantly higher than that in non-IPA group. Results of univariate analysis showed that uncontrolled diabetes, central nervous system symptoms, platelet

Abstract The tailings pond is a dangerous source of man-made debris flow with high potential energy. The oxidative acidification of tailings may cause the instability of the pond and induce serious safety accidents. The influence of oxidation and acidification degree on macro mechanical properties of tailings is discussed from the aspects of mineral composition and microstructure. The results show that as the degree of oxidation and acidification of tailings sand increases, the overall structural performance and load-bearing capacity decrease, and its cohesion (c) and internal friction angle (φ) show a decreasing trend. In fact, the engineering properties of tailings with different oxidation and acidification degrees are dominated by the physicochemical composition and structural characteristics. On the one hand, as the degree of oxidation increases, acidic substance will neutralize with CaCO3 and CaMg(CO3)2, resulting in the loss of cemented substance and the decrease of cementation force between tailing sand particles as well as the gradual destruction of the integrity of tailing sand. On the other hand, the increase of oxidation and acidification degree of tailing sand leads to a gradual reduction of outline (2D) fractal dimension and gray surface (3D) fractal dimension of surface laminated structure as well as the obvious reduction of laminated structure and its roughness of tailings sand.

Abstract Heatwaves have afflicted human health, ecosystem, and socioeconomy and are expected to intensify under warming climate. However, few efforts have been directed to moist heat stress (MHS) considering relative humidity and wind speed, and moist heat stress risk (MHSR) considering exposure and vulnerability. Here we showed MHS and MHSR variations across China during 1998–2100 using China Meteorological Administration Land Data Assimilation System datasets, the 6th Coupled Model Intercomparison Project (CMIP6) merged datasets, Gross Domestic Product, population and leaf area index. We detected increased MHS across China under different Shared Socioeconomic Pathways (SSPs). Specifically, the historical MHS occurred mostly during mid-July to mid-August. We found increasing trends of 0.08%/year, 0.249%/year, and 0.669%/year in the MHS-affected areas under SSP126, SSP245, and SSP585, respectively. Furthermore, we observed the highest increasing rate of MHSR in Northwest and Southwest China, while the MHSR across Northeast and North China under SSP126 shifted from increasing to decreasing trends. Noteworthy is that the increasing trend of MHSR under SSP585 is 1.5–2.6 times larger than that under SSP245, especially in North and South China. This study highlights spatiotemporal evolutions of MHS and MHSR and mitigation to moisture heat stress in a warming climate.

Abstract Background Language deficits frequently occur during the prodromal stages of Alzheimer’s disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. Methods The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. Results In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P

Abstract Background As a key process in transcriptional regulatory mechanisms, alternative splicing (AS) plays a crucial role in maintaining the diversity of RNA and protein expression, and mediates the immune response in infectious diseases, especially for the COVID-19. Therefore, urgent data gathering and more research of AS profiles in microbe-infected human cells are needed to improve understanding of COVID-19 and related infectious diseases. Herein, we have created CASA, the COVID-19 Alternative Splicing Atlas to provide a convenient computing platform for studies of AS in COVID-19 and COVID-19-related infectious diseases. Methods In CASA, we reanalyzed thousands of RNA-seq datasets generated from 65 different tissues, organoids and cell lines to systematically obtain quantitative data on AS events under different conditions. A total of 262,994 AS events from various infectious diseases with differing severity were detected and visualized in this database. In order to explore the potential function of dynamics AS events, we performed analysis of functional annotations and drug-target interactions affected by AS in each dataset. RNA-binding proteins (RBPs), which may regulate these dynamic AS events are also provided for users in this database. Results CASA displays microbe-induced alterations of the host cell splicing landscape across different virus families and helps users identify condition-specific splicing patterns, as well as their potential regulators. CASA may greatly facilitate the exploration of AS profiles and novel mechanisms of host cell splicing by viral manipulation. CASA is freely available at http://www.splicedb.net/casa/ .

Abstract In order to reduce the risk of spontaneous combustion of coal left after long-term flooding in the goaf of the mine, in this paper, the inhibitory properties of different inhibitors on two kinds of water-immersed coals with different metamorphic degrees were studied in depth. The experiment selected Pingzhuang brown coal and Shaqu coking coal as research objects. The raw coal and water-immersed coal samples were compared and analyzed by thermogravimetric experiment method and Fourier transform infrared spectroscopy experiment method. The study showed that the activation temperature of brown coal and coking coal decreased by 7.91 and 2.25 °C respectively, and the activation energy decreased by 43.18 kJ/mol and 20.58 kJ/mol respectively. The natural tendency of coal was enhanced after water immersion, and water immersion had a greater impact on low-metamorphic brown coal. After adding four kinds of inhibitors, MgCl2, TEMPO, TPPI and PA to the two water-immersed coals, it was found that TPPI could significantly reduce the heat release rate of water-immersed brown coal, and the reduction value was 10.49 W/mg. The dry cracking temperature of water-immersed brown coal increased by 11.75 °C, and PA greatly increased the combustion activation energy of water-immersed coking coal by 25.77 kJ/mol. Meanwhile, it was found from the microscopic active groups that TTPI increased the content of water-immersed brown coal ether bonds by 4.84%. The absorption peak intensity of oxygen-containing functional groups such as C=O was significantly weakened. Similarly, PA also produced a large number of stable ethers in water-immersed coking coal, whose content increased by 5.21%, and the hydroxyl content decreased most significantly. The decomposition of TPPI into phosphoric acid after heating can inhibit the growth of active groups such as a large number of oxygen-containing functional groups in the water-immersed brown coal, thereby reducing the risk of spontaneous combustion. As a metal chelator, PA can reduce the catalytic effect of metal ions in water-immersed coking coal with fewer active groups, and inhibit coal spontaneous combustion by generating stable metal complexes to increase activation energy. This indicated that TTPI had the best inhibitory effect on water-immersed brown coal, while PA was more suitable for water-immersed coking coal.