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Abstract Background The ACEF score (age, creatinine, and left ventricular ejection fraction) and the triglyceride-glucose (TyG) index have been identified as robust risk prediction models for adverse outcomes post-percutaneous coronary intervention (PCI) in coronary atherosclerotic heart disease (CHD) patients. This study aimed to assess whether incorporating the TyG index enhances the predictive ability of the ACEF score and enhances risk stratification for CHD patients undergoing PCI. Methods This observational cohort study enrolled 1248 patients diagnosed with CHD who underwent PCI at the Third People’s Hospital of Chengdu, China, between May 2018 and December 2022. Receiver operating characteristic (ROC) curves were employed to establish the optimal cutoff values for the TyG index and ACEF score. The primary endpoint event was defined as major adverse cardiac and cerebrovascular events (MACCEs). Cumulative survival curves were plotted using the Kaplan–Meier method. Univariable and multivariable Cox regression analyses were conducted to identify predictors of MACCEs. The predictive ability of the ACEF score and the TyG index was assessed using the area under the ROC curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results Over a median follow-up period of 30.60 months, 214 patients experienced MACCEs. Kaplan-Meier survival analysis demonstrated a significant association between elevated ACEF score (> 1.27) and TyG index levels (> 8.82) with a heightened incidence of MACCEs (HR = 2.018, 95%CI 1.593–2.789; HR = 2.057, 95%CI 1.572–2.691; Log-Rank test, both P

Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3-H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase ε, govern parental histone H3-H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using fission yeast heterochromatin inheritance systems that eliminate interference from initiation pathways, we show that a Mcm2 histone binding mutation severely disrupts heterochromatin inheritance, while mutations in Dpb3/4 cause only moderate defects. Surprisingly, simultaneous mutations of Mcm2 and Dpb3/4 stabilize heterochromatin inheritance. eSPAN (enrichment and sequencing of protein-associated nascent DNA) analyses confirmed the conservation of Mcm2 and Dpb3/4 functions in parental histone H3-H4 segregation, with their combined absence showing a more symmetric distribution of parental histone H3-H4 than either single mutation alone. Furthermore, the FACT histone chaperone regulates parental histone transfer to both strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone H3-H4 density and faithful heterochromatin inheritance. These results underscore the importance of both symmetric distribution of parental histones and their density at daughter strands for epigenetic inheritance and unveil distinctive properties of parental histone chaperones during DNA replication.

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3' processing machinery.

Background: The Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria were proposed for predicting bleeding risk in patients undergoing percutaneous coronary intervention (PCI). However, there is a lack of research evaluating the risk of in-hospital bleeding following PCI for acute coronary syndrome (ACS) utilizing the ARC-HBR criteria. Methods and results: This study involved 1013 ACS patients who underwent PCI and dual antiplatelet therapy. There were 63 cases of in-hospital bleeding events (6.22 %). According to the ARC-HBR criteria, patients classified as HBR had a significantly greater bleeding rate than non-HBR patients (15.81 % vs. 1.99 %, p

Objective To investigate the related influence factors of neonatal transfusion-associated necrotizing enterocolitis （TANEC）. Methods Clinical data of neonates with necrotizing enterocolitis （NEC） treated by surgery were retrospectively analyzed. All participants were divided into the TANEC and non-TANEC groups. Clinical characteristics， maternal conditions， laboratory test results， intraoperative conditions and clinical prognosis were subject to univariate and multivariate Logistic regression analyses. Related factors of TANEC were identified. The predictive values of these factors were determined by the receiver operating characteristic （ROC） curve and the area under the ROC curve （AUC）. Results A total of 51 infants were enrolled in this study， including 13 cases in the TANEC group and 38 in the non-TANEC group. Univariate analysis showed statistically significant differences in birth weight， Apgar-1 score， gestational age， number of transfusions， patent ductus arteriosus and hemoglobin level between two groups （all P < 0.05）. Multivariate Logistic regression analysis revealed that the number of transfusions and hemoglobin level were the related factors for the incidence of TANEC （both P < 0.05）. ROC curve verified that the AUC of the number of transfusions was 0.882 （95% CI 0.794-0.969）， 0.857 （95% CI 0.747-0.968） for hemoglobin level， and 0.907 （95% CI 0.822-0.992） for the two combined， respectively. Conclusion The number of blood transfusion and hemoglobin level are associated with the occurrence of TANEC， and the combination of these two can better predict the incidence of TANEC.

Transdermal drug delivery (TDD) has gained clinical approval over several decades, with extensive research dedicated to novel drug and device development. Despite notable research progress, the market adoption of TDD devices has not met anticipated levels, with oral administration and injection remaining predominant delivery methods. To maximize the potential of TDD, we identify bottlenecks hindering its widespread clinical application and propose promising research avenues. We begin by analyzing stringent demands necessary to truly benefit patients, addressing significant challenges in biomechanics, nanomedicine, and flexible electronics. Subsequently, we delve into skin anatomy, enhancement strategies, nano-carriers, and their underlining mechanisms, highlighting the importance and framework of quantitative modeling. Based on these discussions, we highlight the core strength of TDD, such as automatic precise administration based on feedback and high delivery efficiencies, especially applicable to localized conditions (e.g., central nervous system diseases, tumors). Finally, we envision the future of intelligent TDD device and its operation scenario, aiming to steer research efforts toward faster translation of laboratory innovations into widely used products for sufferers.

The current study was designed to explore the effects of dietary vitamin E on the ovarian development and health of female largemouth bass (Micropterus salmoides). Five experimental diets were formulated, each containing varying concentrations of vitamin E: 78.25, 98.36, 209.31, 437.77, and 915.49 mg/kg of vitamin E. These diets were administered to female largemouth bass (445.52 ± 13.57 g) for 35 days. The results demonstrated that fishes fed with 209.31 mg/kg vitamin E exhibited a significantly higher gonadosomatic index (GSI), visceral steatosis index, absolute fecundity, and relative fecundity compared to those fed with 78.25 mg/kg of vitamin E (P

Abstract Actomyosin networks constrict cell area and junctions to alter cell and tissue shape. However, during cell expansion under mechanical stress, actomyosin networks are strengthened and polarized to relax stress. Thus, cells face a conflicting situation between the enhanced actomyosin contractile properties and the expansion behaviour of the cell or tissue. To address this paradoxical situation, we study late Drosophila oogenesis and reveal an unusual epithelial expansion wave behaviour. Mechanistically, Rac1 and Rho1 integrate basal pulsatile actomyosin networks with ruffles and focal adhesions to increase and then stabilize basal area of epithelial cells allowing their flattening and elongation. This epithelial expansion behaviour bridges cell changes to oocyte growth and extension, while oocyte growth in turn deforms the epithelium to drive cell spreading. Basal pulsatile actomyosin networks exhibit non-contractile mechanics, non-linear structures and F-actin/Myosin-II spatiotemporal signal separation, implicating unreported expanding properties. Biophysical modelling incorporating these expanding properties well simulates epithelial cell expansion waves. Our work thus highlights actomyosin expanding properties as a key mechanism driving tissue morphogenesis.

The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53null or p53WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.

It has been widely accepted that China is one of the biggest natural gas consumers. Related to the imports of LNG, China stands in a very uncomfortable situation. Most domestic gas reservoirs fall within deep water drive gas reservoirs inordinately, which has entered the production depletion stage. Accurate estimation of SEC recoverable reserves of deep water drive gas reservoirs is of great significance for gas consumption planning and peak shaving. The existing calculation methods of recoverable reserves mainly consist of static methods and dynamic methods. In the early stage of exploration and development, the volumetric method has often been utilized to calculate the recoverable reserves. With the continuous development of gas reservoirs, the main methods for evaluation are dynamic methods, including the successive subtraction of production method, water drive curve method, prediction model method, attenuation curve method, improved virtual curve method, and material balance method for deep gas reservoirs.

Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p. Thus, these results indicated that MiR-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

BackgroundA novel non-contact system for remote parameter testing and reprogramming offers an alternative method for assessing device parameters during cardiac implantable electronic devices (CIEDs) implantation without the need for physical contact with the manufacturer's clinical service technician. The safety and feasibility of using this system in CIEDs implantation procedures remains to be determined.ObjectiveEvaluate the safety and feasibility of remote parameter testing in CIEDs implantation procedures.MethodsA single center, randomized, open-label, non-inferiority trial (ChiCTR2200057587) was conducted to compare the two approaches for interrogating CIEDs during implantation procedures: routine interrogation performed by on-site technicians or remote interrogation performed by technicians using the 5G-Cloud Technology Platform. Patients aged ≥18 years and elected to receive CIEDs were eligible for inclusion. The primary endpoint was the completion rate of the parameter test. Safety and efficiency were evaluated in all randomly assigned participants.ResultsA total of 480 patients were finally enrolled and were randomly assigned to routine group (n = 240) or remote group (n = 240). The primary endpoint was achieved by 100% in both groups (P = 0.0060 for noninferiority). The parameters of sensing, threshold, and impedance regarding the right atrium, right ventricle, and left ventricle had no statistical significance between the two groups (P > 0.05). Procedure time, parameter testing time, and both duration and dose of x-ray irradiation were not significantly different between the two groups (P > 0.05). Shut-open door frequency was significantly higher in the routine group than the remote group [6.00 (4.00, 8.00) vs. 0, P