Search

Keeping steps ahead of the bacteria in the race for more efficacious antibacterial strategies is increasingly difficult with the advent of bacterial resistance genes. Herein, we engineered copper sulfide nanoclusters (CuSx NCs) with variable sulfur defects for enhanced dual-treatment of bacterial infections by manipulating photothermal effects and Fenton-like activity. Next, by encasing CuSx NCs with a complex mixture of amino acids and short peptides derived from Luria-Bertani bacterial culture media as a protein corona, we managed to coax E. Coli to take up these CuSx NCs. As a whole, Amino-Pep-CuSx NCs was perceived as a food source and actively consumed by bacteria, enhancing their effective uptake by at least 1.5-fold greater than full length BSA protein BSA-corona CuSx NCs. Through strategically using defect-engineering, we successfully fine-tune photothermal effect and Fenton-like capacity of CuSx NCs. Increased sulfur defects lead to reduced but sufficient heat generation under solar-light irradiation and increased production of toxic hydroxyl radicals. By fine-tuning sulfur defects during synthesis, we achieve CuSx NCs with an optimal synergistic effect, significantly enhancing their bactericidal properties. These ultra-small and biodegradable CuSx NCs can rapidly break down after treatment for clearance. Thus, Amino-Pep-CuSx NCs demonstrate effective eradication of bacteria both in vitro and in vivo because of their relatively high uptake, optimal balanced photothermal and chemodynamic outcomes. Our study offers a straightforward and efficient method to enhance bacterial uptake of next generation of antibacterial agents.

Abstract Background Polytrauma was defined as a severe traumatic injury and believed that it was a sudden and unpredictable incident. Is polytrauma really just a simple accident? In order to comprehensively answer this question, the study sought to determine the frequency and specific risk factors associated with polytrauma recidivism, while also comparing the initial and subsequent injury events among recidivists. Methods A multicenter, retrospective cohort study was conducted at four Advanced Trauma Centers’ emergency surgery or traumatic intensive care units (TICUs) between August 2020 and July 2023. A total of 2490 consecutive trauma patients who met the criteria consecutively were recruited and analyzed in the study. Risk factors for recurrent polytrauma were identified through the use of logistic regression analysis. A nomogram was created using the results from a multivariate logistic regression analysis and the rms package in R. Results In polytrauma, the rate of recidivism was 44.6% (672/1507), then recidivists were predominantly male (80.4%) and frequently within the 45 to 54 year-old age range (51.3%). Recidivists in polytrauma patients overall had a median time to reinjury of 27 months, as measured by the interquartile range (IQR). The polytrauma patients in the recent traumatic event were often more severe than that in the initial event, as patients had higher ISS scores and lower GCS scores (P

Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of BRCA1/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing BRCA1 dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the BRCA1 promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The BRCA1 promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of BRCA1 expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the BRCA1 promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.

ABSTRACTTherapeutic bioconjugates are emerging as an essential tool to combat human disease. Site-specific conjugation technologies are widely recognized as the optimal approach for producing homogeneous drug products. Non-natural amino acid (nnAA) incorporation allows the introduction of bioconjugation handles at genetically defined locations. Escherichia coli (E. coli) is a facile host for therapeutic nnAA protein synthesis because it can stably replicate plasmids encoding genes for product and nnAA incorporation. Here, we demonstrate that by engineering E. coli to incorporate high levels of nnAAs, it is feasible to produce nnAA-containing antibody fragments and full-length immunoglobulin Gs (IgGs) in the cytoplasm of E. coli. Using high-density fermentation, it was possible to produce both of these types of molecules with site-specifically incorporated nnAAs at titers > 1 g/L. We anticipate this strategy will help simplify the production and manufacture of promising antibody therapeutics.

BackgroundWeight-adjusted waist circumference index (WWI) is a novel index related to obesity and has been associated with the risk and prognosis of several diseases. The aim of the study was to determine the association between WWI and myocardial infarction.MethodsThe study analyzed cross-sectional data from 31,535 participants derived from the 1999–2014 National Health and Nutrition Examination Survey (NHANES) dataset. Multiple logistic regression and restricted cubic spline (RCS) analyses were conducted to assess both linear and nonlinear associations between WWI and myocardial infarction. Subgroup analyses and interaction tests were also performed.ResultsAmong the 31,535 participants analyzed, 1,449 (4.82%) had experienced a myocardial infarction. The fully adjusted models demonstrated a positive association between WWI and myocardial infarction [odds ratio (OR) = 1.34, 95% confidence interval (CI): 1.13–1.58]. Individuals in the highest quartile of WWI were 81% more likely to suffer from a myocardial infarction compared to those in the lowest quartile (OR = 1.81, 95% CI: 1.24–2.63). The analysis employing restricted cubic spline modeling indicated a nonlinear positive correlation between WWI and myocardial infarction. The risk of myocardial infarction was 1.29 times higher when WWI was below 10.97 cm/√kg (OR = 2.29, 95% CI: 1.37–3.84). When WWI exceeded 10.97 cm/√kg, the upward trend in the risk of myocardial infarction significantly slowed with increasing WWI (OR = 1.26, 95%CI:1.03–1.56). A threshold WWI value of greater than 11.15 cm/√kg was identified for predicting myocardial infarction, outperforming waist circumference and body mass index (BMI). Subgroup analyses revealed that the impact of WWI on myocardial infarction varied across different populations. Interaction analyses demonstrated significant interactions between myocardial infarction incidence and WWI with age, hypertension, coronary heart disease, angina pectoris, and stroke (P for interaction 0.05).ConclusionsThe findings suggest that there is a positive and non-linear association between WWI and the incidence of myocardial infarction. We recommend incorporating WWI into routine physical examinations and cardiovascular risk screening as an early warning mechanism. This may facilitate early identification of high-risk individuals and promote earlier preventive interventions.

In the pursuit of sustainable construction practices, the utilization of recycled concrete has emerged as a pivotal strategy, distinguished by its commitment to resource conservation and environmental stewardship. Nevertheless, the inherent micro-porosity and micro-cracking within the old mortar of recycled concrete may lead to weak bonding performance at the interfacial transition zone, culminating in diminished strength, reduced density, and elevated water absorption rates compared to conventional concrete, which critically impairs its performance in cold climates subjected to freeze-thaw cycles. Consequently, this paper provides a structured examination of the frost resistance properties of recycled concrete subjected to freeze-thaw cycling. Initially, the study delineates the mechanisms of frost-induced damage in recycled concrete by synthesizing the degradation pathways observed in both conventional and recycled concrete during freeze-thaw exposure. Subsequently, a detailed analysis is conducted to identify the pivotal factors affecting frost resistance, encompassing the proportion and moisture affinity of recycled aggregates, the addition of silica fume and fly ash, the water-to-cement ratio, and the degree of water saturation. In the final segment, the study compiles and reviews the strategies for bolstering the frost resistance of recycled concrete, including the incorporation of air-entraining admixtures, fiber reinforcement, and aggregate modification approaches. The objective of this research is to offer a thorough comprehension of recycled concrete, with a concentration on the mechanisms of frost damage, the critical determinants of frost resistance, and interventions to augment its resilience against freezing conditions. On this basis, the present paper, in conjunction with the characteristics and current research status of recycled concrete, proposes recommendations for the application of recycled concrete in cold regions. This review is anticipated to facilitate researchers in gaining a comprehensive understanding of the freeze-thaw characteristics of recycled concrete and the measures to enhance its frost resistance. Furthermore, it aims to assist engineering and technical personnel in selecting appropriate treatment methods to improve the frost resistance of recycled concrete in cold regions, thereby promoting the practical engineering application of recycled concrete in such areas.

Since the arid regions of Central Asia (ACA) are located in the interior of Eurasia, water resources play a vital role in the stability of its ecosystem and economic development. Based on the terrestrial water storage anomaly (TWSA) of the Gravity Recovery and Climate Experiment (GRACE), we analyze the observed characteristics of the TWSA over the ACA during 2003–2014. Results indicate that the terrestrial water storage (TWS) in the region showed an overall declining trend from 2003 to 2014, and the autumn TWS in this region is the smallest compared to other seasons and exhibits a strong decreasing trend at least −4.5 cm/decade. This means water resources over the ACA are scarcer and more vulnerable in autumn. The Distance between Indices of Simulation and Observation (DISO) method is employed to evaluate the performance of the sixth phase of the Coupled Model Intercomparison Project (CMIP6) models in simulating the autumn TWSA over the ACA. Compared with observational results, the autumn TWSA values captured by CMIP6 models are larger and the declining TWS trends are weaker. Using the optimal CMIP6 models, the statistical downscaling method constrains the projection results of autumn TWSA values over the ACA using the GRACE datasets. It shows autumn TWS will continue to decrease in most parts of the ACA in the future, and water scarcity will be the most severe in Tajikistan and southwestern Kazakhstan. Under SSP126, Tajikistan’s TWSA is projected to decrease by 11.0 cm in the long term. This study reveals the current situation and possible future changes in TWS over the ACA in autumn, providing references for water resource management and sustainable development policies in this area to avoid losses caused by water scarcity.

Along with abnormalities in glucose metabolism, disturbances in the balance of lipid catabolism and synthesis have emerged as a new area of cancer metabolism that needs to be studied in depth. Disturbances in lipid metabolic homeostasis, represented by fatty acid oxidation (FAO) imbalance, leading to activation of pro-cancer signals and abnormalities in the expression and activity of related metabolically critical rate-limiting enzymes, have become an important part of metabolic remodeling in cancer. The FAO process is a metabolic pathway that facilitates the breakdown of fatty acids into CO2 and H2O and releases large amounts of energy in the body under aerobic conditions. More and more studies have shown that FAO provides an important energy supply for the development of cancer cells. At the same time, the CPT family, including carnitine palmitoyltransferase 1 (CPT1) and carnitine palmitoyltransferase 2 (CPT2), are key rate-limiting enzymes for FAO that exert a pivotal influence on the genesis and progression of neoplastic growth. Therefore, we look at molecular structural properties of the CPT family, the roles they play in tumorigenesis and development, the target drugs, and the possible regulatory roles of CPTs in energy metabolism reprogramming to help understand the current state of CPT family research and to search for new therapeutic strategies.

Abstract Colorectal cancer (CRC) is one of the leading cancers worldwide, with metastasis being a major cause of high mortality rates among patients. In this study, dysregulated gene Tweety homolog 3 (TTYH3) was identified by Gene Expression Omnibus database. Public databases were used to predict potential competing endogenous RNAs (ceRNAs) for TTYH3. Quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry were utilized to analyze TTYH3 and histone deacetylase 7 (HDAC7) levels. Luciferase assays confirmed miR‐1271‐5p directly targeting the 3′ untranslated regions of TTYH3 and HDAC7. In vitro experiments such as transwell and human umbilical vein endothelial cell tube formation, as well as in vivo mouse models, were conducted to assess the biological functions of TTYH3 and HDAC7. We discovered that upregulation of TTYH3 in CRC promotes cell migration by affecting the Epithelial–mesenchymal transition pathway, which was independent of its ion channel activity. Mechanistically, TTYH3 and HDAC7 functioned as ceRNAs, reciprocally regulating each other's expression. TTYH3 competes for binding miR‐1271‐5p, increasing HDAC7 expression, facilitating CRC metastasis and angiogenesis. This study reveals the critical role of TTYH3 in promoting CRC metastasis through ceRNA crosstalk, offering new insights into potential therapeutic targets for clinical intervention.

Abstract Background Clonorchis sinensis (CS) is classified as a group 1 carcinogen and can cause intrahepatic cholangiocarcinoma (ICC). CS extracellular vesicles (CsEVs) play important roles in mediating communication between parasitic helminths and humans. Ferroptosis is a novel cell death mechanism that is mainly induced by lipid peroxidation and iron overload. However, the role of CsEVs in the regulation of ferroptosis in ICC remains unclear. This study aimed to explore the role of CS-secreted miR-96-5p (csi-miR-96-5p) delivered by CsEVs in ICC progression and ferroptosis. Methods Tissue samples were collected from ICC patients with CS infection (CS-ICC) or without CS infection (NC-ICC). The levels of csi-miR-96-5p and PTEN gene were determined by quantitative polymerase chain reaction (qPCR) and western blotting, and survival analysis was performed. CsEVs were isolated and identified by ultracentrifugation and transmission electron microscopy. Lentiviruses were used to establish stable cell lines with csi-miR-96-5p mimic expression, PTEN overexpression (PTEN-EXO) and PTEN CRISPR/Cas9-based knockout (PTEN-KO) and their respective negative controls. Cell proliferation was assessed by performing Cell Counting Kit-8 assays in vitro and in a tumor xenograft model in vivo, and cell migration was assessed by performing Transwell assays. Erastin is used to induce ferroptosis. Ferroptosis levels were evaluated using biomarkers. Results High csi-miR-96-5p and low PTEN expression was observed in CS-ICC tissues and was associated with poor overall survival. csi-miR-96-5p was highly enriched in CsEVs and was taken up by ICC cells. csi-miR-96-5p mimics or PTEN-KO significantly promoted the growth and migration of ICC cells in vitro and in vivo, whereas PTEN-EXO exerted the opposite effect. Mechanistically, csi-miR-96-5p mimics or PTEN-KO inhibited erastin-induced ferroptosis, including reducing the accumulation of Fe2+, lipid reactive oxygen species, and malondialdehyde, increasing the GSH/GSSG ratio and levels of SLC7A11 and GPX4, whereas PTEN-EXOs exerted the opposite effect. Conclusions csi-miR-96-5p delivered by CsEVs reduced ferroptosis by regulating the expression of the PTEN/SLC7A11/GPX4 axis, thereby promoting ICC proliferation and migration. For the first time to our knowledge, we found that CS miRNAs could promote tumor development through ferroptosis. Graphical Abstract

The unique structure and complex deformation characteristics of concrete face rockfill dams (CFRDs) create safety monitoring challenges. This study developed an improved random forest (IRF) model for dam health monitoring modeling by replacing the decision tree in the random forest (RF) model with a novel M5' model tree algorithm. The factors affecting dam deformation were preliminarily selected using the statistical model, and the grey relational degree theory was utilized to reduce the dimensions of model input variables. Finally, a deformation prediction model of CFRDs was established using the IRF model. The ten-fold cross-validation method was used to quantitatively analyze the parameters affecting the IRF algorithm. The performance of the established model was verified using data from three specific measurement points on the Jishixia dam and compared with other dam deformation prediction models. At point ES-10, the performance evaluation indices of the IRF model were superior to those of the M5' model tree and RF models and the classical support vector regression (SVR) and back propagation (BP) neural network models, indicating the satisfactory performance of the IRF model. The IRF model also outperformed the SVR and BP models in settlement prediction at points ES2-8 and ES4-10, demonstrating its strong anti-interference and generalization capabilities. This study has developed a novel method for forecasting and analyzing dam settlements with practical significance. Moreover, the established IRF model can also provide guidance for modeling health monitoring of other structures.

The aim of this study was to evaluate the effect of hydrolysed yeast from Kluyveromyces fragilis (HK) on growth performance, diarrhoea incidence, plasma antioxidant efficiency and immune status, and faecal microbiota of weaned piglets. A total of 100 weaned piglets with BW (7.03 ± 0.14 kg) and age (25 ± 1 days) were randomly allotted to 4 groups with 5 replicates in a 21-day experiment. Piglets were fed with basal diet (NC), NC + 2 g/kg zinc oxide (PC), NC + 7.5 g/kg HK (HK1), or NC + 10 g/kg HK (HK2). Blood and faecal samples were collected on day 21. Significant differences were pointed out in the PC and HK2 piglets compared to the NC group as to the diarrhoea incidence from day 0 to 21 (p

It has always been a common demand to stay away from the harsh environment with narrow space, numerous devices, complex operation process, and hidden hazards, and realize intelligent unmanned mining in the coal industry. To achieve this goal, it is very necessary for us to develop an effective theory of vision computing for underground coalmine applications. Its main task is to build effective models or frameworks for perceiving, describing, recognizing and understanding the environment of underground coalmine, and let intelligent equipment get 3D environment information in coalmine from images or videos. To effectively develop this theory and make it better for intelligent development of coalmine, this paper first analyzed the similarities and differences about computer vision and visual computing in coalmine, and proposed its composition architecture. And then, this paper introduced in detail the key technologies involved in visual computing in coalmine including visual perception and light field computing, feature extraction and feature description, semantic learning and vision understanding, 3D vision reconstruction, and sense computing integration and edge intelligence, which is followed by typical application cases of visual computing in coalmines. Finally, the development trend and prospect of underground visual computing in coalmine was given. In this section, this paper focused on concluding the key challenges and introducing two valuable applications including coalmine Augmented Reality/Mixed Reality and parallel intelligent mining. With the breakthrough of underground vision computing, it will play a more and more important role in the intelligent development of coal mines.

Objective Implant failure is a disastrous complication of the operative treatment of midshaft clavicle fractures, and improving the osteosynthesis plate is a strategy for preventing this. We aimed to investigate whether canceling the notch and adding screw‐hole inserts enhanced the mechanical properties of the plate. Methods A clavicle model was generated based on the CT images of six adult volunteers (age range, 20–40 years; three males and three females; height range 160–175) using dedicated software, and a midshaft fracture model was created. The domestically made seven‐hole locking plate commonly used for midshaft clavicle fractures was simulated (Model I); modifications were made to the plate (Model II). Using 3D finite element analysis, we simulated the fracture construct under three different load conditions—downward cantilever bending, axial compression, and axial torsion—and compared the stress distribution. Results We found that under axial compression, Model II experienced its maximum stress on the plate at 551.9MPa, which was less than that in Model I (790.4 MPa). Moreover, a greater stress concentration at the fracture site was observed under axial torsion, despite the maximum stress of both the models being similar. Conclusion Canceling the notch and filling the screw holes near the fracture can ameliorate stress concentration on the internal fixation construct and enhance its reliability under axial compression. This improvement has substantial effects on the mechanical properties of implants and potentially prevents implant failure. Modern osteosynthesis anatomical implants need to be improved.

Preventing the progression of acute pancreatitis (AP) to severe acute pancreatitis (SAP) is crucial for AP patients. The use of clinical parameters in laboratory facilities for predicting SAP can be rapid, efficient, and cost-effective. This study aimed to investigate the predictive and prognostic value of collected clinical detection parameters, such as serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels, and their ratios, such as ALP-to-hemoglobin (Hb) and LDH-to-Hb ratios, for the prediction of SAP occurrence, complications, and mortality. In all, 50 healthy controls (CON), 455 patients with mild acute pancreatitis (MAP), 127 patients with moderately severe acute pancreatitis (MSAP), and 93 patients with SAP were included in the study. Thirty clinical parameters were collected, measured, compared, and analyzed. The ratios of ALP/Hb and LDH/Hb were subsequently calculated and evaluated with respect to gender and age and whether they could predict SAP occurrence, complications, and mortality. The results revealed that 15 parameters were significant for the prediction of AP. Furthermore, the following 6 indicators are associated with the occurrence of SAP: ALP, ALP/Hb, LDH, LDH/Hb, CRP, and blood glucose. Among these parameters, the predictive abilities of ALP/Hb and LDH/Hb for SAP were most effective. However, they fail to differentiate between MAP and MSAP or gender in SAP patients. Positive correlations were only observed between the levels of these indicators and age at onset of SAP. In addition, receiver operating characteristic (ROC) curves were generated to predict SAP incidence rates, complications, and mortality. The area under the curve (AUC) values for the ALP/Hb ratio ranged from 0.7097 to 0.7837, whereas those for the LDH/Hb ratio ranged from 0.5043 to 0.7778. These findings suggest that ALP and LDH alone or in combination with Hb possess unique predictive characteristics that may serve as independent factors for predicting SAP occurrence, complications, and mortality; of these, the ALP/Hb ratio is especially predictive of SAP mortality.

Short-term precipitation forecasting methods are mainly divided into statistical forecasting, numerical model-based forecasting, and radar image extrapolation techniques. The two methods based on statistical prediction and numerical model have the disadvantages of being unstable and generating large errors. Therefore, this study proposes the use of deep learning for radar image extrapolation for precipitation forecasting, in particular by developing algorithms for ConvLSTM and SmaAT-UNet. The ConvLSTM model is a fusion of a CNN (Convolutional Neural Network) and LSTM (Long Short-Term Memory network), which solves the challenge of processing spatial sequence data, which is a task that traditional LSTM models cannot accomplish. At the same time, SmaAT-UNet enhances the traditional UNet structure by incorporating the CBAM (Convolutional Block Attention Module) attention mechanism and replacing the standard convolutional layer with depthwise separable convolution. This innovative approach aims to improve the efficiency and accuracy of short-term precipitation forecasting by improving feature extraction and data processing techniques. Evaluation and analysis of experimental data show that both models exhibit good predictive ability, with the SmaAT-UNet model outperforming ConvLSTM in terms of accuracy. The results show that the performance indicators of precipitation prediction, especially detection probability (POD) and the Critical Success index (CSI), show a downward trend with the extension of the prediction time. This trend highlights the inherent challenges of maintaining predictive accuracy over longer periods of time and highlights the superior performance and resilience of the SmaAT-UNet model under these conditions. Compared with the statistical forecasting method and numerical model forecasting method, its accuracy in short-term rainfall forecasting is improved.

Background: Ovarian cancer has a poor prognosis, and DNA damage-response (DDR) genes are associated with both its occurrence and prognosis. However, previous studies have mostly focused on genetic mutations, with no clear conclusions on epigenetic factors such as DNA methylation. Methods: In this study, we comprehensively investigated the relationship between promoter methylation of DDR genes and ovarian cancer prognosis. We performed combined multidata analysis of the promoter methylation, expression, homologous recombination defieiency (HRD) score, and drug sensitivity of 377 DDR genes in ovarian cancer by utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We then validated abnormal promoter methylation and its relationship with overall survival in clinical samples. Results: Our analysis identified 52 methylation-driven DDR genes that exhibited abnormal expression due to abnormal promoter methylation. These genes are mostly related to BRCA1-related DNA damage repair and cell cycle regulatory pathways. Further studies revealed six of these genes, BRCA1, PTTG1, TTK, AURKA, CDC6, and E2F1, to be significantly associated with HRD scores. Among them, E2F1, PTTG1, and CDC6 are associated with drug sensitivity. Finally, we verified in 81 ovarian cancer samples that methylation of the promoter of these three genes was significantly associated with patient survival. Conclusions: Our study identified a large number of methylation-driven aberrantly expressed DDR genes in ovarian cancer, some of which affect disease prognosis. Levels of methylation of these gene promoters may serve as potential prognostic markers.

Background Nutrition and immunity play an important role in many chronic diseases. The prognostic nutritional index (PNI) has been proposed as a comprehensive indicator of an individual’s immune and nutritional status. However, there is a lack of evidence regarding the association between the PNI and mortality in patients with chronic kidney disease (CKD).Methods We used National Health and Nutrition Examination Survey (NHANES) data from 2001–2014 for participants with CKD. Mortality data were obtained from the National Death Index and matched to NHANES participants. Cox proportional hazards models were used to estimate hazard ratios for all-cause mortality.Results: The patients were 72.5 ± 9.8 years old, and 47.57% were male. The median follow-up was 58 months, and the mortality rate in patients with CKD was 30.27%. A higher PNI protected against all-cause mortality in patients with CKD, with an adjusted hazard ratio (aHR) of 0.98 (95% confidence interval (CI): 0.97–0.99). After grouping according to PNI quartiles, statistically significant between-group differences were observed in survival probabilities. The aHR for the lowest PNI quartile compared to the highest PNI quartile was 1.64 (95% CI: 1.26–2.14). Sensitivity analysis further supported this association. Restricted cubic spline analysis revealed an L-shaped association between the PNI and all-cause mortality in patients with CKD, with a critical value of 50.5.Conclusions The PNI is a protective factor in patients with CKD, with an L-shaped decrease in all-cause mortality with an increasing PNI.

Objective: To determine the protective effect of Shengmai injection (SMI) on myocardial injury in diabetic rats and its mechanism based on NLRP3/Caspase1 signaling pathway. Materials and methods: Rat H9c2 cardiomyocytes were cultured in vitro, and the cell survival rate of different concentrations of palmitate acid (PA) and different concentrations of SMI were detected by CCK-8. The myocardial injury cell model was induced with PA, treated with SMI, and combined with NLRP3 specific inhibitor (MCC950) to interfere with the high-fat-induced rat H9c2 myocardial cell injury model. The cell changes were observed by Hoechst/PI staining and the expression levels of MDA, SOD, and ROS in each group were detected. The protein and gene changes of the NLRP3/Caspase-1 signaling pathway were detected by Western blot and RT-qPCR, respectively. Results: 200 μmol/L of PA were selected to induce the myocardial injury cell model and 25 μL/mL of SMI was selected for intervention concentration. SMI could significantly reduce MDA expression, increase SOD level, and decrease ROS production. SMI could decrease the gene expression levels of NLRP3, ASC, Caspase-1, and GSDMD, and the protein expressions of NLRP3, ASC, Cleaved Caspase-1, GSDMD, and GSDMD-N. Conclusion: SMI can inhibit the high-fat-induced activation of the NLRP3/Caspase-1 signaling pathway, intervene in cardiomyocyte pyroptosis, and prevent diabetic cardiomyopathy.

IntroductionThis study aimed to evaluate the feasibility of using general Raman spectroscopy as a method to screen for breast cancer. The objective was to develop a machine learning model that utilizes Raman spectroscopy to detect serum samples from breast cancer patients, benign cases, and healthy subjects, with puncture biopsy as the gold standard for comparison. The goal was to explore the value of Raman spectroscopy in the differential diagnosis of breast cancer, benign lesions, and healthy individuals.MethodsIn this study, blood serum samples were collected from a total of 333 participants. Among them, there were 129 cases of tumors (pathologically diagnosed as breast cancer and labeled as cancer), 91 cases of benign lesions (pathologically diagnosed as benign and labeled as benign), and 113 cases of healthy controls (labeled as normal). Raman spectra of the serum samples from each group were collected. To classify the normal, benign, and cancer sample groups, principal component analysis (PCA) combined with support vector machine (SVM) was used. The SVM model was evaluated using a cross-validation method. ResultsThe results of the study revealed significant differences in the mean Raman spectra of the serum samples between the normal and tumor/benign groups. Although the mean Raman spectra showed slight variations between the cancer and benign groups, the SVM model achieved a remarkable prediction accuracy of up to 98% for classifying cancer, benign, and normal groups. DiscussionIn conclusion, this exploratory study has demonstrated the tremendous potential of general Raman spectroscopy as a clinical adjunctive diagnostic and rapid screening tool for breast cancer.

Abstract Background The incidence of colorectal cancer (CRC) is considered to be the third-highest malignant tumor among all carcinomas. The alterations in cellular bioenergetics (metabolic reprogramming) are associated with several malignant phenotypes in CRC, such as tumor cell proliferation, invasion, metastasis, chemotherapy resistance, as well as promotes its immune escape. However, the expression pattern of metabolism-associated genes that mediate metabolic reprogramming in CRC remains unknown. Methods In this study, we screened out CPT2 by investigating the function of a series of metabolism-related genes in CRC progression by integrating the data from the TCGA and GEO databases. Next, we collected CRC tissues (n = 24) and adjacent non-tumor tissues (n = 8) and analyzed mRNA levels by qRT-PCR, and proteins levels of CPT2 in CRC cell lines by western blotting. CCK-8 assay, colony formation assay, Edu assay and flow cytometry assay were performed to assess the effects of CPT2 on proliferation in vitro. Results We identified 236 metabolism-related genes that are differentially expressed in colorectal cancer, of which 49 up-regulated and 187 down-regulated, and found CPT2 as the most significant gene associated with favorable prognosis in CRC. It was revealed that CPT2 expression was consistently down-regulated in CRC cell lines and tissues. Moreover, knockdown of CPT2 could promote the proliferative ability of CRC cells, whereas over-expression of CPT2 significantly suppressed the cell growth. Conclusion In summary, CPT2 can provide new insights about the progression and occurrence of the tumor as it acts as an independent prognostic factor in CRC sufferers.

Abstract Ovarian cancer (OC) is one of the leading gynecologic cancers worldwide. Cancer stem-like cells are correlated with relapse and resistance to chemotherapy. Twist1, which is involved in ovarian cancer stem-like cell differentiation, is positively correlated with CTNNB1 in different differentiation stages of ovarian cancer cells: primary epithelial ovarian cancer cells (primary EOC cells), mesenchymal spheroid-forming cells (MSFCs) and secondary epithelial ovarian cancer cells (sEOC cells). However, the expression of β-catenin is inversed compared to CTNNB1 in these 3 cell states. We further demonstrated that β-catenin is regulated by the protein degradation system in MSFCs and secondary EOC but not in primary EOC cells. The differentiation process from primary EOC cells to MSFCs and sEOC cells might be due to the downregulation of β-catenin protein levels. Finally, we found that TWIST1 can enhance β-catenin degradation by upregulating Axin2.

Summary: It has been proved that Raman spectral intensities could be used to diagnose lung cancer patients. However, the application of Raman spectroscopy in identifying the patients with pulmonary nodules was barely studied. In this study, we revealed that Raman spectra of serum samples from healthy participants and patients with benign and malignant pulmonary nodules were significantly different. A support vector machine (SVM) model was developed for the classification of Raman spectra with wave points, according to ANOVA test results. It got a good performance with a median area under the curve (AUC) of 0.89, when the SVM model was applied in discriminating benign from malignant individuals. Compared with three common clinical models, the SVM model showed a better discriminative ability and added more net benefits to participants, which were also excellent in the small-size nodules. Thus, the Raman spectroscopy could be a less-invasive and low-costly liquid biopsy.

Abstract Background Axonal regeneration following peripheral nerve injury (PNI) depends on the complex interaction between Schwann cells (SCs) and macrophages, but the mechanisms underlying macrophage recruitment and activation in axonal regeneration remain unclear. Methods RNA sequencing (RNA-seq) was conducted to identify differentially expressed long noncoding RNAs (DElncRNAs) between crushed sciatic nerves and intact contralateral nerves. The putative role of lncRNAs in nerve regeneration was analyzed in vitro and in vivo. Results An lncRNA, called axon regeneration-associated transcript (lncARAT), was upregulated in SCs and SC-derived exosomes (SCs-Exo) after sciatic nerve injury. LncARAT contributed to axonal regeneration and improved motor function recovery. Mechanistically, lncARAT epigenetically activated C–C motif ligand 2 (CCL2) expression by recruiting KMT2A to CCL2 promoter, resulting in increased histone 3 lysine 4 trimethylation (H3K4me3) and CCL2 transcription in SCs. CCL2 facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. LncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p in macrophages, resulting in increased suppressor of cytokine signaling (SOCS) 2 expression, which induced a proregenerative function of macrophages through a signal transducer and activator of transcription (STAT) 1/6-dependent pathway. Conclusions LncARAT may represent a promising therapeutic avenue for peripheral nerve repair.

Abstract Background Predicting pathological complete response (pCR) in patients affected by locally advanced rectal cancer (LARC) who undergo neoadjuvant chemoradiotherapy (nCRT) is a challenging field of investigation, but many of the published models are burdened by a lack of reliable external validation. Aim of this study was to evaluate the applicability of a magnetic resonance imaging (MRI) radiomic-based pCR model developed and validated in Europe, to a different cohort of patients from an intercontinental cancer center. Methods The original model was based on two clinical and two radiomics features extracted from T2-weighted 1.5 T MRI of 161 LARC patients acquired before nCRT, considered as training set. Such model is here validated using the T2-w 1.5 and 3 T staging MRI of 59 LARC patients with different clinical characteristics consecutively treated in mainland Chinese cancer center from March 2017 to January 2018. Model performance were evaluated in terms of area under the receiver operator characteristics curve (AUC) and relative parameters, such as accuracy, specificity, negative and positive predictive value (NPV and PPV). Results An AUC of 0.83 (CI 95%, 0.71–0.96) was achieved for the intercontinental cohort versus a value of 0.75 (CI 95%, 0.61–0.88) at the external validation step reported in the original experience. Considering the best cut-off threshold identified in the first experience (0.26), the following predictive performance were obtained: 0.65 as accuracy, 0.64 as specificity, 0.70 as sensitivity, 0.91 as NPV and 0.28 as PPV. Conclusions Despite the introduction of significant different factors, the proposed model appeared to be replicable on a real-world data extra-European patients’ cohort, achieving a TRIPOD 4 level.

Background and purpose: Neoadjuvant Chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) is promising in improving the survival rate for advanced nasopharyngeal carcinoma (NPC) patients relative to CCRT alone. However, not all patients respond well to NAC. Therefore, we aimed to develop and evaluate a modified radiomics model for the NAC response prognosis in NPC patients. Methods: A total of 165 patients with biopsy-proven locally advanced NPC were retrospectively selected from the database of our hospital. 85 out of them were for training and cross-validation, while the other 80 patients were for independent testing. All patients were treated with NAC and underwent MRI inspection, including T1-weighted (T1), T2-weighted (T2), and contrast-enhanced T1-weighted (T1-cs) sequences before and after two cycles of NAC. We classified the patients into the response or non-response groups by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Radiomics features were extracted from the primary and lymph node gross tumor volume in each sequence. To further improve the predictive performance, the permutation of multiple combinations of extraction parameters has first ever been investigated in the NAC prognosis for NPC patients. The model was constructed by logistic regression and cross-validated by bootstrapping with a resampling number of 1000. Independent testing was also implemented. In addition, we also applied an imbalance-adjusted bootstrap strategy to decrease the bias of small samples. Results: For the cross-validation cohort, the resultant AUC, sensitivity, and specificity in terms of 95% confidence interval were 0.948 ± 0.004, 0.849 ± 0.005, and 0.840 ± 0.010. For the independent testing cohort, the model reached an AUC of 0.925, a sensitivity of 0.821, and a specificity of 0.792. There was a significant difference in the estimated radiomics score between the response and non-response groups (P

Abstract Multiple evidence shows that metformin serves as a potential agent for Colorectal Cancer (CRC) treatment, while its molecular mechanisms still require detailed investigation. Here, we revealed that metformin specifically suppressed the proliferation of CRC cells by causing G1/S arrest, and INHBA is a potential target for metformin to play an anti-proliferation effect in CRC. We verified the oncogene role of INHBA by knocking down and overexpressing INHBA in CRC cells. Silencing INHBA abrogated the cell growth, while overexpression INHBA promotes the proliferation of CRC cells. As an oncogene, INHBA was aberrant overexpression in CRC tissues and closely related to the poor prognosis of CRC patients. In mechanism, INHBA is an important ligand of TGF-β signaling and metformin blocked the activation of TGF-β signaling by targeting INHBA, and then down-regulated the activity of PI3K/Akt pathway, leading to the reduction of cyclinD1 and cell cycle arrest. Together, these findings indicate that metformin down-regulates the expression of INHBA, then attenuating TGF-β/PI3K/Akt signaling transduction, thus inhibiting the proliferation of CRC. Our study elucidated a novel molecular mechanism for the anti-proliferation effect of metformin, providing a theoretical basis for the application of metformin in CRC therapy.

Abstract Background The role of the dysfunction of left atrium in the occurrence and development of cardiovascular disease has been gradually recognized. We aim to compare the impact on left atrial (LA) function between patients with hypertrophic cardiomyopathy (HCM) and hypertension (HTN) without LA enlargement using cardiovascular magnetic resonance feature tracking (CMR-FT), and if possible, explore the capability of LA function for providing clinical implication and predicting clinical adverse events in the early stage of cardiovascular disease. Methods Consecutive 60 HCM patients and 60 HTN patients with normal LA size among 1413 patients who underwent CMR were retrospectively analyzed as well as 60 controls. Left atrial and ventricular functions were quantified by volumetric and CMR-FT derived strain analysis from long and short left ventricular view cines. The primary endpoint was a composite of all-cause death, stroke, new-onset or worsening heart failure to hospitalization, and paroxysmal or persistent atrial fibrillation. Results Compared to the controls, both HTN and HCM participants had impaired LA reservoir function (εs) and conduit function (εe) with the different stage of LA booster pump dysfunction (εa). LA strain was more sensitive than LV longitudinal strain (GLS) for evaluate primary endpoint (εs: 33.9% ± 7.5 vs. 41.2% ± 14.3, p = 0.02; εe: 13.6% ± 6.2 vs. 17.4% ± 10.4, p = 0.03; εa: 20.2% ± 6.0 vs. 23.7% ± 8.8, p = 0.07; GLS: -19.4% ± 6.4 vs. -20.0% ± 6.8, p = 0.70, respectively). After a mean follow-up of 6.8 years, 23 patients reached primary endpoint. Cox regression analyses indicated impaired LA reservoir and booster pump strain were associated with clinical outcomes in patients at the early stage of HTN and HCM (p

Abstract Purpose This study aims to further enhance a validated radiomics-based model for predicting pathologic complete response (pCR) after chemo‑radiotherapy in locally advanced rectal cancer (LARC) for use in clinical practice. Methods A generalized linear model (GLM) to predict pCR in LARC patients previously trained in Europe and validated with an external inter-continental cohort (59 patients), was first examined with further 88 intercontinental patient datasets to assess its reproducibility; then new radiomics and clinical features, and validation methods were investigated to build a new model for enhancing the pCR prediction for patients admitted to our department. The patients were divided into training group (75%) and validation group (25%) according to their demographic. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to reduce the dimensionality of the extracted features of the training group and select the optimal ones; the performance of the reference GLM and enhanced models was compared through the area under curve (AUC) of the receiver operating characteristics. Results The value of AUC of the reference model was 0.831 (95% CI, 0.701–0.961), and 0.828 (95% CI, 0.700–0.956) in the original and new validation cohorts, respectively, showing a reproducibility in the applicability of the GLM model. Eight features were found to be significant with LASSO and used to establish an enhanced model. The AUC of the enhanced model of 0.926 (95% CI, 0.859–0.993) for training, and 0.926 (95% CI, 0.767–1.00) for the validation group shows better performance than the reference model. Conclusions The GLM model shows good reproducibility in predicting pCR in LARC; the enhanced model has the potential to improve prediction accuracy and may be a candidate in clinical practice.

Abstract Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.

Abstract Sphingosine kinase 1 (SphK1) expression and activity are elevated in human osteosarcoma (OS) and is a promising target of therapy. SKI-V is a non-competitive and highly-efficient non-lipid SphK1 inhibitor. The potential anti-OS cell activity by the SphK1 inhibitor was studied here. In primary OS cells and immortalized cell lines, SKI-V robustly suppressed cell survival, growth and proliferation as well as cell mobility, and inducing profound OS cell death and apoptosis. The SphK1 inhibitor was however non-cytotoxic nor pro-apoptotic in human osteoblasts. SKI-V robustly inhibited SphK1 activation and induced accumulation of ceramides, without affecting SphK1 expression in primary OS cells. The SphK1 activator K6PC-5 or sphingosine-1-phosphate partially inhibited SKI-V-induced OS cell death. We showed that SKI-V concurrently blocked Akt-mTOR activation in primary OS cells. A constitutively-active Akt1 (ca-Akt1, S473D) construct restored Akt-mTOR activation and mitigated SKI-V-mediated cytotoxicity in primary OS cells. In vivo, daily injection of SKI-V potently suppressed OS xenograft tumor growth in nude mice. In SKI-V-administrated OS xenograft tissues, SphK1 inhibition, ceramide increase and Akt-mTOR inhibition were detected. Together, SKI-V exerts significant anti-OS activity by inhibiting SphK1 and Akt-mTOR cascades in OS cells.

Abstract Background The decoction of Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) has been reported as a potential antitumor agent for colorectal cancer (CRC) in experimental and clinical studies, but its underlying mechanism is still unclear. Methods The current research aims to explore the potential of Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) decoction (AR decoction) in the treatment of CRC and explore the underlying mechanism. SW620 cells were transient transfection to overexpress or knock down wnt 5 or β-Catenin. Astragalus membranaceus (Huangqi) and Rhizoma curcumae (Ezhu) -containing serum (AR-CS) was used to interfere with SW620 cells. Additional AR-CS, Wnt5 inhibitor (IWP-4), and β-Catenin inhibitor (JW55) were used to intervene in SW620 cells. Furthermore, subcutaneously injection of SW620 cells into the right flank of nude mice replicated xenograft mice, which were treated with AR decoction for 21 days. Results AR-CS significantly reduced the mRNA and protein expression levels of Wnt5, β-Catenin, ARF6, and N-Cadherin in SW620 cells, while inhibiting the proliferation and migration of SW620 cells. In cells overexpressing Wnt5 or β-Catenin, these effects of AR-CS were significantly suppressed. On the contrary, the inhibitory effect of AR-CS on the mRNA and protein levels of ARF6 and N-Cadherin and cell proliferation and migration of SW620 was enhanced, when Wnt5 or β-Catenin were knocked down or suppressed by the inhibitors. Moreover, in the mouse model of xenograft tumors, AR decoction not only reduced the tumor volume and inhibited the mRNA levels and protein levels of Wnt5, β-Catenin, ARF6, and N-Cadherin in the tumor, but also inhibit the protein levels of LRP5, LRP6, TCF-4, and LEF1.The histopathology of mice also showed increased apoptosis in tumor tissues, and AR decoction treatment did not cause pathological damage to the kidney and liver. Conclusions Our results provide evidence that AR decoction inhibits Wnt5/β-catenin signaling and inhibits the development of CRC, which is a promising traditional medicine in the clinical treatment of CRC.

Abstract The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.

Soil moisture is an important factor affecting the change of land surface hydrological processes and the distribution of material and energy exchanges between the land and atmosphere and vegetation’s temporal and spatial distributions, especially in arid and semi-arid regions. This paper focuses on soil moisture features across Northwest China, the core region of the Silk Road Economic Belt. Six soil moisture datasets from the period 1981–2020 were employed, which included ERA5 (the European Centre for Medium-Range Weather Forecasts Atmospheric Reanalysis 5), ESA-CCI (European Space Agency Climate Change Initiative), GLDAS (Global Land Data Assimilation System), MERRA-2 (The Modern-Era Retrospective Analysis for Research and Applications, Version 2), RSSSM (A Remote Sensing-based global 10-day resolution Surface Soil Moisture dataset), and SSM-Feng (Regional multimodal fusion of surface soil moisture data in China). The temporal and spatial variation of the linear trend and abrupt change characteristics at seasonal and annual scale were explored. The results are as follows: 1) ESA-CCI, GLDAS, and MERRA-2 showed a slow increase in annual soil moisture tendency at a rate of less than 0.001 m3/m3/year, while ERA5 and SSM-Feng showed a significant decreasing linear trend at a rate of 1.31 × 10−4 m3/m3/year and 1.01 × 10−4 m3/m3/year (p < 0.05), respectively. 2) In autumn and winter, only GLDAS and MERRA-2 showed significant increasing trends. In the growing season (i.e., from April to October), the soil moisture of ESA-CCI, GLDAS, and MERRA-2 significantly increased at the rates of 3.29 × 10−4 m3/m3/year, 3.30 × 10−4 m3/m3/year, and 6.64 × 10−4 m3/m3/year (p < 0.05), respectively. 3) ERA5 and ESA-CCI have frequent abrupt changes in 1984, 1987, and 2006 for ERA5, 2010–2012 and 2019–2020 for ESA-CCI. 4) In terms of spatial variations, most datasets show that soil moisture has increased across most regions. The ERA5, ESA-CCI, GLDAS, MERRA-2, and SSM-Feng datasets show decreased soil moisture in the Tarim Basin. The conclusions of this study deepen the understanding of temporal and spatial variation in soil moisture in arid areas of Northwest China. Through these conclusions, a certain theoretical basis can be provided for the complex water cycle process in the arid region.

Summary: Background: The pathophysiology and subsequent myocardial dysfunction of heart failure with preserved ejection fraction (HFpEF) with comorbid obesity has not been extensively described. This study aimed to investigate the clinical features and cardiovascular magnetic resonance (CMR) derived myocardial strain and tissue characteristics in patients with HFpEF and comorbid obesity phenotype. Methods: In this prospective cohort study, we included consecutive patients admitted to Fuwai hospital in China who underwent CMR. Patients with HFpEF or obesity were diagnosed with demographic data, clinical presentation, laboratory test, and echocardiography or CMR imaging. The key exclusion criteria were cardiomyopathy, primary valvular heart disease, and significant coronary artery disease. Participant data were obtained from the electronic medical records database or inquiry. Comparisons of clinical features and CMR derived structural and functional parameters amongst different groups were made using one-way analysis of variance, or χ2 tests, and post hoc Bonferroni analysis where appropriate. Findings: Between January 1, 2019 and July 31, 2021, 280 participants (108 patients with HFpEF and obesity, 50 patients with HFpEF and normal weight, 72 patients with obesity, and 50 healthy controls) were enrolled. Compared with patients with HFpEF and normal weight, patients with HFpEF and obesity were younger males, and had higher plasma volume, uric acid and hemoglobin levels, yet less often atrial fibrillation, and lower NT-proBNP levels, and had higher left ventricular mass index, end-diastole/systole volume index, lower left atrial volume index, and worse myocardial strains (all p ≤ 0.05), but no remarkable difference in late gadolinium enhancement (LGE) presence and extracellular volume fraction (ECV). After adjusting for age, atrial fibrillation, and coronary artery disease, only global longitudinal strain (GLS, p = 0.031) and early-diastolic global longitudinal strain rate (eGLSR, p = 0.043) were considerably worse in patients with HFpEF and obesity versus patients with HFpEF and normal weight. Furthermore, early-diastolic strain rates showed no linear association with ECV in patients with HFpEF and obesity. Moreover, GLS demonstrated the highest diagnostic ability when compared with traditional CMR structural parameters and ECV to diagnose patients with HFpEF and obesity in the setting of obesity. Interpretation: Higher systemic inflammation, and worse GLS and eGLSR may be the distinct features of obesity-related HFpEF phenotype; strains and ECV may represent different mechanisms of HFpEF with obesity, deserving further study. Funding: The Construction Research Project of Key Laboratory (Cultivation) of Chinese Academy of Medical Sciences (2019PT310025); National Natural Science Foundation of China (81971588); Capital’s Funds for Health Improvement and Research (CFH 2020-2-4034); Youth Key Program of High-level Hospital Clinical Research (2022-GSP-QZ-5).

IntroductionColorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients.MethodsTo identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan–Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results.ResultsThe IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan–Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signatureDiscussionThus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.

Owing to global warming, extreme precipitation events in the arid regions of Central Asia have increased, resulting in significant consequences for water resources and ecosystems. Hence, to address the features and corresponding physical mechanisms of these rainstorms, we examined the rainstorm that occurred in Hotan, Xinjiang in June 2021 as a case study. We employed multiple datasets, including meteorological stations, sounding observations, satellite precipitation data, and reanalysis datasets. The results indicate that the Global Precipitation Measurement satellite precipitation product accurately captured the temporal and spatial variations in this rainstorm, as verified against hourly in situ observation data. Some meteorological stations recorded values greater than twice their historical records, such as Luopu, Pishan, Moyu, and Hotan. Moreover, the duration of the precipitation was longer than 2 days. For the physical mechanisms of this rainstorm, the water vapor in this rainstorm is sourced from the 45°–65°N region of the North Atlantic Ocean crosses the Ural Mountains and the West Siberian Plain to southern Xinjiang. The low-pressure levels (e.g., 700 hPa and 850 hPa) have the more water vapor flux and specific humidity than the high-pressure levels. Our findings can aid the understanding of extreme precipitation events in Central Asia and provide a reference for dealing with meteorological disasters, including extreme precipitation, in the context of global climate change.