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Abstract Background Spontaneous Coronary Artery Dissection (SCAD) is an acute coronary event of uncertain origin. SCAD occurs when the coronary artery wall dissects non-traumatically and non-atherosclerotically, leading to the formation of an intramural hematoma or intimal tear, ultimately compressing and restricting the true lumen, or even occluding it. The management of SCAD remains controversial despite modern imaging techniques. In addition to supportive drug therapy, percutaneous coronary intervention (PCI) is another option that can be used as an effective treatment modality. Case presentation We describe A 50-year-old male with SCAD presented to the hospital emergency department complaining of chest pain. Coronary angiography incidentally showed spiral dissection from the proximal to distal right coronary artery (RCA). Three overlapping coroflex stents were deployed from the distal to the proximal RCA. Conclusions To stabilize the coronary artery in Acute Coronary Syndrome (ACS) patients due to SCAD, prompt interventions such as stenting and angioplasty are needed. However, it is necessary to pay attention to the clinical condition of patients and quick diagnosis for the recovery of patients and reduction of complications.

Abstract Purpose This study aimed to preliminarily investigate the association and possible mechanisms between Helicobacter. pylori (H. pylori) infection and type 2 diabetes mellitus (T2DM) through data collection, statistical analysis, and bioinformatics analysis. Methods A retrospective cohort study, including a total of 4406 participants who attended annual health checkups at Xian GEM Flower Changqing Hospital, was conducted to explore the correlation between the incidence of T2DM and H. pylori infection. To uncover the potential mechanisms underlying the interaction between the two diseases, differentially expressed genes (DEGs) common to T2DM and H. pylori infection were identified using the GEO database and Venn diagrams. These DEGs were then analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) analysis. Results In total, 2053 participants were classified into the H. pylori-positive group and 2353 into the H. pylori-negative group. H. pylori infection was associated with a higher risk of T2DM occurrence (adjusted HR 1.59; 95% CI 1.17–2.15, P = 0.003). The average disease-free survival time was 34.81 months (95% CI 34.60-35.03 months) in the H. pylori positive group and 35.42 months (95% CI 35.28–35.56 months) in the H. pylori negative group. Multivariate analysis and subgroup analyses also showed that H. pylori infection increased the risk of developing T2DM. A total of 21 DEGs between T2DM and H. pylori infection were identified and enriched in 7 signaling pathways, indicating specific protein interactions. Conclusions The prevalence of T2DM was associated with H. pylori infection. T2DM and H. pylori infection may interact with each other through metabolic and immune pathways.

Abstract Background TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear. Methods Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients’ survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7. Results In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155–27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients’ survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified. Conclusion TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.

Abstract Background Chitinase-3 like-protein-1 (CHI3L1) is a member of the mammalian chitinase-like proteins and elevated serum CHI3L1 level has been proved to be associated with poor prognosis in hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between serum CHI3L1 levels and body composition parameters in patients with HCC after liver transplantation (LT). Methods This retrospective study enrolled 200 patients after LT for HCC. Blood samples were collected and serum concentrations of CHI3L1 were measured by enzyme-linked immunosorbent assay. Computer tomography (CT) were used to estimate skeletal muscle and adipose tissue mass. Spearman’s rank correlation test was performed to assess associations between serum CHI3L1 levels and these body composition parameters. A Cox proportional-hazards regression model was performed to identify independent prognostic factors. Overall survival (OS) and recurrence-free survival (RFS) curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Results Total 71 patients (35.5%) were diagnosed with myosteatosis according to skeletal muscle radiation attenuation (SMRA). The 5-year OS rates were 66.9% in non-myosteatosis group, significantly higher than 49.5% in myosteatosis group (p = 0.025), while the RFS of myosteatosis group (5-year RFS: 52.6%) or non-myosteatosis group (5-year RFS: 42.0%) shown no significant difference (p = 0.068). The serum CHI3L1 level were significantly negative correlated with SMRA (r = -0.3, p

Abstract Background This study aims to evaluate the association of metabolic syndrome (MetS) with the risk of all-cause mortality in elderly patients with acute respiratory distress syndrome (ARDS). Methods Elderly ARDS patients (≥ 65 years) enrolled from our hospital between January 2018 and July 2023 were divided into the MetS group or the non-MetS group. The outcomes were 28-day and 90-day all-cause mortality rates in the total population and two subgroups stratified by age (65–75 years and ≥ 75 years). Multivariate Cox regression was employed to assess the association of MetS with all-cause mortality, after controlling for potential cofounding factors. Results A total of 946 patients were divided into the MetS group (n = 410) or the non-MetS group (n = 536). The 28-day and 90-day all-cause mortality rates were significantly higher for MetS group compared to non-MetS group in the total population and two subgroups (all P

Abstract Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.

Abstract Background Eosinophilic esophagitis is a chronic inflammatory disorder of the esophagus. This real-world study used patient and physician surveys to describe the clinical characteristics and disease burden of eosinophilic esophagitis—overall and in a subgroup of patients with dysphagia despite treatment. Methods Data analyzed in this study were collected in 2020 from US and EU patients with eosinophilic esophagitis. Eligible patients were aged ≥ 12 years with a diagnosis of eosinophilic esophagitis, had an esophageal count of ≥ 15 eosinophils/high-power field at diagnosis, and were currently prescribed treatment for eosinophilic esophagitis. Results Overall, 1001 patients were included, of whom 356 (36%) had dysphagia despite treatment. Demographics and clinical characteristics were similar in both populations. The severity of eosinophilic esophagitis was mild in more patients overall (69%) versus those with dysphagia despite treatment (48%). Patient disease history was similar in both populations, with some exceptions: common patient-reported symptoms were dysphagia (70% and 86%) and heartburn/acid reflux (55% and 49%), and common physician-reported symptoms were dysphagia (75% and 91%) and food impaction (46% and 52%). Treatment history was similar in both populations; overall, the most common treatments were proton pump inhibitors (83%) and topical corticosteroids (51%). Patients reported slightly more days with symptoms, higher impacts on activities of daily living, and slightly higher anxiety or depression in the dysphagia-despite-treatment population versus the overall population. Conclusions Eosinophilic esophagitis presents severe symptoms and comorbidities that substantially impact patients’ well-being and quality of life. Greater awareness of and novel treatments for eosinophilic esophagitis are needed.

Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

Abstract Background Lung cancer is a common cause of brain metastases, approximately 40% of patients with lung cancer will develop brain metastases at some point during their disease. Hypofractionated stereotactic radiotherapy (HSRT) has been demonstrated to be effective in controlling limited brain metastases. However, there is still no conclusive on the optimal segmentation of HSRT. The aim of our study was to explore the correlation between the HSRT dosage and its treatment effect and toxicity. Methods A retrospective analysis was conducted on patients with non-small cell lung cancer (NSCLC) brain metastasis at Hangzhou Cancer Hospital from 1 January 2019 to 1 January 2021. The number of brain metastases did not exceed 10 in all patients and the number of fractions of HSRT was 5. The prescription dose ranges from 25 to 40 Gy. The Kaplan–Meier method was used for estimation of the localised intracranial control rate (iLC). Adverse radiation effects (AREs) were evaluated according to CTCAE 5.0. This study was approved by the Institutional Ethics Review Board of the Hangzhou Cancer Hospital (#73/HZCH-2022). Results Forty eligible patients with a total of 70 brain metastases were included in this study. The 1-year iLC was 76% and 89% in the prescribed dose ≤ 30 Gy and > 30 Gy group, respectively (P

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear. Methods Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays. Results The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients. Conclusions This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.

Hepatocellular carcinoma (HCC) is one of the cancers with the highest incidence and mortality rates in China and often presents with insidious early clinical manifestations. This frequency results in the majority of patients being diagnosed at middle and advanced stage of the disease, thereby missing the opportunity for potentially curative surgical interventions. For patients who are ineligible for radical surgical resection, a variety of therapeutic approaches, including systemic antitumor therapy, local radiotherapy, interventional treatment, and liver transplantation, have been employed. Moreover, neoadjuvant therapies have transformed a subset of initially unresectable HCC cases into operable ones. Nevertheless, many patients fail to benefit from these treatments, underscoring the urgent need for novel therapeutic targets. Cancer-associated fibroblasts (CAFs), a principal component of the solid tumor microenvironment, play a pivotal role in the proliferation, migration, invasion, and treatment resistance of cancer cells. This review delineates the origins of CAFs and their mechanisms of action in the pathogenesis and progression of HCC and discusses potential therapeutic strategies targeting CAFs.

Objective To compare the differences in gut microbiota between cirrhosis patients receiving transjugular intrahepatic portosystemic shunt (TIPS) and those not, and explore the relationship between TIPS surgery and gut microbiota in order to provide new ideas for improving the prognosis of cirrhosis patients after TIPS surgery based on gut microbiota. Methods Those who had received TIPS surgery previously were assigned into the operation group, and those without the surgery served as the control group. Their stool samples were collected for 16S rRNA sequencing, and the correlation between gut microbiota and clinical indicators was analyzed. Results There were no significant differences in gender, age, body mass index (BMI), etiology and other baseline data between the 2 groups (P>0.05), but obvious differences were observed in clinical serological indicators between them, including INR, APTT, RBC and PT counts, and HGB, ALP, ALB, total bilirubin (TBIL), and URE levels (P0.05), but beta diversity was obviously different (P

Abstract Hepatic ischemia–reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P

The regenerative capability of the liver is remarkable, but further research is required to understand the role that neutrophils play in this process. In the present study, we reanalyzed single‐cell RNA sequencing data from a mouse partial hepatectomy (PH) model to track the transcriptional changes in hepatocytes and non‐parenchymal cells. Notably, we unraveled the regenerative capacity of hepatocytes at diverse temporal points after PH, unveiling the contributions of three distinct zones in the liver regeneration process. In addition, we observed that the depletion of neutrophils reduced the survival and liver volume after PH, confirming the important role of neutrophils in liver regeneration. CellChat analysis revealed an intricate crosstalk between neutrophils and macrophages promoting liver regeneration and, using weighted gene correlation network analysis, we identified the most significant genetic module associated with liver regeneration. Our study found that hepatocytes in the periportal zone of the liver are more active than in other zones, suggesting that the crosstalk between neutrophils and macrophages might be a potential target for liver regeneration treatment.

Liver transplantation (LT) is the standard therapy for individuals afflicted with end-stage liver disease. Despite notable advancements in LT technology, the incidence of early allograft dysfunction (EAD) remains a critical concern, exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients. Unfortunately, the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD. Herein, we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients, with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages. Comparison of the 75 231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells, granzyme B+ (GZMB+) granzyme K+ (GZMK+) natural killer cells, and S100 calcium binding protein A12+ (S100A12+) neutrophils. Moreover, we verified this immune niche and its association with EAD occurrence in two independent cohorts. Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level, thus, offering valuable insights into EAD onset.

Abstract Charge loss at grain boundaries of kesterite Cu2ZnSn(S, Se)4 polycrystalline absorbers is an important cause limiting the performance of this emerging thin-film solar cell. Herein, we report a Pd element assisted reaction strategy to suppress atomic vacancy defects in GB regions. The Pd, on one hand in the form of PdSe x compounds, can heterogeneously cover the GBs of the absorber film, suppressing Sn and Se volatilization loss and the formation of their vacancy defects (i.e. VSn and VSe), and on the other hand, in the form of Pd(II)/Pd(IV) redox shuttle, can assist the capture and exchange of Se atoms, thus contributing to eliminating the already-existing VSe defects within GBs. These collective effects have effectively reduced charge recombination loss and enhanced p-type characteristics of the kesterite absorber. As a result, high-performance kesterite solar cells with a total-area efficiency of 14.5% (certified at 14.3%) have been achieved.

Abstract Background To improve patient outcomes and provider team practice, the California Perinatal Quality Care Collaborative (CPQCC) created the Simulating Success quality improvement program to assist hospitals in implementing a neonatal resuscitation training curriculum. This study aimed to examine the costs associated with the design and implementation of the Simulating Success program. Methods From 2017–2020, a total of 14 sites participated in the Simulating Success program and 4 of them systematically collected resource utilization data. Using a micro-costing approach, we examined costs for the design and implementation of the program occurring at CPQCC and the 4 study sites. Data collection forms were used to track personnel time, equipment/supplies, space use, and travel (including transportation, food, and lodging). Cost analysis was conducted from the healthcare sector perspective. Costs incurred by CPQCC were allocated to participant sites and then combined with site-specific costs to estimate the mean cost per site, along with its 95% confidence interval (CI). Cost estimates were inflation-adjusted to 2022 U.S. dollars. Results Designing and implementing the Simulating Success program cost $228,148.36 at CPQCC, with personnel cost accounting for the largest share (92.2%), followed by program-related travel (6.1%), equipment/supplies (1.5%), and space use (0.2%). Allocating these costs across participant sites and accounting for site-specific resource utilizations resulted in a mean cost of $39,210.69 per participant site (95% CI: $34,094.52-$44,326.86). In sensitivity analysis varying several study assumptions (e.g., number of participant sites, exclusion of design costs, and useful life span of manikins), the mean cost per site changed from $35,645.22 to $39,935.73. At all four sites, monthly cost of other neonatal resuscitation training was lower during the program implementation period (mean = $1,112.52 per site) than pre-implementation period (mean = $2,504.01 per site). In the 3 months after the Simulating Success program ended, monthly cost of neonatal resuscitation training was also lower than the pre-implementation period at two of the four sites. Conclusions Establishing a multi-site neonatal in situ simulation program requires investment of sufficient resources. However, such programs may have financial and non-financial benefits in the long run by offsetting the need for other neonatal resuscitation training and improving practice.

Objective: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC. Methods: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied. Results: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM ( P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival ( P < 0.05). Conclusions: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation.

BackgroundMore than 1 million women have their labor induced in the United States each year, and synthetic oxytocin infusion is the most common method used. However, compared to spontaneous labor, medical induction is resource intensive, has increased obstetric risks, and is associated with less successful breastfeeding. In contrast to the endogenous oxytocin hormone, which is released in a pulsatile fashion in the brain, synthetic oxytocin is continuously infused intravenously, resulting in important limitations related to efficacy, safety, and cost. Akin to spontaneous labor contractions, infant suckling of the breast nipple is known to stimulate the pulsatile release of endogenous oxytocin from the posterior pituitary gland. Nipple stimulation therapy via an electric breast pump similarly stimulates endogenous oxytocin release and may be a favorable inpatient method for patients undergoing labor induction. ObjectiveThis study aims to examine whether inpatient nipple stimulation therapy is an efficacious labor induction method that increases the likelihood of spontaneous vaginal delivery and sustained breastfeeding and determine whether it is a cost-effective approach. MethodsThis is a multicenter, pragmatic, open-label, parallel-group randomized controlled trial of nulliparous patients with singleton gestations ≥36 weeks undergoing labor induction. This trial compares inpatient nipple stimulation therapy via an electric breast pump versus immediate synthetic oxytocin infusion without nipple stimulation. This trial including 988 nulliparas will provide adequate statistical power to detect clinically meaningful differences in delivery mode and breast milk as the sole source of nutrition for newborns at hospital discharge or 72 hours after birth. ResultsThe project received pilot funding in 2021 and full funding in 2023. Enrollment for this study began in November 2021 at a single site, and as of May 2024, recruitment is underway at 3 study sites. It is anticipated that enrollment will be completed by late 2026. ConclusionsSuccessful completion of this trial will provide rigorous data to determine whether inpatient nipple stimulation therapy with an electric breast pump can improve the way we induce labor and positively impact breastfeeding success and early infant nutrition through lactation. Trial RegistrationClinicalTrials.gov NCT05079841; https://clinicaltrials.gov/study/NCT05079841 International Registered Report Identifier (IRRID)DERR1-10.2196/63463

ObjectiveWe conducted this meta-analysis to comprehensively explore the prognostic value of the preoperative plasma fibrinogen in Asian patients diagnosed with urothelial cancer (UC).MethodsAfter a systematic search of Web of Science, PubMed, and Embase before May 2024, we included 10 studies in our meta-analysis. The hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression free survival (PFS) were estimated using fixed effect model.ResultsThis meta-analysis included a total of 2875 patients. UC patients with an elevated preoperative plasma fibrinogen had worse OS (pooled HR: 2.13, 95% CI: 1.81-2.51; P

Objectives: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI. Methods: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome. Results: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway. Conclusions: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1β pathway.

BackgroundCuproptosis is copper-induced cell death. Copper metabolism related genes (CMRGs) were demonstrated that used to assess the prognosis out of tumors. In the study, CMRGs were tested for their effect on TME cell infiltration in Ewing’s sarcoma (ES).MethodsThe GEO and ICGC databases provided the mRNA expression profiles and clinical features for downloading. In the GSE17674 dataset, 22prognostic-related copper metabolism related genes (PR-CMRGs) was identified by using univariate regression analysis. Subsequently, in order to compare the survival rates of groups with high and low expression of these PR-CMRGs,Kaplan-Meier analysis was implemented. Additionally, correlations among them were examined. The study employed functional enrichment analysis to investigate probable underlying pathways, while GSVA was applied to evaluate enriched pathways in the ES (Expression Set). Through an unsupervised clustering algorithm, samples were classified into two clusters, revealing significant differences in survival rates and levels of immune infiltration.ResultsUsing Lasso and step regression methods, five genes (TFRC, SORD, SLC11A2, FKBP4, and AANAT) were selected as risk signatures. According to the Kaplan-Meier survival analysis, the high-risk group had considerably lower survival rates than the low-risk group(p=6.013e-09). The area under the curve (AUC) values for the receiver operating characteristic (ROC) curve were 0.876, 0.883, and 0.979 for 1, 3, and 5 years, respectively. The risk model was further validated in additional datasets, namely GSE63155, GSE63156, and the ICGC datasets. To aid in outcome prediction, a nomogram was developed that incorporated risk levels and clinical features. This nomogram’s performance was effectively validated through calibration curves.Additionally, the study evaluated the variations in immune infiltration across different risk groups, as well as high-expression and low-expression groups. Importantly, several drugs were identified that displayed sensitivity, offering potential therapeutic options for ES.ConclusionThe findings above strongly indicate that CMRGs play crucial roles in predicting prognosis and immune status in ES.

Background: To assess the alterations in gingival thickness and the occurrence gingival recession subsequent to orthodontic-orthognathic treatment of mandibular incisors in skeletal Class III and identify risk factors associated with gingival recession. Methods: In this retrospective cohort study, we enrolled 33 patients exhibiting skeletal Class III malocclusion, totaling 131 mandibular incisors, who were undergoing orthodontic- orthognathic treatment that did not involve extraction of mandibular teeth. The subjects were categorized into surgery group (S; n = 17; ANB = −5.55 ± 3.26; IOFTN = 4.60 ± 0.51, scores ranging: 4.3–5.3) and non-surgery group (NS; n = 16; ANB = −3.00 ± 4.08; IOFTN = 4.63 ± 0.50, scores ranging: 4.3–5.4), based on if they had history of Periodontally Accelerated Osteogenic Orthodontics surgery (S) or not (NS). Patients in S group received orthognathic surgery about 1–1.5 years after Periodontally Accelerated Osteogenic Orthodontics surgery. Alterations in gingival thickness, gingival recession, and keratinized gingival width were compared before and after orthodontic-orthognathic treatment. Logistic regression analysis was used to construct a gingival recession prediction model and draw nomograms. Results: After orthodontic-orthognathic treatment, the gingival thickness and keratinized gingival width in NS group decreased by 0.15 ± 0.21 mm and 0.74 ± 0.91 mm, whereas those in the S group increased by 0.32 ± 0.28 mm and 2.09 ± 1.51 mm (P

Background: Approximately 50% of patients harbor the T790M mutation after developing first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Evidence has showed the major treatment failure is local relapses and limited metastases. Several studies have demonstrated the value of radiotherapy in metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation after the development of TKI resistance. The aim of this study was to explore the role of radiation in T790M-mutant NSCLC and the value of early radiotherapy for NSCLC with T790M-mediated EGFR-TKI resistance. Methods: Gefitinib-resistant NSCLC cell lines were established via stepwise exposure to increasing concentrations of gefitinib (PC-9-GR). Droplet digital PCR was used to determine the relative T790M subclone abundance. In vitro and in vivo models were established using different mixtures of PC-9-GR and PC-9 cells. Differentially expressed genes were identified using RNA sequencing. Two research models were constructed (salvage and prophylactic radiotherapy) to determine the effects of early radiotherapy on gefitinib-resistant cells. Results: PC-9-GR cells exhibited higher radiosensitivity than PC-9 cells (sensitivity enhancement ratio = 1.5). Salvage radiation reduced the number of T790M-mutant subclones, and the relative T790M abundance was significantly lower than that without radiation at 90 days (10.94% vs. 21.54%). Prophylactic radiation prevented the development of T790M subclones. These results were also confirmed in vivo. qRT-PCR revealed threefold elevation of miR-1243 in PC-9-GR cells, and the increased radiosensitivity of PC-9-GR cells was inhibited when miR-1243 was knocked down. RNA sequencing revealed that SPOCK1 was downregulated in PC-9-GR cells. Interestingly, bioinformatic analysis showed that SPOCK1 was a target gene of miR-1243. SPOCK1 knockdown markedly increased the radiosensitivity of PC-9 cells. Conclusion: Gefitinib-resistant NSCLC with the T790M mutation had higher radiosensitivity than that without the mutation, possibly mediated by SPOCK1. Early radiotherapy can eliminate T790M subclones, providing evidence for the benefit of early local treatment in patients with TKI-resistant NSCLC.

● Objective based county-level AGD evaluation index system was established.● A typical agricultural county of Quzhou County in the North China Plain was use as a representative study.● Unbalanced development was revealed as well as large gaps relative to targets.● Spearman rank correlation analysis revealed more synergistic effect than trade-off effect.● Trade-off existed between eco-environment and both food production and socioeconomic dimensions.Agriculture green development (AGD) has become an unavoidable choice to address the unique national circumstances of China. This study established a county-level AGD evaluation index system, comprised three dimensions, food production, ecological environment and socioeconomic development, using 20 indicators. The assessment delved into historical trend and current situation, utilizing Spearman rank correlation analysis to analyze trade-off and synergy relationships, using Quzhou County, Hebei Province as a case study. The main findings were in four areas. Firstly, the index for AGD in Quzhou County increased by 58.9% from 1978 to 2019. The major contribution were the social economy (65.8%) and food production (53.5%), whereas the ecological environment was found to have had a negative impact. Secondly, in 2019, the AGD index was only 56.4, indicating substantial potential for improvement relative to the target value. A notable difference in scores existed between the three dimensions, with the order being ecological environment (66.3) > food production (61.7) > socioeconomic (41.3). Also, 90% of the indicators did not reach the target value. Thirdly, relationship analysis of the indicators revealed that the synergistic effect exceeded the trade-off effect. Specifically, 46.3% of the indicators had no significant relationship, 35.3% had a synergistic relationship, and 18.4% had a trade-off relationship. Finally, interdimensional indicator relationships exhibited a trade-off effect between the ecological environment and both food production and socioeconomic dimensions. However, a positive trend of synergy between production and ecology has emerged since 2015. In conclusion, the quantitative evaluation index system exposed the unbalanced development and significant potential relative to the target value of AGD in Quzhou County, despite notable progress.

The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation. The portal system plays a crucial role in the dual blood supply to the liver, making it a significant factor in hepatic function. Several surgical strategies, such as portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy, and dual vein embolization, have highlighted the portal system's importance in liver regeneration. Following hepatectomy or liver transplantation, the hemodynamic properties of the portal system change dramatically, triggering regeneration via shear stress and the induction of hypoxia. However, excessive portal hyperperfusion can harm the liver and negatively affect patient outcomes. Furthermore, as the importance of the gut–liver axis has gradually been revealed, the effect of metabolites and cytokines from gut microbes carried by portal blood on liver regeneration has been acknowledged. From these perspectives, this review outlines the molecular mechanisms of the portal system's role in liver regeneration and summarizes therapeutic strategies based on the portal system intervention to promote liver regeneration.

The bank slope rock mass below the flood control restricted water level (145 m) in the Three Gorges Reservoir area has experienced long-term immersion in the process of reservoir water lifting and lowering; the water level changes lead to the rock mass being subjected to two working conditions, tangential loading shearing and normal unloading shearing. The difference in rock shearing characteristics directly affects the stability evaluation of bank slopes in different reservoir operation stages. Tangential loading and normal unloading shear tests were carried out on the typical feldspar quartz sandstone after different soaking days; then the characteristics changes of sandstone shear under the two stress conditions were obtained. The microscopic mechanism of the differences was revealed by solution test, SEM test, and nuclear magnetic resonance test. The results show that: (1) compared with the initial sample, after soaking for 80 days, the cohesion loss of the sample is greater than the loss of internal friction angle. The cohesion of the sample under tangential loading is reduced by 40.5%, and the internal friction Angle is only reduced by 2%, while the cohesion of the sample under normal unloading shear is reduced by 31%, and the internal friction Angle is reduced by 8%. (2) The long-term immersion of the sample results in the dissolution of the cement minerals, the gradual development and penetration of the secondary pores, and the increase of porosity. After 60 days of immersion, basically， the water content, porosity, and pore structure of the sample reach a stable state; the particle skeleton overcoming the shear action is almost no longer affected by the soaking water. This is the reason why the shear properties of the samples with long-term water saturation gradually weaken and become stable. (3) Under normal unloading shear conditions, the deviation between the main crack surface and the theoretical shear surface increases; the fracture surface is more inclined to form “S” and “M” types. The increase of the actual shear plane increases the peak shear stress that the rock can bear. Because the biggest contribution to the rock is the skeleton particle, the internal friction angle is larger, and the filling cementing material that provides cohesion makes less contribution to the tensile shear failure. The cohesion obtained by normal unloading is also lower. This study can provide basic information for the stability evaluation of wading slope in reservoir area with the fluctuation of water level and the selection of test method considering the actual working conditions.

Abstract Sirolimus is a regularly applied immunosuppressant for patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Sirolimus not only significantly inhibits HCC recurrence but also protects renal function. However, the improvement effect of sirolimus on nontumour-related death in patients is still unknown. The aim of our study was to investigate the therapeutic effect of sirolimus on nontumour-related deaths. In this study, we retrospectively enrolled 403 LT patients with HCC from January 1, 2015, to December 31, 2018. The median follow-up time was 47.1 months. The patients were divided into the sirolimus group (N = 184) and the sirolimus-free group (N = 219). There were no significant differences between the sirolimus group and the sirolimus-free group in survival (P = 0.054). In transplant patients who exceeded the Milan or Hangzhou criteria, the sirolimus group achieved higher survival than the sirolimus-free group (P = 0.005; P = 0.02). Moreover, multivariate analysis showed that sirolimus strongly reduced the hazard ratio (HR) for nontumour-related death in LT patients who exceeded the Milan (HR: 0.42; 95% CI: 0.18–1; P = 0.05) or Hangzhou criteria (HR: 0.26; 95% CI: 0.08–0.89; P = 0.032). HCC recurrence increased the risk of nontumour-related death. In conclusion, sirolimus-based immunosuppression can significantly reduce nontumour-related death in LT patients who exceed the criteria for transplantation. In addition, this finding will further promote the application of sirolimus after liver transplantation for hepatocellular carcinoma.

Abstract The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes the physiological function of the SOX family and their multiple roles in tumors, with a focus on the relationship between the SOX family and TIME, aiming to propose their potential role in cancer and promising methods for treatment.

Abstract Background circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear. Methods circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo. Results circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo. Conclusion circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.

Abstract Bird sex chromosomes play a unique role in sex-determination, and affect the sexual morphology and behavior of bird species. Core waterbirds, a major clade of birds, share the common characteristics of being sexually monomorphic and having lower levels of inter-sexual conflict, yet their sex chromosome evolution remains poorly understood. Here, by we analyse of a chromosome-level assembly of a female crested ibis (Nipponia nippon), a typical core waterbird. We identify neo-sex chromosomes resulting from fusion of microchromosomes with ancient sex chromosomes. These fusion events likely occurred following the divergence of Threskiornithidae and Ardeidae. The neo-W chromosome of the crested ibis exhibits the characteristics of slow degradation, which is reflected in its retention of abundant gametologous genes. Neo-W chromosome genes display an apparent ovary-biased gene expression, which is largely driven by genes that are retained on the crested ibis W chromosome but lost in other bird species. These results provide new insights into the evolutionary history and expression patterns for the sex chromosomes of bird species.

Abstract Background The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. Methods The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). Results Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. Conclusion Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function. Graphical Abstract Tet2 interacts with Stat1 in the cytoplasm and suppresses IFN-γ-induced macrophage activation. Tet2 inhibitor decreases the combination of Stat1 and Tet2, activating the macrophages through the Jak-Stat pathway. The activation of macrophages increases the transcription and translation of the IL-6 and promotes liver regeneration. Video Abstract

Abstract Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. Graphical Abstract

Abstract Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap ‘n’ Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.

Abstract In the evolving landscape of global education, the significance of inclusivity and equity has never been more important. Emphasizing the United Nation Sustainable Development Goal 4, this paper explores the innovative application of blockchain-powered Zero-Knowledge Proofs (ZKPs) technology in education, with a particular focus on disability inclusion. This study introduces a novel disability management system powered by Zero-Knowledge Succinct Non-Interactive Argument of Knowledge (zk-SNARK). This advanced system enables educational institutions to verify the status of students with disabilities without compromising their personal information, thereby preserving their privacy and reinforcing their identity. This paper evaluates the potential operational efficiency of this prototype system against the existing costs incurred by higher education institutions in disability schemes. It also examines the system’s potential to enhance self-disclosure among students with disability, which is pivotal for their academic success. By advocating for privacy and inclusivity, this study highlights the transformative potential of ZKP in creating an educational environment where students with disabilities can comfortably disclose their needs. This approach not only protects their confidentiality but also empowers them academically, aligning with the global commitment to accessible and inclusive education.

Abstract Osteosarcopenia is defined as the concurrent occurrence of osteopenia/osteoporosis and sarcopenia. The aim of the current study was to perform a systematic review with meta‐analysis to determine the global prevalence, risk factors and clinical outcomes of osteosarcopenia. This review was registered in PROSPERO (CRD42022351229). PubMed, Cochrane, Medline and Embase were searched from inception to February 2023 to retrieve eligible observational population‐based studies. Pooled osteosarcopenia prevalence was calculated with 95% confidence interval (CI), and subgroup analyses were performed. The risk factor of osteosarcopenia and its association with clinical outcomes were expressed as odds ratio (OR) and hazard ratio (HR), respectively. Heterogeneity was estimated using the I2 test. Study quality was assessed using validated instruments matched to study designs. The search identified 55 158 studies, and 66 studies (64 404 participants, mean age from 46.6 to 93 years) were analysed in the final analysis, including 48 cross‐sectional studies, 17 cohort studies and 1 case–control study. Overall, the pooled prevalence of osteosarcopenia was 18.5% (95% CI: 16.7–20.3, I2 = 98.7%), including 15.3% (95% CI: 13.2–17.4, I2 = 97.6%) in men and 19.4% (95% CI: 16.9–21.9, I2 = 98.5%) in women. The prevalence of osteosarcopenia diagnosed using sarcopenia plus osteopenia/osteoporosis was 20.7% (95% CI: 17.1–24.4, I2 = 98.55%), and the prevalence of using sarcopenia plus osteoporosis was 16.1% (95% CI: 13.3–18.9, I2 = 98.0%). The global osteosarcopenia prevalence varied in different regions with 22.9% in Oceania, 21.6% in Asia, 20.8% in South America, 15.7% in North America and 10.9% in Europe. A statistically significant difference was found in the subgroups of the study population between the hospital (24.7%) and community (12.9%) (P = 0.001). Frailty (OR = 4.72, 95% CI: 2.71–8.23, I2 = 61.1%), malnutrition (OR = 2.35, 95% CI: 1.62–3.40, I2 = 50.0%), female sex (OR = 5.07, 95% CI: 2.96–8.69, I2 = 73.0%) and higher age (OR = 1.10, 95% CI: 1.06–1.15, I2==86.0%) were significantly associated with a higher risk for osteosarcopenia. Meta‐analysis of cohort studies showed that osteosarcopenia significantly increased the risk of fall (HR = 1.54, 95% CI: 1.20–1.97; I2 = 1.0%, three studies), fracture (HR = 2.13, 95% CI: 1.61–2.81; I2 = 67.8%, seven studies) and mortality (HR = 1.75, 95% CI: 1.34–2.28; I2 = 0.0%, five studies). Despite the heterogeneity arising from varied definitions and criteria, our findings highlight a significant global prevalence of osteosarcopenia and its negative impact on clinical health. Standardizing diagnostic criteria for osteosarcopenia would be advantageous in the future, and early detection and management should be emphasized in this patient population.

Abstract Eukaryotic messenger RNAs (mRNAs) are often modified with methyl groups at the N6 position of adenosine (m6A), and these changes are interpreted by YTH domain-containing proteins to regulate the metabolism of m6A-modified mRNAs. Although alfalfa (Medicago sativa) is an established model organism for forage development, the understanding of YTH proteins in alfalfa is still limited. In the present investigation, 53 putative YTH genes, each encoding a YT521 domain-containing protein, were identified within the alfalfa genome. These genes were categorized into two subfamilies: YTHDF (49 members) and YTHDC (four members). Each subfamily demonstrates analogous motif distributions and domain architectures. Specifically, proteins encoded by MsYTHDF genes incorporate a single domain structure, while those corresponding to MsYTH5, 8, 12, 16 who are identified as members of the MsYTHDC subfamily, exhibit CCCH-type zinc finger repeats at their N-termini. It is also observed that the predicted aromatic cage pocket that binds the m6A residue of MsYTHDC consists of a sequence of two tryptophan residues and one tyrosine residue (WWY). Conversely, in MsYTHDF, the binding pocket comprises two highly conserved tryptophan residues and either one tryptophan residue (WWW) or tyrosine residue (WWY) in MsYTHDF. Through comparative analysis of qRT-PCR data, we observed distinct expression patterns in specific genes under abiotic stress, indicating their potential regulatory roles. Notably, five genes (MsYTH2, 14, 26, 27, 48) consistently exhibit upregulation, and two genes (MsYTH33, 35) are downregulated in response to both cold and salt stress. This suggests a common mechanism among these YTH proteins in response to various abiotic stressors in alfalfa. Further, integrating qRT-PCR with RNA-seq data revealed that MsYTH2, MsYTH14, and MsYTH16 are highly expressed in leaves at various development stages, underscoring their potential roles in regulating the growth of these plant parts. The obtained findings shed further light on the biological functions of MsYTH genes and may aid in the selection of suitable candidate genes for future genetic enhancement endeavors aimed at improving salt and cold tolerance in alfalfa.

Abstract Although chromatin organizations in plants have been dissected at the scales of compartments and topologically associating domain (TAD)-like domains, there remains a gap in resolving fine-scale structures. Here, we use Micro-C-XL, a high-throughput chromosome conformation capture (Hi-C)-based technology that involves micrococcal nuclease (instead of restriction enzymes) and long cross-linkers, to dissect single nucleosome-resolution chromatin organization in Arabidopsis. Insulation analysis reveals more than 14,000 boundaries, which mostly include chromatin accessibility, epigenetic modifications, and transcription factors. Micro-C-XL reveals associations between RNA Pols and local chromatin organizations, suggesting that gene transcription substantially contributes to the establishment of local chromatin domains. By perturbing Pol II both genetically and chemically at the gene level, we confirm its function in regulating chromatin organization. Visible loops and stripes are assigned to super-enhancers and their targeted genes, thus providing direct insights for the identification and mechanistic analysis of distal CREs and their working modes in plants. We further investigate possible factors regulating these chromatin loops. Subsequently, we expand Micro-C-XL to soybean and rice. In summary, we use Micro-C-XL for analyses of plants, which reveal fine-scale chromatin organization and enhancer-promoter loops and provide insights regarding three-dimensional genomes in plants.

Remote sensing semantic change detection (SCD) involves extracting information about changes in land cover/land use (LCLU) within the same area at different times. This issue is of crucial significance in many Earth observation tasks, such as precise urban planning and natural resource management. However, the current methods primarily focus on spatial feature extraction, lacking awareness of temporal features. Consequently, there are challenges in extracting change features, making distinguishing intraclass and interclass differences difficult. This also contributes to pseudochange, posing challenges for SCD tasks. To overcome the limitations of existing methods, we present a dual-dimension feature interaction network (DFINet) for SCD. First, to enhance the assessment and perceptual abilities related to intraclass and interclass differences, we introduce a temporal difference feature enhancement (TDFE) module. This module comprehensively captures features from the temporal dimension. Then, to address the interrelation between multitemporal and multilevel features, we investigate the feature selection interaction (FSIA) and interaction attention modules (IAM), which enable multidimensional deep fusion and interaction of change features. This enhances the capacity for information transfer and integration among the features within multitemporal remote sensing images (RSIs). The experimental results demonstrate that, compared to existing methods, the proposed architecture achieves a significant improvement in accuracy. Additionally, the design enhancements added to DFINet boost the practicality of remote sensing SCD, underscoring its substantial research value.

Transplantation represents the most effective treatment for end-stage liver diseases but is limited by the shortage of healthy donor organs. Extended criteria donor (ECD) liver grafts are increasingly utilized in clinical practice to mitigate this challenge. However, impaired ischemic tolerance of these grafts jeopardizes organ viability during cold storage. Machine perfusion (MP) was designed to improve organ preservation and reduce posttransplant complications. Nevertheless, it is increasingly evident that MP alone may not preserve ECD grafts optimally. Increasing emphasis has thus been placed on modified MP strategies, including the use of different perfusates, modified perfusion modalities, and different therapeutic interventions. Here, we introduce a novel term, “MP Plus,” denoting these additional strategies that are designed to restore organ function and potentially enable regeneration of ECD grafts. In this review, we summarize the existing and potential modified MP strategies and discuss their advantages in reconditioning different ECD grafts in clinical settings.

The vehicle-to-grid (V2G) technology enables the bidirectional power flow between electric vehicle (EV) batteries and the power grid, making EV-based mobile energy storage an appealing supplement to stationary energy storage systems. However, the stochastic and volatile charging behaviors pose a challenge for EV fleets to engage directly in multi-agent cooperation. To unlock the scheduling potential of EVs, this paper proposes a source-load-storage cooperative low-carbon scheduling strategy considering V2G aggregators. The uncertainty of EV charging patterns is managed through a rolling-horizon control framework, where the scheduling and control horizons are adaptively adjusted according to the availability periods of EVs. Moreover, a Minkowski-sum based aggregation method is employed to evaluate the scheduling potential of aggregated EV fleets within a given scheduling horizon. This method effectively reduces the variable dimension while preserving the charging and discharging constraints of individual EVs. Subsequently, a Nash bargaining based cooperative scheduling model involving a distribution system operator (DSO), an EV aggregator (EVA), and a load aggregator (LA) is established to maximize the social welfare and improve the low-carbon performance of the system. This model is solved by the alternating direction method of multipliers (ADMM) algorithm in a distributed manner, with privacy of participants fully preserved. The proposed strategy is proven to achieve the objective of low-carbon economic operation.

Background & Aims: Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. Methods: Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. Results: We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. Conclusions: These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.

Abstract Multiple myeloma (MM) remains an incurable hematological malignancy disease characterized by the progressive dysfunction of the patient’s immune system. In this context, immunotherapy for MM has emerged as a prominent area of research in recent years. Various targeted immunotherapy strategies, such as monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T cells/natural killer (NK) cells, and checkpoint inhibitors have been developed for MM. This review aims to discuss promising experimental and clinical evidence as well as the mechanisms of action underlying these immunotherapies. Specifically, we will explore the design of exosome-based bispecific monoclonal antibodies that offer cell-free immunotherapy options. The treatment landscape for myeloma continues to evolve with the development of numerous emerging immunotherapies. Given their significant advantages in modulating the MM immune environment through immune-targeted therapy, these approaches provide novel perspectives in selecting cutting-edge treatments for MM.

Abstract Background Orthodontic tooth movement (OTM) in a region containing alveolar bone defects with insufficient height and width is hard to achieve. Bovine bone mineral (Bio-Oss) is available to restore the alveolar defect; however, whether the region augmented with a bovine bone mineral graft (BG) is feasible for OTM, and the mechanisms by which macrophages remodel the BG material, is uncertain under the mechanical force induced by OTM. Material and methods Rats were divided into three groups: OTM (O), OTM + BG material (O + B), and Control (C). First molars were extracted to create bone defects in the O and O + B groups with bovine bone mineral grafting in the latter. Second molars received OTM towards the bone defects in both groups. After 28 days, maxillae were analyzed using microfocus-computed tomography (μCT) and scanning-electron-microscopy (SEM); and macrophages (M1/M2) were stained using immunofluorescence. THP-1 cell-induced macrophages were cultured under mechanical force (F), BG material (B), or both (F + B). Phagocytosis-related signaling molecules (cAMP/PKA/RAC1) were analyzed, and conditioned media was analyzed for MMP-9 and cytokines (IL-1β, IL-4). Results Our study demonstrated that alveolar defects grafted with BG materials are feasible for OTM, with significantly increased OTM distance, bone volume, and trabecular thickness in this region. SEM observation revealed that the grafts served as a scaffold for cells to migrate and remodel the BG materials in the defect during OTM. Moreover, the population of M2 macrophages increased markedly both in vivo and in cell culture, with enhanced phagocytosis via the cAMP/PKA/RAC1 pathway in response to mechanical force in combination with BG particles. By contrast, M1 macrophage populations were decreased under the same circumstances. In addition, M2 macrophage polarization was also indicated by elevated IL-4 levels, reduced IL-1β levels, and less active MMP-9 in cell culture. Conclusion This study explored the mechanisms of mechanical force-induced alveolar bone remodeling with bovine bone mineral grafts during OTM. The results might provide molecular insights into the related clinical problems of whether we can move teeth into the grafted materials; and how these materials become biologically remodeled and degraded under mechanical force.

In this study, a composite coating comprising a ceramic film and layered double hydroxide (LDHs) layer was prepared on the surface of extruded 2195 Al–Li alloy. The preparation method, surface morphology, and chemical composition of the coating were described and characterized in detail. The corrosion and wear protection of the coating on the Al–Li alloy substrate were tested, and the mechanisms of corrosion and wear resistance were discussed. The results indicate that plasma electrolytic oxidation processing can form a thick ceramic film with good interface bonding on the surface of 2195 Al–Li alloy. Hydrothermal reaction in an alkaline solution produces a nanoscale layer of Mg/Al LDHs on the surface of the ceramic film. The LDHs layer fills the micro-pores and cracks in the film and effectively prevents the corrosion medium from permeating and damaging the alloy matrix. The composite coating reduces the surface corrosion efficiency by 99.98 %. Moreover, the composite-coated samples exhibit long-lasting corrosion resistance in seawater and exfoliation corrosion environments. Additionally, the composite-coated Al–Li alloy exhibits wear resistance 1-2 orders of magnitude higher than that of the bare alloy at both room and high temperatures. This study proposes a novel strategy for corrosion and wear protection of Al–Li alloys.

Manganese (Mn) is necessary for various biological processes, yet its function in innate immunity has been less studied, especially in fish. Stimulator of interferon (IFN) genes (STING) is an essential factor for IFN induction in virus infection. Our study demonstrated that Mn2+ increases the ability of zebrafish to resist spring viraemia of carp virus (SVCV) infection by enhancing the expression of STING. Further mechanistic studies indicated that Mn2+ promotes the expression of STING by increasing its ubiquitination. Furthermore, Mn2+treatment promoted STING-mediated activation of IFN and reversed the decrease in STING protein induced by SVCV. Collectively, our findings showed the vital involvement and necessity of Mn2+ in protecting fish against SVCV infection.