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Abstract Background Jackfruit (Artocarpus heterophyllus Lam.) is the world’s largest and heaviest fruit and adapts to hot, humid tropical climates. Low-temperature injury in winter is a primary abiotic stress, which affects jackfruit growth and development. Therefore, breeding cold-resistant varieties and identifying the vital genes in the process of cold resistance are essential. The dehydration-responsive element binding (DREB) gene family is among the subfamily of the APETALA2/ethylene response factor transcription factor family and is significant in plant abiotic stress responses. Methods In this study, a comparative analysis of the cold resistance property of ‘GuangXi’ (‘GX’) and ‘Thailand’ (‘THA’) jackfruit strains with different cold resistance characteristics was performed through chlorophyll fluorescence and transcriptome sequencing. Results We found that differentially expressed genes (DEGs) are significantly enriched in the metabolic processes. Here, 93 DREB genes were identified in the jackfruit genome, and phylogenetic analysis was used to classify them into seven groups. Gene structure, conserved motifs, chromosomal location, and homologous relationships were used to analyze the structural characteristics of the DREB family. Transcriptomics indicated that most of the AhDREB genes exhibited down-regulated expression in ‘THA.’ The DEGs AhDREB12, AhDREB21, AhDREB29, and AhDREB34 were selected for quantitative real-time PCR, and the results showed that these genes also had down-regulated expression in ‘THA.’ Conclusions The above results suggest the significance of the DREB family in improving the cold resistance property of ‘GX.’

Flavonoid glycosides are widespread in plants, and are of great interest owing to their diverse biological activities and effectiveness in preventing chronic diseases. Periploca forrestii, a renowned medicinal plant of the Apocynaceae family, contains diverse flavonoid glycosides and is clinically used to treat rheumatoid arthritis and traumatic injuries. However, the mechanisms underlying the biosynthesis of these flavonoid glycosides have not yet been elucidated. In this study, we used widely targeted metabolomics and full-length transcriptome sequencing to identify flavonoid diversity and biosynthetic genes in P. forrestii. A total of 120 flavonoid glycosides, including 21 C-, 96 O-, and 3 C/O-glycosides, were identified and annotated. Based on 24,123 full-length coding sequences, 99 uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) were identified and classified into 14 groups. Biochemical assays revealed that four UGTs exhibited O-glycosyltransferase activity toward apigenin and luteolin. Among them, PfUGT74B4 and PfUGT92A8 were highly promiscuous and exhibited multisite O-glycosylation or consecutive glycosylation activities toward various flavonoid aglycones. These four glycosyltransferases may significantly contribute to the diversity of flavonoid glycosides in P. forrestii. Our findings provide a valuable genetic resource for further studies on P. forrestii and insights into the metabolic engineering of bioactive flavonoid glycosides.

Abstract Background Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies. Methods Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2–4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker. Results Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35–2.66) for C-Alb, and 1.89 [1.27–2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10–1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707–0.743] with C-Alb and 0.725 [0.707–0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics. Conclusions C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

The aging process is crucial for Chinese Baijiu production, significantly enhancing the spirit's flavor, aroma and quality. However, aging involves a complex interplay of numerous compounds, and the extensive duration required for aging leads to a scarcity of samples available for scientific research. These limitations pose a challenge in analyzing high-dimensional data with collinearity, complicating the understanding of the intricate chemical processes at play. In this article, a two-step framework was proposed that integrated Relaxed Lasso regression models with Lasso-selected predictors to address this issue. Baijiu samples subjected to various aging conditions were analyzed using direct GC-MS and HS-GC-MS, and the obtained data was processed by this approach. The results demonstrate significantly superior performance compared to other methods, including PLSR and Gradient Boosting. Analyses were also performed on a previously documented dataset, yielding enhanced results and underscoring the method's advantage in processing high dimensional data with multicollinearity. Moreover, this method proved effective in screening of potential indicative compounds, highlighting its utility in Baijiu aging research.

Background Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke. Methods and Results Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3‐month follow‐up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58–0.91]; P=0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47–0.74]; P

Rationale & Objective: Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. Study Design: In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439). Setting & Participants: CRIC is a multicenter prospective cohort of adults with CKD. Exposure: MMP-2 measured in plasma at baseline and at year 2. Outcomes: A composite kidney endpoint (KRT/eGFR halving) Analytical Approach: Weighted Cox proportional hazards models for case-cohort participants. Results: Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein

Abstract Background Tumor-associated macrophages (TAMs) play a pivotal role in reshaping the tumor microenvironment following radiotherapy. The mechanisms underlying this reprogramming process remain to be elucidated. Methods Subcutaneous Lewis lung carcinoma (LLC) murine model was treated with hypofrationated radiotherapy (8 Gy × 3F). Single-cell RNA sequencing was utilized to identify subclusters and functions of TAMs. Multiplex assay and enzyme-linked immunosorbent assay (ELISA) were employed to measure serum chemokine levels. Bindarit was used to inhibit CCL8, CCL7, and CCL2. The infiltration of TAMs after combination treatment with hypofractionated radiotherapy and Bindarit was quantified with flow cytometry, while the influx of CD206 and CCL8 was assessed by immunostaining. Results Transcriptome analysis identified a distinct subset of M2-like macrophages characterized by elevated Ccl8 expression level following hypofractionated radiotherapy in LLC-bearing mice. Remarkbly, hypofractionated radiotherapy not only promoted CCL8high macrophages infiltration but also reprogrammed them by upregulating immunosuppressive genes, thereby fostering an immunosuppressive tumor microenvironment. Additioinally, hypofractionated radiotherapy enhanced the CCL signaling pathway, augmenting the pro-tumorigenic functions of CCL8high macrophages and boosting TAMs recruitment. The adjunctive treatment combining hypofractionated radiotherapy with Bindarit effectively reduced M2 macrophages infiltration and prolonged the duration of local tumor control. Conclusions Hypofractionated radiotherapy enhances the infiltration of CCL8high macrophages and amplifies their roles in macrophage recruitment through the CCL signaling pathway, leading to an immunosuppressive tumor microenvironment. These findings highlight the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.

The distribution features of coal particle size are closely related to the analysis of methane gas propagation in coal. At present, the coal particle size analysis method based on image segmentation has become one of the mainstream solutions to obtain coal particle size. But there are problems such as loss of contextual information, improper fusion of coal particle features resulting in missed segmentation and over-segmentation of coal particles. In order to solve the above problems, a coal particle size analysis model based on bi-level routing attention (BRA) is designed. The BRA module is embedded in the residual U-shaped network ResNet-UNet to obtain the B-ResUNet network model. To reduce the problem of missed segmentation in coal particle segmentation, a BRA module is added before upsampling in the ResNet-UNet network. It allows the network to adjust the importance of the current feature layer based on the features of the previous layer, enhance the expression capability of features, and improve the transmission capability of long-distance information. To reduce the problem of over segmentation in coal particle segmentation, a BRA module is added after the feature concatenation module of the ResNet-UNet network. By dynamically selecting and aggregating important features, more effective feature fusion is achieved. The feature information from the segmented coal particles is extracted. The coal particle size of the coal particle dataset used in the experimental analysis is equivalent to the cell size. In order to accurately characterize the coal particle size, equivalent circular particle size is used to obtain the coal particle size and size distribution. The experimental results show the following points. ① The accuracy, average intersection to union ratio, and recall of the B-ResUNet network model have been improved by 06.%, 14.3%, and 35.9% compared to the ResNet-UNet basic network, with an accuracy of 99.6%, an average intersection to union ratio of 92.6%, and a recall of 94.4%. The B-ResUNet network model has good segmentation performance in coal samples and can detect relatively complete particle structures. ② When the BRA module is introduced before upsampling and after feature concatenation, the network pays sufficient attention to the edge areas of coal particles and reduces attention to some less important areas, thereby improving the computational efficiency of the network. ③ The particle size of coal particles shows a relatively balanced distribution trend within 1-2 mm, with the maximum proportion of coal particles within 1-2 mm being 99.04% and the minimum being 90.59%. It indicates that the image processing method based on BRA has high accuracy in particle size analysis.

Based on the study of the distribution of intra-platform shoals and the characteristics of dolomite reservoirs in the Middle Permian Qixia Formation in the Gaoshiti–Moxi area of the Sichuan Basin, SW China, the controlling factors of reservoir development were analyzed, and the formation model of “intra-platform shoal thin-layer dolomite reservoir” was established. The Qixia Formation is a regressive cycle from bottom to top, in which the first member (Qi1 Member) develops low-energy open sea microfacies, and the second member (Qi2 Member) evolves into intra-platform shoal and inter-shoal sea with decreases in sea level. The intra-platform shoal is mainly distributed near the top of two secondary shallowing cycles of the Qi2 Member. The most important reservoir rock of the Qixia Formation is thin-layer fractured-vuggy dolomite, followed by vuggy dolomite. The semi-filled saddle dolomite is common in fracture-vug, and intercrystalline pores and residual dissolution pores combined with fractures to form the effective pore-fracture network. Based on the coupling analysis of sedimentary and diagenesis characteristics, the reservoir formation model of “pre-depositional micro-palaeogeomorphology controlling shoal, sedimentary shoal controlling dolomite, penecontemporaneous dolomite benefiting preservation of pores, and late hydrothermal action effectively improving reservoir quality” was systematically established. The “first-order high zone” micro-paleogeomorphology before the deposition of the Qixia Formation controlled the development of large area of intra-platform shoals in Gaoshiti area during the deposition of the Qi2 Member. Shoal facies is the basic condition of early dolomitization, and the distribution range of intra-platform shoal and dolomite reservoir is highly consistent. The grain limestone of shoal facies is transformed by two stages of dolomitization. The penecontemporaneous dolomitization is conducive to the preservation of primary pores and secondary dissolved pores. The burial hydrothermal fluid enters the early dolomite body along the fractures associated with the Emeishan basalt event, makes it recrystallized into medium–coarse crystal dolomite. With the intercrystalline pores and the residual vugs after the hydrothermal dissolution along the fractures, the high-quality intra-platform shoal-type thin-layer dolomite reservoirs are formed. The establishment of this reservoir formation model can provide important theoretical support for the sustainable development of Permian gas reservoirs in the Sichuan Basin.

Background and purpose Several clinical studies have demonstrated the potential of molecular-targeted agents for the treatment of recurrent or metastatic adenoid cystic carcinoma (R/M ACC). However, there is currently no consensus regarding the efficacy of molecular-targeted agents for patients with R/M ACC. This study aimed to evaluate the therapeutic efficacy and safety of molecular-targeted agents in patients with R/M ACC and provide insights to guide clinical decision-making.Materials and methods Five databases (PubMed, Embase, Cochrane, ProQuest, and Scopus) were searched based on the search strategy and selection criteria. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS), metastatic sites, and adverse events (AE). Pooled estimates were calculated using a random-effects meta-analysis.Results Finally, 28 studies, involving 849 patients, were included. The most common metastatic sites were the lungs, bones, liver, lymph nodes, and kidneys. The pooled ORR was 4.0% (95% CI, 0.7–8.8%), the pooled DCR was 80.5% (95% CI, 72.2%–87.7%). Compared with other-target drugs, multiple kinase inhibitors (MKIs) improved the ORR (pooled ORR for single-target drugs vs. MKIs: 5.9% vs. 0%). The combination of MKIs and immune checkpoint inhibitors (ICIs) had a significantly higher ORR (17.9% in the axitinib + avelumab group). The pooled median PFS and OS were 8.35 and 25.62 months, respectively. MKIs improved the median PFS compared to other-target drugs (9.43 months vs 5.06 months). In addition, the most common adverse events (AEs) were fatigue (51.6%), hypertension (44.2%), and nausea (40.0%), followed by hand-foot skin syndrome (36.8%), diarrhoea (34.4%), weight loss (34.2%), anorexia (31.8%), rash (31.7%), and headache (29.0%).Conclusion The findings of this study suggest that MKIs have a better therapeutic efficacy than single-target drugs in patients with R/M ACC. Future studies are warranted to verify the synergistic role of the combination strategy of MKIs plus ICIs, given the limited number of studies on this topic conducted and published to date.

Backgroundβ-blockers have been widely used in patients with extensive cardiovascular disease (CVD) and have provided benefits. However, they are more likely to cause symptomatic bradycardia, hypotension, or glucose metabolism disorders, which may lead to an increased risk of atrial fibrillation (AF), but evidence is lacking.AimsThis study was to analyze the association between the use of β-blockers and the risk of developing AF.MethodsThis nationwide, prospective cohort study utilized data from the 2013–2020 National Health and Nutrition Examination Survey (NHANES). The patients were stratified into a β-blocker treatment group (n = 2585) and a non-β-blocker treatment group (n = 8525). Univariate and multivariate logistic regression analyses were performed to identify the relationship between β-blockades and the risk of AF. Propensity matching analysis was used to balance patient baseline characteristics and to control for confounders.ResultsA total of 11,110 subjects were included in this study (mean [SD] age, 59.89 [15.07] years; 5657 [49.7%] males). A total of 111/2585 subjects developed AF in the β-blocker treatment group, and 75/8525 developed AF in the non-β-blocker treatment group (incidence rate, 4.2% vs. 0.8%). Compared with the non-β-blocker group, the β-blocker group had an increased risk of incident AF (aOR, 2.339; 95% CI, 1.614–3.410). Some sensitivity analyses also revealed consistent findings of increased AF risk associated with β-blocker treatment.ConclusionThe findings from this study suggest that β-blocker treatment is associated with an increased risk of incident AF and may help physicians select a modest medication for patients while also assessing the risk of AF.

Cyanobacterial blooms (CBs) present significant challenges to Chinese mitten crab (CMC) culture, posing hazards to the aquatic microbial ecology. However, the current focus on the microbial ecological changes within the CMC culture system under the influence of CBs is somewhat insufficient. There’s an urgent need to analyze the microbial ecosystem of the CMC culture system under CBs. This study employed 16S rRNA gene amplicon sequencing to investigate the dynamics of the environmental microbial community in both the rice-crab co-culture (RC) and crab monoculture (CM) models. The results revealed that cyanobacteria reached high levels in the CM water in July, while they began to increase in the RC water in August. Notably, OTU147 (uncultured bacterium g_Planktothrix NIVA-CYA 15), identified as the dominant taxon associated with CBs, showed a significant linear relationship with TP, NO2−-N, and the N:P ratio. TP, TN, NO2−-N, and CODMn had a more pronounced impact on the structure of bacterial communities and cyanobacterial taxa in the water. The bacterial community structure involved in carbon metabolism displayed temporal succession in the water. The co-occurrence network of the bacterial community primarily consisted of Chloroflexi, Proteobacteria, and Firnicutes in the sediment, and Actinobacteria, Proteobacteria, Chloroflexi, and Bacteroidota in the water. In contrast, the co-occurrence network included different peripheral species in the sediment and water. Keystone species were predominantly represented by OTU22 (uncultured actinobacterium g_ hgcI clade) and OTU12 (uncultured Opitutae bacterium g_ norank) in the RC water, and by OTU25 (uncultured bacterium g_ Limnohabitans) in the CM water. TP, TN, NO2−-N, and CODMn were identified as the primary environmental factors influencing these keystone taxa within the culture water. In conclusion, this study on the microbial ecology of the CMC culture system under the influence of CBs provides valuable insights that can be instrumental in subsequent management efforts.

Background Higher cardiovascular health (CVH) score is associated with lower risks of cardiovascular disease (CVD) and mortality in the general population. However, it is unclear whether cumulative CVH is associated with CVD, end‐stage kidney disease (ESKD), and death in patients with chronic kidney disease. Methods and Results Among individuals from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we used the percentage of the maximum possible CVH score attained from baseline to the year 5 visit to calculate cumulative CVH score. Multivariable‐adjusted Cox proportional hazards regression was used to investigate the associations of cumulative CVH with risks of adjudicated CVD (myocardial infarction, stroke, and heart failure), ESKD, and all‐cause mortality. A total of 3939 participants (mean age, 57.7 years; 54.9% men) were included. The mean (SD) cumulative CVH score attained during 5 years was 55.5% (12.3%). Over a subsequent median 10.2‐year follow‐up, 597 participants developed CVD, 656 had ESKD, and 1324 died. A higher cumulative CVH score was significantly associated with lower risks of CVD, ESKD, and mortality, independent of the CVH score at year 5. Multivariable‐adjusted hazard ratios and 95% CIs per 10% higher cumulative CVH score during 5 years were 0.81 (0.69–0.95) for CVD, 0.82 (0.70–0.97) for ESKD, and 0.80 (0.72–0.89) for mortality. Conclusions Among patients with chronic kidney disease stages 2 to 4, a better CVH status maintained throughout 5 years is associated with lower risks of CVD, ESKD, and all‐cause mortality. The findings support the need for interventions to maintain ideal CVH status for prevention of adverse outcomes in the population with chronic kidney disease.

The roof breaking movement of steeply inclined and ultra-thick coal seam mining is complex, and the evolution law of stress and energy is special. Under the influence of deep ‘three highs and one disturbance’, the prevention and control of rock burst is not optimistic. Based on the experience of rock burst prevention and control in horizontal section mining of steeply inclined and ultra-thick coal seam after the rock burst accident in a mine in 2016, the experience of rock burst prevention and control in steeply inclined and ultra-thick coal seam in the past seven years is introduced in detail from the mechanism of rock burst in horizontal section mining of steeply inclined and ultra-thick coal seam, the comprehensive prevention and control of gas outburst and rock burst and the management of rock burst. In terms of the mechanism of rock burst, the inclined cantilever beam model of roof strata is established, the evolution process of fracture instability of roof and floor overburden structure is revealed, and the ‘clamping theory’ of rock burst in steeply inclined and ultra-thick coal seam is put forward. In terms of comprehensive prevention and control of gas outburst and rock burst, based on the theory of strength weakening and rock burst reduction of rock burst disaster control and disaster relief technology, combined with the original outburst prevention measures system, this paper puts forward the measures that can prevent and benefit the outburst prevention, forms a mine gas/carbon dioxide outburst/rock burst ‘integrated control’ technology system, and establishes a rock burst prevention and control system suitable for the horizontal section mining of steeply inclined thick coal seam in a mine. The intensity of gas outburst prevention and control is verified by the amount of drilling cuttings and the value of gas absorption and desorption. At the same time, the distribution of microseismic events and the total frequency and energy of each energy level are compared in the working face with pressure relief measures. The effectiveness of the control effect of the pressure relief scheme is demonstrated. In terms of rock burst management, a “six-in-one” comprehensive prevention and control framework has been formed, including prediction and evaluation, monitoring and early warning, treatment and prevention, effect test, safety protection and education and training. Based on the “Coal Mine Safety Regulations” and “Detailed Rules for Prevention and Control of Coal Mine Rock Burst” and other provisions, the Q/YJMD-FC 0104-2022“Yaojie Coal and Electricity Group Co., Ltd. Coal Mine Rock Burst Prevention and Control Part IV: Technical Specification for Prevention and Control of Rock Burst” was formulated.

Abstract The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR). As an adaptive cellular response to hostile microenvironments, such as hypoxia, nutrient deprivation, oxidative stress, and chemotherapeutic drugs, the UPR is activated in diverse cancer types and functions as a dynamic tumour promoter in cancer development; this role of the UPR indicates that regulation of the UPR can be utilized as a target for tumour treatment. T-cell exhaustion mainly refers to effector T cells losing their effector functions and expressing inhibitory receptors, leading to tumour immune evasion and the loss of tumour control. Emerging evidence suggests that the UPR plays a crucial role in T-cell exhaustion, immune evasion, and resistance to immunotherapy. In this review, we summarize the molecular basis of UPR activation, the effect of the UPR on immune evasion, the emerging mechanisms of the UPR in chemotherapy and immunotherapy resistance, and agents that target the UPR for tumour therapeutics. An understanding of the role of the UPR in immune evasion and therapeutic resistance will be helpful to identify new therapeutic modalities for cancer treatment. Video Abstract

Abstract Objective To investigate the improvement of perioperative sleep quality and neurocognitive impairment in elderly patients under general anesthesia by nasal administration of dexmedetomidine. Methods One hundred and twenty patients admitted to our hospital for various laparoscopic elective gynecological surgeries lasting more than 1 h under general anesthesia from July 2021 to March 2023 were selected. All subjects were divided into 3 groups according to the random number table method. From 21:00 to 21:30 every night from one day before to 5 days after surgery, group A was given alprazolam 0.4 mg orally; group B was given dexmedetomidine 1.5ug/kg nasal drip; group C was given saline nasal drip. All subjects were observed for general information, sleep quality, postoperative cognitive function, anxiety status, sleep quality, adverse effects and complication occurrence. Results The difference in general information between the three groups was not statistically significant, P > 0.05; the sleep quality scores of the three groups on admission were not statistically significant, P > 0.05. At the Preoperative 1d, postoperative 1d, 3d and 5d, the RCSQ scores of the subjects in group A and group B were higher than those in groups C, and with the postoperative RCSQ scores of subjects in group B were higher as the time increased; the assessment of anxiety status in the three groups 1d before surgery was not statistically significant, P > 0.05. The cognitive function scores of subjects in the three groups were not statistically significant in the preoperative 1d, P > 0.05. The postoperative 1d (24.63 ± 2.23), 3d (25.83 ± 2.53), and 5d (26.15 ± 2.01) scores of the subjects in group B were higher than those in groups A and C (P 0.05). The scores in group B were lower than those in group C on the postoperative 1d, 3d, 5 d (P

Abstract Background The association between weight change during early adulthood and cardiometabolic diseases remains uncertain in Chinese population. Whether the association varies with comprehensive cardiovascular health (CVH) in midlife assessed by “Life’s Essential 8” has not been characterized. We aim to examine the associations of early adulthood weight change and midlife “Life’s Essential 8” CVH status with cardiometabolic outcomes in a Chinese cohort. Methods The study participants were from the China Cardiometabolic Disease and Cancer Cohort (4 C) Study. This analysis included 72,610 middle-aged and older participants followed for a median of 3.6 years. At baseline, the participants recalled body weight at age 20 and 40 years, and we calculated change in weight and BMI between 20 and 40 years of age. Health behaviors information in “Life’s Essential 8” was collected by questionnaire, and health factors were measured in the study center. During follow-up, we ascertained incident cardiovascular events based on medical records, and diagnosed incident diabetes according to the American Diabetes Association 2010 criteria. Results 72,610 study participants were included with a mean age of 56.0 ± 8.8 years and 29% of them were males. Weight gain of more than 10 kg between 20 and 40 years of age was associated with 22% increased risk of incident cardiovascular events (HR: 1.22; 95%CI: 1.04–1.43) and 38% increased risk of diabetes (HR: 1.38; 95%CI: 1.25–1.53) compared to stable weight. Besides, the association of weight gain more than 10 kg in early adulthood with cardiometabolic risk was even stronger in those with low CVH score in midlife (HR: 2.44; 95%CI: 2.01–2.97 for incident cardiovascular events; HR: 2.20; 95%CI: 1.90–2.55 for incident diabetes) or with few ideal cardiovascular health metrics in midlife. Conclusions Our study indicated that weight gain in early adulthood was associated with significantly increased risk of cardiometabolic diseases. And the association could be stronger in those with poor CVH profiles in midlife. These findings confirmed the significance of weight management during early adulthood and suggested that individuals who experienced substantial weight gain in early life should be encouraged to maintain good CVH status in Chinese population.

Intelligence is the direction of coal mine development, and intelligent video analysis is an effective way to promote coal mine intelligence. The mine-wide intelligent video analysis technology has real-time monitoring, early warning, and decision support capabilities. It helps to improve the safety, production efficiency, resource utilization efficiency, and environmental sustainability of mining enterprises. The key technologies of mine-wide intelligent video analysis are introduced in detail, including video acquisition and processing technologies such as video acquisition equipment, video pre-processing, video compression and coding, basic video analysis technologies such as object detection and tracking, motion detection and analysis, object recognition and classification, and advanced video analysis technologies such as behaviour recognition and analysis, event detection and alarm, video monitoring and arming. A mining intelligent AI visual intelligence service platform that integrates video recognition analysis and industrial linkage control functions is developed. The paper introduces the application of intelligent video analysis technology in mining production scenarios such as intelligent water and gas exploration and discharge systems, coal rock recognition and cutting systems, heading working faces, fully mechanized working faces, coal flow transportation systems, mine hoist systems, auxiliary transportation systems, coal preparation plants, and intelligent loading and coal blending systems. The analysis points out that the current mine-wide intelligent video analysis technology still faces challenges in terms of video quality, complex backgrounds, real-time requirements, data privacy and security, system reliability and stability, etc. It is suggested to strengthen the research on algorithm improvement and optimization, multimodal data fusion, real-time analysis and edge computing, enhanced learning and independent decision-making, data privacy and security protection, hardware equipment and sensor technology in the future. Therefore, the development of mine-wide intelligent video analysis technology is comprehensively promoted and promote the process of mine intelligence is promoted.

ABSTRACT: Hypoxia-inducible factor 1 (HIF-1) is a transcriptional regulator that mediates cellular adaptive responses to hypoxia. Hypoxia-inducible factor 1α (HIF-1α) is involved in the development of ascites syndrome (AS) in broiler chickens. Therefore, studying the effect of HIF-1α on the cellular transcriptome under hypoxic conditions will help to better understand the mechanism of HIF-1α in the development of AS in broilers. In this study, we analyzed the gene expression profile of the chicken fibroblast cell line (DF-1) under hypoxic conditions by RNA-seq. Additionally, we constructed the HIF-1α knockdown DF-1 cell line by using the RNAi method and analyzed the gene expression profile under hypoxic conditions. The results showed that exposure to hypoxia for 48 h had a significant impact on the expression of genes in the DF-1 cell line, which related to cell proliferation, stress response, and apoptosis. In addition, after HIF-1α knockdown more differential expression genes appeared than in wild-type cells, and the expression of most hypoxia-related genes was either down-regulated or remained unchanged. Pathway analysis results showed that differentially expressed genes were mainly enriched in pathways related to cell proliferation, apoptosis, and oxidative phosphorylation. Our study obtained transcriptomic data from chicken fibroblasts at different hypoxic times and identified the potential regulatory network associated with HIF-1α. This data provides valuable support for understanding the transcriptional regulatory mechanism of HIF-1α in the development of AS in broilers.

Abstract Background Acute graft‐versus‐host disease (aGVHD) arises from the imbalance of host T cells. Galectin‐9 negatively regulates CD4 effector T cell (Th1 and Th17) function by binding to Tim‐3. However, the relationship between Galectin‐9/Tim‐3 and CD4+ T subsets in patients with aGVHD after Haplo‐HSCT (haploidentical peripheral blood hematopoietic stem cell transplantation) has not been fully elucidated. Here, we investigated the role of Galectin‐9 and CD4+T subsets in aGVHD after haplo‐HSCT. Methods Forty‐two patients underwent Haplo‐HSCT (26 without aGVHD and 16 with aGVHD), and 20 healthy controls were included. The concentrations of Galectin‐9, interferon‐gamma (IFN‐γ), interleukin (IL)‐4, transforming growth factor (TGF)‐β, and IL‐17 in the serum and culture supernatant were measured using enzyme‐linked immunosorbent assay or cytometric bead array. The expression levels of Galectin‐9, PI3K, p‐PI3K, and p‐mTOR protein were detected by western blot analysis. Flow cytometry was used to analyze the proportions of CD4+ T cell subsets. Bioinformatics analysis was performed. Results In patients with aGVHD, regulatory T (Treg) cells and Galectin‐9 decreased, and the Th1, Th17, and Treg cells were significantly imbalanced. Moreover, Treg and Galectin‐9 were rapidly reconstituted in the early stage of patients without aGVHD after Haplo‐HSCT, but Th17 cells were reconstituted slowly. Furthermore, Tim‐3 upregulation on Th17 and Th1 cells was associated with excessive activation of the PI3K/AKT pathway in patients with aGVHD. Specifically, in vitro treatment with Galectin‐9 reduced IFN‐γ and IL‐17 production while augmenting TGF‐β secretion. Bioinformatics analysis suggested the potential involvement of the PI3K/AKT/mTOR pathway in aGVHD. Mechanistically, exogenous Galectin‐9 was found to mitigate aGVHD by restoring the Treg/Teffs (effector T cells) balance and suppressing PI3K. Conclusion Galectin‐9 may ameliorate aGVHD after haplo‐HSCT by modulating Treg/Teffs balance and regulating the PI3K/AKT/mTOR pathway. Targeting Galectin‐9 may hold potential value for the treatment of aGVHD.

Abstract Background Metastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour‐associated macrophages (TAMs) in CRC metastasis was explored. Methods Immunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA‐seq) and liquid chromatography‒mass spectrometry (LC‒MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM‐derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells. Results Our results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC‐38 and CT‐26 cells via EVs. According to the RNA‐seq data, TAM‐EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM‐EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver‐metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours. Conclusions Overall, our findings suggest that DOCK7 delivered via TAM‐EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.

BackgroundMaternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. ObjectiveThis study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). MethodsThis case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was

Background Patients with stroke are often affected by varying degrees of functional disability and have different evolution patterns in functional disability. However, little is known about the predictive usefulness of disability changes after stroke. We aimed to describe 1‐year disability trajectories and to assess the associations of longitudinal disability trajectories with 24‐month clinical outcomes after ischemic stroke. Methods and Results A total of 3533 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) were studied. Distinct trajectories of disability were identified by the group‐based trajectory model, as measured by modified Rankin Scale score within 12 months. Cox proportional hazards regression models were used to examine the associations of disability trajectories with 24‐month cardiovascular events and all‐cause mortality. We identified 4 distinct disability trajectories: no significant disability (562 participants [15.9%]), slight disability to recovery (1575 participants [44.6%]), severe to moderate disability (1087 participants [30.8%]), and persistent severe disability (309 participants [8.7%]). Compared with no significant disability trajectory, the multivariable adjusted hazard ratios (95% CIs) of patients within the persistent heavy–severe trajectory were 2.63 (1.20–5.76) for cardiovascular events, 2.55 (1.12–5.79) for recurrent stroke, and 6.10 (2.22–16.72) for all‐cause mortality; notably, the hazard ratios (95% CIs) for patients within the severe to moderate disability trajectory were 1.99 (1.01–3.94) for cardiovascular events and 1.85 (1.03–3.33) for the composite outcome of cardiovascular events and all‐cause mortality. Conclusions Functional disability trajectories within 12 months after stroke onset were associated with the risk of 24‐month adverse outcomes. Patients with persistent severe disability or severe to moderate disability had higher risk of cardiovascular events and all‐cause mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072

Abstract Background and objectives Evidence on the associations between baseline stromal cell-derived factor (SDF)-1 and clinical outcomes in acute ischemic stroke patients is lacking. The present study aimed to examine the relationship between plasma SDF-1 levels and clinical outcomes based on a large multicenter study of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Methods Secondary analysis was conducted among 3,255 participants from the CATIS trial with a baseline measurement of plasma SDF-1 levels. We evaluated the associations between plasma SDF-1 levels and one-year recurrent stroke, cardiovascular events, and all-cause mortality using Cox regression models. We further investigated the prognostic effect of SDF-1 on clinical outcomes in patients with different characteristics. Results Higher plasma SDF-1 levels were not associated with recurrent stroke, cardiovascular events, and all-cause mortality at one-year after ischemic stroke (all P trend ≥ 0.05). There were significant interactions between plasma SDF-1 levels and history of diabetes mellitus on recurrent stroke (P = 0.005), cardiovascular events (P = 0.007) and all-cause mortality (P = 0.04) at one year. In patients with diabetes mellitus, plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events after adjustment for confounders. For example, 1-SD higher log–SDF-1 was associated with a hazard ratio (95% confidence interval) of 1.65 (1.18–2.32) for recurrent stroke and 1.47 (1.08–1.99) for the cardiovascular events, but not all-cause mortality 1.36 (0.96–1.93) at one year. However, there were no associations between plasma SDF-1 and clinical outcomes in patients without diabetes mellitus (all P > 0.05). The addition of plasma SDF-1 to the conventional risk factors model significantly improved the risk prediction of all outcomes. Similarly, findings between elevated SDF-1 levels and two-year outcomes were found only in patients with diabetes mellitus. Conclusions Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus.

Abstract Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD+ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD+ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD+ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD+ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1β generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD+ degradation due to enhanced macrophage-derived IL-1β production was responsible for BP elevation and vascular damage in hypertension. NAD+ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.

The cooling performance of the energy-saving water spray window cooling system under summer conditions in Nanning city in southern China, is experimentally examined in this study. By constructing two identical test rooms for comparison, in the experiment we analyzed the effects of water temperature (22 °C, 26 °C, 30 °C), spray frequency (8, 10, 12, 15 min intervals), glass structure (single-layer, double-layer, triple-layer), air conditioning temperature (26 °C, 27 °C, 28 °C, 29 °C), and outer lamination thickness (30, 50, 100, 200 mm) on the cooling effect of windows, aiming to determine the optimal operating conditions. The experimental outcomes demonstrate that the appropriate operating mode for the water spray window system involves using the coldest water source (22 °C), with a spray interval of 8 min, a three-layer air cavity sprayed glass construction, an air cavity thickness set at 100 mm, and the best air conditioning temperature (26 °C). The study found that the water spray system can reduce the outer glass surface temperature of the window by 6 °C and the inner surface temperature by 2 °C. Moreover, the more glass layers and the thicker the lamination, the higher the energy saving rate; with a maximum energy saving rate of 35.19%. The water spray window has good adaptability and significant energy-saving effects in Southeast Asia. By scientifically selecting energy-saving glass types and fine-tuning operating modes, it is expected that efficient building energy conservation in hot climates can be achieved.

Abstract Background Tumour-infiltrating lymphocytes (TILs), including T and B cells, have been demonstrated to be associated with tumour progression. However, the different subpopulations of TILs and their roles in breast cancer remain poorly understood. Large-scale analysis using multiomics data could uncover potential mechanisms and provide promising biomarkers for predicting immunotherapy response. Methods Single-cell transcriptome data for breast cancer samples were analysed to identify unique TIL subsets. Based on the expression profiles of marker genes in these subsets, a TIL-related prognostic model was developed by univariate and multivariate Cox analyses and LASSO regression for the TCGA training cohort containing 1089 breast cancer patients. Multiplex immunohistochemistry was used to confirm the presence of TIL subsets in breast cancer samples. The model was validated with a large-scale transcriptomic dataset for 3619 breast cancer patients, including the METABRIC cohort, six chemotherapy transcriptomic cohorts, and two immunotherapy transcriptomic cohorts. Results We identified two TIL subsets with high expression of CD103 and LAG3 (CD103+LAG3+), including a CD8+ T-cell subset and a B-cell subset. Based on the expression profiles of marker genes in these two subpopulations, we further developed a CD103+LAG3+ TIL-related prognostic model (CLTRP) based on CXCL13 and BIRC3 genes for predicting the prognosis of breast cancer patients. CLTRP-low patients had a better prognosis than CLTRP-high patients. The comprehensive results showed that a low CLTRP score was associated with a high TP53 mutation rate, high infiltration of CD8 T cells, helper T cells, and CD4 T cells, high sensitivity to chemotherapeutic drugs, and a good response to immunotherapy. In contrast, a high CLTRP score was correlated with a low TP53 mutation rate, high infiltration of M0 and M2 macrophages, low sensitivity to chemotherapeutic drugs, and a poor response to immunotherapy. Conclusions Our present study showed that the CLTRP score is a promising biomarker for distinguishing prognosis, drug sensitivity, molecular and immune characteristics, and immunotherapy outcomes in breast cancer patients. The CLTRP could serve as a valuable tool for clinical decision making regarding immunotherapy.

Abstract Purpose This study aimed to explore the survival significance of surgery and age on the prognosis of patients with primary trachea malignancies. Methods The entire cohort of 637 patients with primary malignant trachea tumors was used to perform the main analyses. The data of those patients were from a public database. Overall survival (OS) curves were drawn by the Kaplan-Meier method and compared by the Log-rank test. The univariable and multivariable Cox regression analyses calculated the hazard ratio (HR) and 95% confidence interval (CI) for overall mortality. The propensity-score matching analysis was used to reduce the selection bias. Results Age, surgery, histological type, N classification, M classification, marital status, and tumor grading were identified as independent prognostic factors after eliminating confounding factors. The results of the Kaplan-Meier method revealed that patients with age

Background. Uncontrolled hypertension is a major public health challenge in low- and middle-income countries. The Hypertension Control Program in Argentina (HCPIA) showed that a community health worker-led multicomponent intervention was effective for blood pressure (BP) reduction in resource-limited settings, but whether the intervention was equally effective across participant subgroups is unknown. Objective. To identify participants who benefit the most from the HCPIA BP control intervention. Methods. This secondary analysis used data from HCPIA, a successful 18-month cluster-randomized trial in 18 health centers with 1,432 low-income hypertensive patients in Argentina. Fifteen baseline characteristics were used to define subgroups. The proportion of controlled BP ( −24 mmHg). Women (p=0.01), those who were physically inactive (p=0.03), and those not taking antihypertensive medications at baseline (p=0.001) had the greatest BP response. Conclusion. The effect of the intervention was consistent across many subgroups with some key groups showing a particularly strong intervention effect. These findings could be useful for planning future hypertension control programs in low- and middle-income countries.

Background Diabetes and diabetes complications are on the rise in US adults aged

AbstractCoal bursts caused by mining-induced seismicity occur in the working face in steeply inclined and extra thick coal seams (SIETCSs). This article presents a case study in SIETCS through discrete element simulation as well as field investigation. The evolution of the coal burst was studied from the perspective of stress distribution, crack propagation and coal fragment ejection. The results showed that dynamic failure mainly occurred in the coal near the roof. The deep bottom coal and the top coal near the roof are under high static stress due to the clamping effect of the roof and floor and the rotation of the deep roof. The coal burst in the working face was triggered by mining-induced seismicity. The coal burst occurred when the sum of the static stress and the dynamic stress caused by the mining-induced seismicity exceeds the sum of the ultimate strength of the coal and the support strength, which was called the ‘clamping-rotation-dynamic loads’ mechanism. During the coal burst, the cracks developed rapidly into the deep bottom coal and the top coal on the roof side. The results can serve as an important reference for the coal burst failure mechanism in the working face in SIETCSs.

Designing tactile sensors with high spatial resolution are crucial to manufacture large scale flexible electronics. Here, the authors develop a micro-cage structure by exploiting photo-reticulated strain localization films (prslPDMS), which shows the strain local confinement effect and could be used to prepare ultralow crosstalk sensor arrays.

Abstract We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.

Abstract Background Due to its rarity, the features and prognosis of giant cell carcinoma of the lung (GCCL) are not well defined. The present study aimed to describe the clinicopathological features and prognostic analysis of this rare disease, compare it with lung adenocarcinoma (LAC), further determine the prognostic factors and establish a nomogram. Methods Patients diagnosed with GCCL and LAC were identified from the SEER database between 2004 and 2016. The features and survival between GCCL and LAC were compared in the unmatched and matched cohorts after propensity score matching (PSM) analysis. Univariate and multivariate Cox analyses were used to identify the prognostic factors, and a nomogram was constructed. Area under the curve (AUC), C‐index, calibration curve and decision curve analysis (DCA) were used to confirm the established nomogram. Results A total of 295 patient diagnosed with GCCL and 149 082 patients with LAC were identified. Compared with LAC, patients with GCCL tend to be younger, male, black and have pathological Grade III/IV GCCL, more proportion of AJCC‐TNM‐IV, T3/T4 and distant metastases. The 1‐, 2‐ and 5‐year OS rates of the patients with GCCL were 21.7%, 13.4% and 7.9%, respectively. The median OS and CSS were 3 and 4 months, respectively. Patients with GCCL had significantly shorter OS and CSS than those with LAC in the unmatched and matched cohorts after PSM. Multivariate Cox analysis demonstrated that T, N and M stages and use of chemotherapy and surgery were independent of survival. Furthermore, we constructed a prognostic nomogram for OS and CSS by using independent prognostic factors. The C‐index of OS‐specific nomogram is 0.78 (0.74–0.81), and the C‐index of CSS‐specific nomogram is 0.77 (0.73–0.80). The calibration curve and ROC analysis showed good predictive capability of these nomograms. DCA showed that the nomogram had greater clinical practical value in predicting the OS and CSS of GCCL than TNM staging. Conclusion GCCL have distinct clinicopathological characteristics and significantly worse clinical outcomes. Prognostic nomograms for overall survival (OS) and CSS were constructed.

Abstract Background The growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification. However, standard TSP methods do not accommodate covariates that could heavily influence feature selection for the top-scoring pair. Herein, we propose a covariate-adjusted TSP method, which uses residuals from a regression of features on the covariates for identifying top scoring pairs. We conduct simulations and a data application to investigate our method, and compare it to existing classifiers, LASSO and random forests. Results Our simulations found that features that were highly correlated with clinical variables had high likelihood of being selected as top scoring pairs in the standard TSP setting. However, through residualization, our covariate-adjusted TSP was able to identify new top scoring pairs, that were largely uncorrelated with clinical variables. In the data application, using patients with diabetes (n = 977) selected for metabolomic profiling in the Chronic Renal Insufficiency Cohort (CRIC) study, the standard TSP algorithm identified (valine-betaine, dimethyl-arg) as the top-scoring metabolite pair for classifying diabetic kidney disease (DKD) severity, whereas the covariate-adjusted TSP method identified the pair (pipazethate, octaethylene glycol) as top-scoring. Valine-betaine and dimethyl-arg had, respectively, ≥ 0.4 absolute correlation with urine albumin and serum creatinine, known prognosticators of DKD. Thus without covariate-adjustment the top-scoring pair largely reflected known markers of disease severity, whereas covariate-adjusted TSP uncovered features liberated from confounding, and identified independent prognostic markers of DKD severity. Furthermore, TSP-based methods achieved competitive classification accuracy in DKD to LASSO and random forests, while providing more parsimonious models. Conclusions We extended TSP-based methods to account for covariates, via a simple, easy to implement residualizing process. Our covariate-adjusted TSP method identified metabolite features, uncorrelated from clinical covariates, that discriminate DKD severity stage based on the relative ordering between two features, and thus provide insights into future studies on the order reversals in early vs advanced disease states.

Upper protective layer (UPL) mining is extensively utilised as a pressure relief strategy to prevent outbursts and coal bursts. However, when the excavation height of the protected layer is substantial, the depressurisation efficacy of the protective layer may be diminished. This paper takes the Haishiwan coal mine in China as a case study and explores the stress evolution and influencing factors in the mining of extra-thick coal seam beneath the protective layer through theoretical analysis, numerical simulation, and field observation. The results indicate that increasing the excavation height of the coal seam will lead to the upward development of the collapse zone in the overburden of the goaf, with the “masonry beam” structure formed at a higher position by key strata blocks. The overburden above the masonry beam will be supported by the coal rock masse on both sides of the structure, leading to increased stress on the coal seam near the goaf and eliminating the depressurisation effect of the protective layer. Numerical simulation shows that factors such as faults, protective layers, interlayer spacing, and the height of coal seam excavation significantly affect the stress distribution in the protected layer. With the increase in interlayer spacing and the thickness of coal seam extraction, the stress reduction phenomenon of the UPL gradually decreases, especially with an abnormal stress concentration of the gob-side coal seam. Observations of Surface subsidence and the distribution of mining-induced seismic events corroborate the conclusions of theoretical analysis and numerical simulations. The results offer valuable guidance for the mining of extra-thick coal seams and the selection of the UPL.

Background We aimed to evaluate the relationships between the magnitude of systolic blood pressure (SBP) reduction and achieved SBP in the acute phase of ischemic stroke onset and subsequent clinical outcomes. Methods and Results This study was a secondary analysis of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), a multicenter randomized controlled trial of 4071 patients with acute ischemic stroke. SBP reduction was defined as the proportional SBP changes from baseline to 24 hours after randomization, and achieved SBP was the mean of SBP measurements at day 7. The study outcomes included functional outcome of death or major disability (modified Rankin Scale score ≥3), death, and cardiovascular events at 3 months after recruitment. Compared with the reference group of increase or no change in SBP within the first 24 hours, the odds ratios (95% CIs) of functional outcome of death or major disability were 0.62 (0.47–0.83) and 0.61 (0.42–0.87) for the reduction of 11% to 20% and >20%, respectively. Compared with participants in highest achieved SBP group (≥160 mm Hg) at day 7, odds ratios or hazard ratios of lower achieved SBP (

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Abstract Intelligent technologies based on artificial intelligence and big data hold great potential for health monitoring and human–machine capability enhancement. However, electronics must be connected to the human body to realize this vision. Thus, tissue or skin‐like electronics with high stretchability and low stiffness mechanical properties are highly desirable. Ultrathin materials have attracted significant attention from the research community and the industry because of their high performance and flexibility. Over the past few years, considerable progress has been made in flexible ultrathin sensors and devices based on ultrathin materials. Here, we review the developments in this area and examine representative research progress in ultrathin materials fabrication and device construction. Strategies for the fabrication of stretchable ultrathin materials and devices are considered. The relationship between the thin‐film structure and performance is emphasized and highlighted. Finally, the current capabilities and limitations of ultrathin devices were explored.

Objective We aimed to establish an easy-to-use screening questionnaire with risk factors and suspected symptoms of COPD for primary health care settings. Methods Based on a nationwide epidemiological study of pulmonary health among adults in mainland China (China Pulmonary Health, CPH study) between 2012 and 2015, participants ≥40 years who completed the questionnaire and spirometry tests were recruited and randomly divided into development set and validation set by the ratio of 2:1. Parameters including sex, age, BMI, residence, education, smoking status, smoking pack-years, biomass exposure, parental history of respiratory diseases and daily respiratory symptoms were initially selected for the development of scoring system. Receiver operating characteristic (ROC) curve, area under curve (AUC), positive and negative predictive values were calculated in development set and validation set. Results After random split by 2:1 ratio, 22443 individuals were assigned to development set and 11221 to validation set. Ten variables were significantly associated with COPD independently in development set after a stepwise selection by multivariable logistic model and used to develop scoring system. The scoring system yielded good discrimination, as measured by AUC of 0.7737, and in the validation set, the AUC was 0.7711. When applying a cutoff point of ≥16, the sensitivity in development set was 0.69 (0.67 − 0.71); specificity 0.72 (0.71 − 0.73), PPV 0.25 (0.24 − 0.26) and NPV 0.94 (0.94 − 0.95). Conclusion We developed and validated a comprehensive screening questionnaire, COPD-CPHS, with good discrimination. The score system still needs to be validated by large cohort in the future. Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2022.2042504 .

Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with increasing incidence. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin has been used for the treatment of T2DM worldwide. Although sitagliptin has excellent therapeutic outcome, adverse effects are observed. In addition, previous studies have suggested that sitagliptin may have pleiotropic effects other than treating T2DM. These pieces of evidence point to the importance of further investigation of the molecular mechanisms of sitagliptin, starting from the identification of sitagliptin-binding proteins. In this study, by combining affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), we discover seven high-confidence targets that can interact with sitagliptin. Surface plasmon resonance (SPR) assay confirms the binding of sitagliptin to three proteins, i. e., LYPLAL1, TCP1, and CCAR2, with binding affinities (K D) ranging from 50.1 μM to 1490 μM. Molecular docking followed by molecular dynamic (MD) simulation reveals hydrogen binding between sitagliptin and the catalytic triad of LYPLAL1, and also between sitagliptin and the P-loop of ATP-binding pocket of TCP1. Molecular mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis indicates that sitagliptin can stably bind to LYPLAL1 and TCP1 in active sites, which may have an impact on the functions of these proteins. SPR analysis validates the binding affinity of sitagliptin to TCP1 mutant D88A is ~10 times lower than that to the wild-type TCP1. Our findings provide insights into the sitagliptin-targets interplay and demonstrate the potential of sitagliptin in regulating gluconeogenesis and in anti-tumor drug development.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Abstract Background Mechanisms by which AKI leads to CKD progression remain unclear. Several urine biomarkers have been identified as independent predictors of progressive CKD. It is unknown whether AKI may result in long-term changes in these urine biomarkers, which may mediate the effect of AKI on CKD progression. Methods We selected 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥ 1.5) among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. We matched the best non-AKI hospitalization (unique patients) for each AKI hospitalization using pre-hospitalization characteristics including eGFR and urine protein/creatinine ratio. Biomarkers were measured in banked urine samples collected at annual CRIC study visits. Results Urine biomarker measurements occurred a median of 7 months before and 5 months after hospitalization. There were no significant differences in the change in urine biomarker-to-creatinine ratio between the AKI and non-AKI groups: KIM-1/Cr + 9% vs + 7%, MCP-1/Cr + 4% vs + 1%, YKL-40/Cr + 7% vs -20%, EGF/Cr -11% vs -8%, UMOD/Cr -2% vs -7% and albumin/Cr + 17% vs + 13% (all p > 0.05). Conclusion In this cohort of adults with CKD, AKI did not associate with long-term changes in urine biomarkers.

Background We examined whether the relationship between baseline platelet count and clinical outcomes is modulated by HS‐CRP (high‐sensitivity C‐reactive protein) in patients with ischemic stroke. Methods and Results A total of 3267 patients with ischemic stroke were included in the analysis. The primary outcome was a combination of death and major disability at 1 year after ischemic stroke. Secondary outcomes included major disability, death, vascular events, composite outcome of vascular events or death, and an ordered 7‐level categorical score of the modified Rankin Scale at 1 year. Multivariate logistic regression and Cox proportional hazards regression models were used to assess the association between the baseline platelet count and clinical outcomes stratified by HS‐CRP levels when appropriate. There was an interaction effect of platelet count and HS‐CRP on the adverse clinical outcomes after ischemic stroke (all Pinteraction

IntroductionCapparis spinosa L. fruits as edible and medicinal plant, has anti-inflammatory activities. The different morphological characteristics of C. spinosa fruits from Ili, Turpan, and Karamay may affect their anti-inflammatory components and functions.MethodsThe anti-inflammatory activity of C. spinosa fruit was assessed using an LPS-induced inflammatory cell model. Furthermore, the differences in anti-inflammatory compounds were analyzed by metabolome and RNA-seq. Additionally, the anti-inflammatory mechanism was elucidated using network pharmacology.ResultsIn the study, we found that the 95% ethanol extracts (CSE) obtained from the three kinds of fruits showed remarkable anti-inflammatory effects both in vivo and in vitro. However, the CSE derived from Ili fruits significantly reduced CD86 levels on DCs. As a result of metabolomic analysis, the metabolic profiles of Ili fruits differed significantly from those of the other two habitats, which were consistent with transcriptome analysis. A total of 15 compounds exhibiting anti-inflammatory activity were subjected to screening, revealing a greater accumulation of flavonoids in the Turpan and Karamay districts. Notably, phenolic compounds were identified as the principal anti-inflammatory components in C. spinosa.ConclusionThere were significant differences in the morphology, metabolites, transcriptional levels, and anti-inflammatory activity of C. spinosa from the three districts.