Positional cloning and characterization reveal the role of TaSRN-3D and TaBSR1 in the regulation of seminal root number in wheat.

Seminal roots play a critical role in water and nutrient absorption, particularly in the early developmental stages of wheat. However, the genes responsible for controlling SRN in wheat remain largely unknown. Genetic mapping and functional analyses identified a candidate gene (TraesCS3D01G137200, TaSRN-3D) encoding a Ser/Thr kinase glycogen synthase kinase 3 (STKc_GSK3) that regulated SRN in wheat. Additionally, experiments involving hormone treatment, nitrate absorption and protein interaction were conducted to explore the regulatory mechanism of TaSRN-3D. Results showed that the TaSRN-3D4332 allele inhibited seminal roots initiation and development, while loss-of-function mutants showed significantly higher seminal root number (SRN). Exogenous application of epi-brassinolide could increase the SRN in a HS2-allelic background. Furthermore, chlorate sensitivity and 15N uptake assays revealed that a higher number of seminal roots promoted nitrate accumulation. TaBSR1 (BIN2-related SRN Regulator 1, orthologous to OsGRF4/GL2 in rice) acts as an interactor of TaSRN-3D and promotes TaBSR1 degradation to reduce SRN. This study provides valuable insights into understanding the genetic basis and regulatory network of SRN in wheat, highlighting their roles as potential targets for root-based improvement in wheat breeding.

Calpain inhibition protects against atrial fibrillation by mitigating diabetes-associated atrial fibrosis and calcium handling dysfunction in type 2 diabetes mice.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF. OBJECTIVE: The purpose of this study was to investigate the role of calpain in diabetes-associated AF, fibrosis, and calcium handling dysfunction. METHODS: DM-associated AF was induced in wild-type (WT) mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet feeding followed by low-dose streptozotocin injection (75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophageal atrial pacing. Intracellular Ca2+ transients, spontaneous Ca2+ release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy. RESULTS: WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca2+ handling dysfunction relative to control treated animals. CAST-OE mice with DM had a similar level of hyperglycemia as diabetic WT littermates but lacked significant atrial fibrosis and AF susceptibility. DM-induced atrial calpain activity and downregulation of the calpain substrate junctophilin-2 were prevented by CAST-OE. Atrial myocytes of diabetic CAST-OE mice exhibited improved T-tubule membrane organization, Ca2+ handling, and reduced spontaneous Ca2+ release events compared to littermate controls. CONCLUSION: This study confirmed that DM promotes calpain activation, atrial fibrosis, and AF in mice. CAST-OE effectively inhibits DM-induced calpain activation and reduces atrial remodeling and AF incidence through improved intracellular Ca2+ homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex.

BACKGROUND: Cardiac transverse tubules (T-tubules) are anchored to sarcomeric Z-discs by costameres to establish a regular spaced pattern. One of the major components of costameres is the dystrophin-glycoprotein complex (DGC). Nevertheless, how the assembly of the DGC coordinates with the formation and maintenance of T-tubules under physiological and pathological conditions remains unclear. METHODS: Given the known role of Ptpn23 (protein tyrosine phosphatase, nonreceptor type 23) in regulating membrane deformation, its expression in patients with dilated cardiomyopathy was determined. Taking advantage of Cre/Loxp, CRISPR/Cas9, and adeno-associated virus 9 (AAV9)-mediated in vivo gene editing, we generated cardiomyocyte-specific Ptpn23 and Actn2 (α-actinin-2, a major component of Z-discs) knockout mice. We also perturbed the DGC by using dystrophin global knockout mice (DmdE4*). MM 4-64 and Di-8-ANEPPS staining, Cav3 immunofluorescence, and transmission electron microscopy were performed to determine T-tubule structure in isolated cells and intact hearts. In addition, the assembly of the DGC with Ptpn23 and dystrophin loss of function was determined by glycerol-gradient fractionation and SDS-PAGE analysis. RESULTS: The expression level of Ptpn23 was reduced in failing hearts from dilated cardiomyopathy patients and mice. Genetic deletion of Ptpn23 resulted in disorganized T-tubules with enlarged diameters and progressive dilated cardiomyopathy without affecting sarcomere organization. AAV9-mediated mosaic somatic mutagenesis further indicated a cell-autonomous role of Ptpn23 in regulating T-tubule formation. Genetic and biochemical analyses showed that Ptpn23 was essential for the integrity of costameres, which anchor the T-tubule membrane to Z-discs, through interactions with α-actinin and dystrophin. Deletion of α-actinin altered the subcellular localization of Ptpn23 and DGCs. In addition, genetic inactivation of dystrophin caused similar T-tubule defects to Ptpn23 loss-of-function without affecting Ptpn23 localization at Z-discs. Last, inducible Ptpn23 knockout at 1 month of age showed Ptpn23 is also required for the maintenance of T-tubules in adult cardiomyocytes. CONCLUSIONS: Ptpn23 is essential for cardiac T-tubule formation and maintenance along Z-discs. During postnatal heart development, Ptpn23 interacts with sarcomeric α-actinin and coordinates the assembly of the DGC at costameres to sculpt T-tubule spatial patterning and morphology.

Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Structure, Function, and Regulation of the Junctophilin Family.

In both excitable and nonexcitable cells, diverse physiological processes are linked to different calcium microdomains within nanoscale junctions that form between the plasma membrane and endo-sarcoplasmic reticula. It is now appreciated that the junctophilin protein family is responsible for establishing, maintaining, and modulating the structure and function of these junctions. We review foundational findings from more than two decades of research that have uncovered how junctophilin-organized ultrastructural domains regulate evolutionarily conserved biological processes. We discuss what is known about the junctophilin family of proteins. Our goal is to summarize the current knowledge of junctophilin domain structure, function, and regulation and to highlight emerging avenues of research that help our understanding of the transcriptional, translational, and post-translational regulation of this gene family and its roles in health and during disease.

Modulation of miR-29 influences myocardial compliance likely through coordinated regulation of calcium handling and extracellular matrix.

MicroRNAs (miRNAs) control the expression of diverse subsets of target mRNAs, and studies have found miRNA dysregulation in failing hearts. Expression of miR-29 is abundant in heart, increases with aging, and is altered in cardiomyopathies. Prior studies demonstrate that miR-29 reduction via genetic knockout or pharmacologic blockade can blunt cardiac hypertrophy and fibrosis in mice. Surprisingly, this depended on specifically blunting miR-29 actions in cardiomyocytes versus fibroblasts. To begin developing more translationally relevant vectors, we generated a novel transgene-encoded miR-29 inhibitor (TuD-29) that can be incorporated into a viral-mediated gene therapy for cardioprotection. Here, we corroborate that miR-29 expression and activity is higher in cardiomyocytes versus fibroblasts and demonstrate that TuD-29 effectively blunts hypertrophic responses in cultured cardiomyocytes and mouse hearts. Furthermore, we found that adeno-associated virus (AAV)-mediated miR-29 overexpression in mouse hearts induces early diastolic dysfunction, whereas AAV:TuD-29 treatment improves cardiac output by increasing end-diastolic and stroke volumes. The integration of RNA sequencing and miRNA-target interactomes reveals that miR-29 regulates genes involved in calcium handling, cell stress and hypertrophy, metabolism, ion transport, and extracellular matrix remodeling. These investigations support a likely versatile role for miR-29 in influencing myocardial compliance and relaxation, potentially providing a unique therapeutic avenue to improve diastolic function in heart failure patients.

Using machine learning to predict adverse events in acute coronary syndrome: A retrospective study.

BACKGROUND: Up to 30% of patients with acute coronary syndrome (ACS) die from adverse events, mainly renal failure and myocardial infarction (MI). Accurate prediction of adverse events is therefore essential to improve patient prognosis. HYPOTHESIS: Machine learning (ML) methods can accurately identify risk factors and predict adverse events. METHODS: A total of 5240 patients diagnosed with ACS who underwent PCI were enrolled and followed for 1 year. Support vector machine, extreme gradient boosting, adaptive boosting, K-nearest neighbors, random forest, decision tree, categorical boosting, and linear discriminant analysis (LDA) were developed with 10-fold cross-validation to predict acute kidney injury (AKI), MI during hospitalization, and all-cause mortality within 1 year. Features with mean Shapley Additive exPlanations score >0.1 were screened by XGBoost method as input for model construction. Accuracy, F1 score, area under curve (AUC), and precision/recall curve were used to evaluate the performance of the models. RESULTS: Overall, 2.6% of patients died within 1 year, 4.2% had AKI, and 4.7% had MI during hospitalization. The LDA model was superior to the other seven ML models, with an AUC of 0.83, F1 score of 0.90, accuracy of 0.85, recall of 0.85, specificity of 0.68, and precision of 0.99 in predicting all-cause mortality. For AKI and MI, the LDA model also showed good discriminating capacity with an AUC of 0.74. CONCLUSION: The LDA model, using easily accessible variables from in-hospital patients, showed the potential to effectively predict the risk of adverse events and mortality within 1 year in ACS patients after PCI.

TaACTIN7-D regulates plant height and grain shape in bread wheat.

Exploitation of new gene resources and genetic networks contributing to the control of crop yield-related traits, such as plant height, grain size, and shape, may enable us to breed modern high-yielding wheat varieties through molecular methods. In this study, via ethylmethanesulfonate mutagenesis, we identify a wheat mutant plant, mu-597, that shows semi-dwarf plant architecture and round grain shape. Through bulked segregant RNA-seq and map-based cloning, the causal gene for the semi-dwarf phenotype of mu-597 is located. We find that a single-base mutation in the coding region of TaACTIN7-D (TaACT7-D), leading to a Gly-to-Ser (G65S) amino acid mutation at the 65th residue of the deduced TaACT7-D protein, can explain the semi-dwarfism and round grain shape of mu-597. Further evidence shows that the G65S mutation in TaACT7-D hinders the polymerization of actin from monomeric (G-actin) to filamentous (F-actin) status while attenuates wheat responses to multiple phytohormones, including brassinosteroids, auxin, and gibberellin. Together, these findings not only define a new semi-dwarfing gene resource that can be potentially used to design plant height and grain shape of bread wheat but also establish a direct link between actin structure modulation and phytohormone signal transduction.

Prediction model of atrial fibrillation recurrence after Cox-Maze IV procedure in patients with chronic valvular disease and atrial fibrillation based on machine learning algorithm. / åŸºäºŽæœºå™¨å­¦ä¹ çš„æ ¢æ€§ç“£è†œç— åˆå¹¶å¿ƒæˆ¿é¢¤åŠ¨æ‚£è€ è¡ŒCox迷宫IV手术后心房颤动复发风险预测模型.

OBJECTIVES: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia, and Cox-maze IV procedure (CMP-IV) is a commonly employed surgical technique for its treatment. Currently, the risk factors for atrial fibrillation recurrence following CMP-IV remain relatively unclear. In recent years, machine learning algorithms have demonstrated immense potential in enhancing diagnostic accuracy, predicting patient outcomes, and devising personalized treatment strategies. This study aims to evaluate the efficacy of CMP-IV on treating chronic valvular disease with AF, utilize machine learning algorithms to identify potential risk factors for AF recurrence, construct a CMP-IV postoperative AF recurrence prediction model. METHODS: A total of 555 patients with AF combined with chronic valvular disease, who met the criteria, were enrolled from January 2012 to December 2019 from the Second Xiangya Hospital of Central South University and the Affiliated Xinqiao Hospital of the Army Medical University, with an average age of (57.95±7.96) years, including an AF recurrence group (n=117) and an AF non-recurrence group (n=438). Kaplan-Meier method was used to analyze the sinus rhythm maintenance rate, and 9 machine learning models were developed including random forest, gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), bootstrap aggregating, logistic regression, categorical boosting (CatBoost), support vector machine, adaptive boosting, and multi-layer perceptron. Five-fold cross-validation and model evaluation indicators [including F1 score, accuracy, precision, recall, and area under the curve (AUC)] were used to evaluate the performance of the models. The 2 best-performing models were selected for further analyze, including feature importance evaluation and Shapley additive explanations (SHAP) analysis, identifying AF recurrence risk factors, and building an AF recurrence risk prediction model. RESULTS: The 5-year sinus rhythm maintenance rate for the patients was 82.13% (95% CI 78.51% to 85.93%). Among the 9 machine learning models, XGBoost and CatBoost models performed best, with the AUC of 0.768 (95% CI 0.742 to 0.786) and 0.762 (95% CI 0.723 to 0.801), respectively. Feature importance and SHAP analysis showed that duration of AF, preoperative left ventricular ejection fraction, postoperative heart rhythm, preoperative neutrophil-to-lymphocyte ratio, preoperative left atrial diameter, preoperative heart rate, and preoperative white blood cell were important factors for AF recurrence. Conclusion: Machine learning algorithms can be effectively used to identify potential risk factors for AF recurrence after CMP-IV. This study successfuly constructs 2 prediction model which may enhance individualized treatment plans.

CIB2 Is a Novel Endogenous Repressor of Atrial Remodeling.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent condition that can cause or exacerbate heart failure, is an important risk factor for stroke, and is associated with pronounced morbidity and death. Genes uniquely expressed in the atria are known to be essential for maintaining atrial structure and function. Atrial tissue remodeling contributes to arrhythmia recurrence and maintenance. However, the mechanism underlying atrial remodeling remains poorly understood. This study was designed to investigate whether other uncharacterized atrial specific genes play important roles in atrial physiology and arrhythmogenesis. METHODS: RNA-sequencing analysis was used to identify atrial myocyte specific and angiotensin II-responsive genes. Genetically modified, cardiomyocyte-specific mouse models (knockout and overexpression) were generated. In vivo and in vitro electrophysiological, histology, and biochemical analyses were performed to determine the consequences of CIB2 (calcium and integrin binding family member 2 protein) gain and loss of function in the atrium. RESULTS: Using RNA-sequencing analysis, we identified CIB2 as an atrial-enriched protein that is significantly downregulated in the left atria of patients with AF and mouse models of AF from angiotensin II infusion or pressure overload. Using cardiomyocyte-specific Cib2 knockout (Cib2-/-) and atrial myocyte-specific Cib2-overexpressing mouse models, we found that loss of Cib2 enhances AF occurrence, prolongs AF duration, and correlates with a significant increase in atrial fibrosis under stress. Conversely, Cib2 overexpression mitigates AF occurrence and atrial fibrosis triggered by angiotensin II stress. Mechanistically, we revealed that CIB2 competes with and inhibits CIB1-mediated calcineurin activation, thereby negating stress-induced structural remodeling and AF. CONCLUSIONS: Our data suggest that CIB2 represents a novel endogenous and atrial-enriched regulator that protects against atrial remodeling and AF under stress conditions. Therefore, CIB2 may represent a new potential target for treating AF.

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.

Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh Syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.

Machine learning-based analysis of risk factors for atrial fibrillation recurrence after Cox-Maze IV procedure in patients with atrial fibrillation and chronic valvular disease: A retrospective cohort study with a control group.

Objectives: To evaluate the efficacy of the Cox-Maze IV procedure (CMP-IV) in combination with valve surgery in patients with both atrial fibrillation (AF) and valvular disease and use machine learning algorithms to identify potential risk factors of AF recurrence. Methods: A total of 1,026 patients with AF and valvular disease from two hospitals were included in the study. 555 patients received the CMP-IV procedure in addition to valve surgery and left atrial appendage ligation (CMP-IV group), while 471 patients only received valve surgery and left atrial appendage ligation (Non-CMP-IV group). Kaplan-Meier analysis was used to calculate the sinus rhythm maintenance rate. 58 variables were selected as variables for each group and 10 machine learning models were developed respectively. The performance of the models was evaluated using five-fold cross-validation and metrics including F1 score, accuracy, precision, and recall. The four best-performing models for each group were selected for further analysis, including feature importance evaluation and SHAP analysis. Results: The 5-year sinus rhythm maintenance rate in the CMP-IV group was 82.13% (95% CI: 78.51%, 85.93%), while in the Non-CMP-IV group, it was 13.40% (95% CI: 10.44%, 17.20%). The eXtreme Gradient Boosting (XGBoost), LightGBM, Category Boosting (CatBoost) and Random Fores (RF) models performed the best in the CMP-IV group, with area under the curve (AUC) values of 0.768 (95% CI: 0.742, 0.786), 0.766 (95% CI: 0.744, 0.792), 0.762 (95% CI: 0.723, 0.801), and 0.732 (95% CI: 0.701, 0.763), respectively. In the Non-CMP-IV group, the LightGBM, XGBoost, CatBoost and RF models performed the best, with AUC values of 0.738 (95% CI: 0.699, 0.777), 0.732 (95% CI: 0.694, 0.770), 0.724 (95% CI: 0.668, 0.789), and 0.716 (95% CI: 0.656, 0.774), respectively. Analysis of feature importance and SHAP revealed that duration of AF, preoperative left ventricular ejection fraction, postoperative heart rhythm, preoperative neutrophil-lymphocyte ratio, preoperative left atrial diameter and heart rate were significant factors in AF recurrence. Conclusion: CMP-IV is effective in treating AF and multiple machine learning models were successfully developed, and several risk factors were identified for AF recurrence, which may aid clinical decision-making and optimize the individual surgical management of AF.

Reducing brassinosteroid signalling enhances grain yield in semi-dwarf wheat.

Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles1. However, both Rht-B1b and Rht-D1b are gain-of-function mutant alleles encoding gibberellin signalling repressors that stably repress plant growth and negatively affect nitrogen-use efficiency and grain filling2-5. Therefore, the green revolution varieties of wheat harbouring Rht-B1b or Rht-D1b usually produce smaller grain and require higher nitrogen fertilizer inputs to maintain their grain yields. Here we describe a strategy to design semi-dwarf wheat varieties without the need for Rht-B1b or Rht-D1b alleles. We discovered that absence of Rht-B1 and ZnF-B (encoding a RING-type E3 ligase) through a natural deletion of a haploblock of about 500 kilobases shaped semi-dwarf plants with more compact plant architecture and substantially improved grain yield (up to 15.2%) in field trials. Further genetic analysis confirmed that the deletion of ZnF-B induced the semi-dwarf trait in the absence of the Rht-B1b and Rht-D1b alleles through attenuating brassinosteroid (BR) perception. ZnF acts as a BR signalling activator to facilitate proteasomal destruction of the BR signalling repressor BRI1 kinase inhibitor 1 (TaBKI1), and loss of ZnF stabilizes TaBKI1 to block BR signalling transduction. Our findings not only identified a pivotal BR signalling modulator but also provided a creative strategy to design high-yield semi-dwarf wheat varieties by manipulating the BR signal pathway to sustain wheat production.

Clinical efficacy and safety of Cox-maze IV procedure for atrial fibrillation in patients with aortic valve calcification.

Objective: Atrial fibrillation is associated with a high incidence of heart valve disease. There are few prospective clinical research comparing aortic valve replacement with and without surgical ablation for safety and effectiveness. The purpose of this study was to compare the results of aortic valve replacement with and without the Cox-maze IV procedure in patients with calcific aortic valvular disease and atrial fibrillation. Methods: We analyzed one hundred and eight patients with calcific aortic valve disease and atrial fibrillation who underwent aortic valve replacement. Patients were divided into concomitant Cox maze surgery (Cox-maze group) and no concomitant Cox-maze operation (no Cox-maze group). After surgery, freedom from atrial fibrillation recurrence and all-cause mortality were evaluated. Results: Freedom from all-cause mortality after aortic valve replacement at 1 year was 100% in the Cox-maze group and 89%, respectively, in the no Cox-maze group. No Cox-maze group had a lower rate of freedom from atrial fibrillation recurrence and arrhythmia control than those in the Cox-maze group (P = 0.003 and P = 0.012, respectively). Pre-operatively higher systolic blood pressure (hazard ratio, 1.096; 95% CI, 1.004-1.196; P = 0.04) and post-operatively increased right atrium diameters (hazard ratio, 1.755; 95% CI, 1.182-2.604; P = 0.005) were associated with atrial fibrillation recurrence. Conclusion: The Cox-maze IV surgery combined with aortic valve replacement increased mid-term survival and decreased mid-term atrial fibrillation recurrence in patients with calcific aortic valve disease and atrial fibrillation. Pre-operatively higher systolic blood pressure and post-operatively increased right atrium diameters are associated with the prediction of recurrence of atrial fibrillation.

Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors.

A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC50 values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC50 = 0.64 µM, HeLa IDO1 IC50 = 1.04 µM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV-visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor-bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents.

Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents.

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 µM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.

The effects of different types of Tai Chi exercise on anxiety and depression in older adults: a systematic review and network meta-analysis.

Background: The body of evidence supporting the beneficial effects of Tai Chi in reducing anxiety and depressive symptoms in older adults is steadily increasing. Nonetheless, there remains a scarcity of studies directly comparing the clinical effectiveness of various Tai Chi exercises in addressing anxiety and depressive symptoms in older adults. Thus, this study aimed to systematically review and analyze the therapeutic efficacy of four types of Tai Chi interventions in enhancing anxiety and depressive symptoms in older adults. Methods: During the period up to July 26, 2023, searches were conducted in the Web of Science, PubMed, the Cochrane Library, CNKI, and the Chinese Scientific Journal Database (VIP). The language scope encompassed both English and Chinese. Two independent reviewers conducted the literature review and data extraction. Review Manager 5.4 was employed for traditional meta-analysis and risk assessment, while version 15 of STATA software was used for generating evidence and funnel plots for network meta-analysis. This study was registered in PROSPERO number CRD 42023442270. Result: In this analysis, a total of 20 studies were included, involving 1798 participants. The findings of the pairwise meta-analysis revealed that Tai Chi intervention was more effective than the control group in reducing anxiety (SMD: -1.19, 95% CI: -2.04, -0.34, p < 0.05) and depression (SMD: -0.65, 95% CI: -0.95, -0.65, p < 0.05) symptoms among older adults. The network meta-analysis specifically focused on anxiety symptoms and found that Yang-style Tai Chi (69.9%) had the most favorable outcome, followed by the 24-form Simplified Tai Chi (66.8%). In terms of depression symptoms, the Tai Chi Exercise Program (92.6%) had the highest performance, followed by Yang-style Tai Chi (77.9%). Conclusion: The findings of this study imply that Tai Chi can have beneficial outcomes in the reduction of anxiety and depressive symptoms among older individuals. Specifically, when examining various forms of Tai Chi interventions, it was observed that Yang-style Tai Chi exhibited a greater efficacy in alleviating anxiety symptoms, whereas Tai Chi exercise programs demonstrated a higher effectiveness in improving depressive symptoms. Nonetheless, it is strongly advised that older adults select an exercise program that aligns with their interests and preferences, as this can enhance social integration and overall well-being. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023442270, identifier [CRD42023442270].

Case report: Right ventricular outflow tract obstruction caused by multicomponent mesenchymal tumor.

Right ventricular outflow tract obstruction (RVOTO) is a cause of hemodynamic instability that can lead to right ventricular dysfunction. Cardiac tumors located in the right ventricle or surrounding structures can cause RVOTO. Herein, we present a rare case of a 21-year-old male with palpitations due to RVOTO caused by a cardiac multicomponent mesenchymal tumor. The tumor was localized in the right ventricular outflow tract, resulting in right side heart enlargement, tricuspid regurgitation, and RVOTO. Hence, tumor resection was performed. The patient was in a stable condition and discharged home on the 6th post-operative day. However, histopathological examination of the tumor specimen suggested a three-component mesenchymal tumor containing mucinous components, formed blood vessels, and fibrous tissue, which is like an atypical capillary hemangioma. After seven years of follow-up, the patient had no right heart enlargement, tricuspid regurgitation, and tumor recurrence. We believe surgical treatment is effective, and this case will provide a reference for clinicians to treat and evaluate the prognosis of similar three-component mesenchymal cardiac tumor cases in the future.