Umpolung Strategy for the One-Pot Synthesis of Highly Steric Bispirooxindoles via the l-Amino Acid Ester-Promoted In Situ Reduction/Nucleophilic Addition/Cyclization Cascade Reaction.

On the basis of a novel umpolung strategy, an efficient l-amino acid ester-mediated in situ reduction of 2-(2-oxoindolin-3-ylidene)malononitrile and sequential nucleophilic addition/cyclization cascade reaction is reported. Various densely substituted cyclopentene bispirooxindoles and dihydrofuran bispirooxindoles with two quaternary spirocenters were constructed in high yields (≤93%) with excellent diastereoselectivities (>20:1 dr). The method has advantages of readily available starting materials, mild reaction conditions, a one-pot process, a metal-free biomimetic reducing agent, a wide substrate scope, and operational simplicity (single filtration without column chromatography).

Cu-Promoted Divergent Phosphination of Alkynylsulfonium Salts with Diarylphosphines.

An efficient copper-promoted divergent phosphination of alkynylsulfonium salts 1 with secondary diarylphosphines 2 that tolerates a wide range of functional groups under mild conditions is reported. The use of excess alkynyl dibenzothiophenium salts (1/2 > 1, mole ratio) enables the phosphination to deliver alkynyl monophosphine products via a C(sp)-P cross-coupling in good to high yields, while the use of excess secondary diarylphosphines (1/2 < 0.5, mole ratio) leads to a type of cis-ethenyl bisphosphine products via sequential stereoselective double phosphination.

Guidelines for the diagnosis and treatment of neurally mediated syncope in children and adolescents (revised 2024).

BACKGROUND: Significant progress has been made in the diagnosis and treatment of pediatric syncope since the publication of the "2018 Chinese Pediatric Cardiology Society (CPCS) guideline for diagnosis and treatment of syncope in children and adolescents" ("2018 Edition Guidelines"). Therefore, we have revised and updated it to assist pediatricians in effectively managing children with syncope. DATA SOURCES: According to the "2018 Edition Guidelines", the expert groups collected clinical evidence, evaluated preliminary recommendations, and then organized open-ended discussions to form the recommendations. This guideline was developed by reviewing the literature and studies in databases including PubMed, Cochrane, EMBASE, China Biomedical Database, and Chinese Journal Full-text Database up to April 2024. Search terms included "syncope", "children", "adolescents", "diagnosis", and "treatment." RESULTS: The guidelines were based on the latest global research progress and were evidence-based. The classification of syncope etiology, diagnostic procedures, postural tests, such as the active standing test, head-up tilt test, and active sitting test, clinical diagnosis, and individualized treatment for neurally mediated syncope in pediatric population were included. CONCLUSIONS: The guidelines were updated based on the latest literature. The concepts of sitting tachycardia syndrome and sitting hypertension were introduced and the comorbidities of neurally mediated syncope were emphasized. Some biomarkers used for individualized treatment were underlined. Specific suggestions were put forward for non-pharmacological therapies as well as the follow-up process. The new guidelines will provide comprehensive guidance and reference for the diagnosis and treatment of neurally mediated syncope in children and adolescents.

Research landscape of genetics in dilated cardiomyopathy: insight from a bibliometric analysis.

Background: Dilated cardiomyopathy (DCM) is a heterogeneous myocardial disorder with diverse genetic or acquired origins. Notable advances have been achieved in discovering and understanding the genetics of DCM. This study aimed to depict the distribution of the main research forces, hotspots, and frontiers in the genetics of DCM, thus shaping future research directions. Methods: Based on the documents published in the Web of Science Core Collection database from 2013 to 2022, co-authorship of authors, institutions, and countries/regions, co-citation of references, and co-occurrence of keywords were conducted respectively to present the distribution of the leading research forces, research hotspots, and emerging trends in the genetics of DCM. Results: 4,141 documents were included, and the annual publications have steadily increased. Seidman, Christine E, Meder, Benjamin, Sinagra, Gianfranco were the most productive authors, German Centre for Cardiovascular Research was the most productive institution, and the USA, China, and Germany were the most prolific countries. The co-occurrence of keywords has generated 8 clusters, including DCM, lamin a/c, heart failure, sudden cardiac death, hypertrophic cardiomyopathy, cardiac hypertrophy, arrhythmogenic cardiomyopathy, and next-generation sequencing. Frequent keywords with average publication time after 2019 mainly included arrhythmogenic cardiomyopathy, whole-exome sequencing, RBM 20, phenotype, risk stratification, precision medicine, genotype, and machine learning. Conclusion: The research landscape of genetics in DCM is continuously evolving. Deciphering the genetic profiles by next-generation sequencing and illustrating pathogenic mechanisms of gene variants, establishing innovative treatments for heart failure and improved risk stratification for SCD, uncovering the genetic overlaps between DCM and other inherited cardiomyopathies, as well as identifying genotype-phenotype correlations are the main research hotspots and frontiers in this field.

Palladium-catalyzed regio- and stereo-selective phosphination of cyclic biarylsulfonium salts to access atropoisomeric phosphines.

A palladium-catalyzed regio- and stereo-selective phosphination of cyclic biarylsulfonium salts (racemic) with HPAr3Ar4 for straightforward synthesis of atropoisomeric phosphines (P,S-ligands) bearing a stereogenic axis or both a stereogenic axis and a P-stereogenic center is reported. The high reactivity and regio- and stereo-selectivity originate from the torsional strain release and palladium catalysis, and the construction of a P-stereogenic center is enabled by an efficient dynamic kinetic resolution. The high performance of the nascent P,S-ligands has been demonstrated in palladium-catalyzed asymmetric allylic substitutions, indicating the great potential of the present methodology.

Prognostic insights and immune microenvironment delineation in acute myeloid leukemia by ferroptosis-derived signature.

Acute myeloid leukemia (AML) represents as a prevalent and formidable hematological malignancy, characterized by notably low 5-year survival rates. Ferroptosis has been found to be correlated with cancer initiation, therapeutic response, and clinical outcome. Nevertheless, the involvement of Ferroptosis-related genes (FRGs) in AML remains ambiguous. Five independent AML cohorts totaling 1,470 (GSE37642, GSE12417, GSE10358, Beat-AML, and TCGA-AML) patients with clinical information were used to systematically investigated the influence of these FRGs expression on outcome and tumor microenvironment. The integration of these datasets led to the subdivision into training and validation sets. Nineteen FRGs were identified as correlated with the overall survival (OS) of AML patients, primarily enriched in ferroptosis, fatty acid metabolism, and leukemia-related signaling pathways. The prognostic signature, consisting of 11 FRGs, was formulated using LASSO-Cox stepwise regression analysis. Patients with high-risk scores exhibited reduced survival compared to those in the low-risk group. The receiver operating characteristic (ROC) analysis underscored the signature's robust predictive accuracy. The high predictive efficacy was confirmed by both internal and external validation datasets. Leukemia and signaling related to immune regulation were mainly enriched pathways of the differentially expressed genes by comparing high- and low-risk groups. The immune composition deconvolution might indicate an immunosuppressive niche in the high-risk patients. The pRRophetic algorithm exploration unveiled chemical drugs with potentially sensitivity among patients in both groups. Collectively, our study developed a ferroptosis-derived prognostic signature that provides the OS prediction and identifies the immune microenvironment for AML patients on large-scale AML cohorts.

Lycorine inhibits Ang II-induced heart remodeling and inflammation by suppressing the PI3K-AKT/NF-κB pathway.

BACKGROUND: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. METHODS: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. RESULTS: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. CONCLUSION: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.

An Examination of the Effect of Aspirin and Salicylic Acid on Soluble Fms-like Tyrosine Kinase-1 Release from Human Placental Trophoblasts.

Low-dose aspirin (LDA) is efficacious in preventing preeclampsia, but its mechanism of action is unclear. Conflicting evidence suggests that it may inhibit placental trophoblast release of soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. We examined whether, and at what concentrations, aspirin and its principal metabolite, salicylic acid, modulate sFlt1 release and/or expression in trophoblasts. Human trophoblast lines BeWo and HTR-8/SVneo were cultured; BeWo cells were also treated with 1% oxygen vs. normoxia to mimic hypoxia in preeclamptic placentas. Cells were treated with aspirin or salicylic acid vs. vehicle for 24 h at concentrations relevant to LDA and at higher concentrations. Protein concentrations (ELISA) and mRNA expression (RT-PCR) of sFlt1 were determined. Under normoxia, LDA-relevant concentrations of aspirin (10-50 µmol/L) or salicylic acid (20-100 µmol/L) had no significant effect on sFlt1 protein release or mRNA expression in BeWo cells. However, inhibition was observed at higher concentrations (1 mmol/L for aspirin and ≥200 µmol/L for salicylic acid). Hypoxia enhanced sFlt1 protein release and mRNA expression in BeWo cells, but these responses were not significantly affected by either aspirin or salicylic acid at LDA concentrations. Similarly, neither drug altered sFlt1 protein secretion or mRNA expression in normoxic HTR-8/SVneo cells at LDA concentrations. We suggest that direct modulation of trophoblast release or expression of sFlt1 is unlikely to be a mechanism underlying the clinical efficacy of LDA in preeclampsia.

CVTrack: Combined Convolutional Neural Network and Vision Transformer Fusion Model for Visual Tracking.

Most single-object trackers currently employ either a convolutional neural network (CNN) or a vision transformer as the backbone for object tracking. In CNNs, convolutional operations excel at extracting local features but struggle to capture global representations. On the other hand, vision transformers utilize cascaded self-attention modules to capture long-range feature dependencies but may overlook local feature details. To address these limitations, we propose a target-tracking algorithm called CVTrack, which leverages a parallel dual-branch backbone network combining CNN and Transformer for feature extraction and fusion. Firstly, CVTrack utilizes a parallel dual-branch feature extraction network with CNN and transformer branches to extract local and global features from the input image. Through bidirectional information interaction channels, the local features from the CNN branch and the global features from the transformer branch are able to interact and fuse information effectively. Secondly, deep cross-correlation operations and transformer-based methods are employed to fuse the template and search region features, enabling comprehensive interaction between them. Subsequently, the fused features are fed into the prediction module to accomplish the object-tracking task. Our tracker achieves state-of-the-art performance on five benchmark datasets while maintaining real-time execution speed. Finally, we conduct ablation studies to demonstrate the efficacy of each module in the parallel dual-branch feature extraction backbone network.

Let-7a-5p abrogates progression of papillary thyroid carcinoma cells by decreasing nuclear receptor subfamily 6 group a member 1-mediated lipogenesis.

Increasing evidence shows that microRNAs (miRNAs) contribute vital roles in papillary thyroid carcinoma (PTC) carcinogenesis, proliferation, invasion, and so on. As the most common endocrine malignancy, there still have largely unknown molecular events. First, our analysis and open access database information indicates that the downregulation of let-7a-5p accelerates PTC progression. Next, lentivirus mediates the overexpression of let-7a-5p PTC cells, and found let-7a-5p suppressed cancer cells proliferation and invasion. Interestingly, bioinformatics analysis hints NR6A1 is the potential target gene of let-7a-5p. The regulation was validated by luciferase and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in PTC tissue and the clinic tumors. Moreover, let-7a-5p regulated NR6A1 involved in PTC cells lipogensis in vitro and in vivo. Finally, let-7a-5p abrogates PCT xenograft tumors growth, NR6A1 expression and lipogenesis. Taken together, our data indicates that let-7a-5p suppresses PCT progression through decreased lipogenesis, the related let-7a-5p/NR6A1axis might be promising candidate targets for PTC treatment.

Light physical activity predicts long-term mortality in individuals with a different cardiovascular health status: a cohort study.

Studies have showed that LIPA seems to be favorably associated with mortality in the general population and illness individuals, but the association between different cardiovascular health status and mortality is not clear. After adjustment , the HRs of LIPA in individuals with CVRF and CVD from quartiles 2-4 were less than 1, which were 0.78 (95%CI, 0.61 ~ 0.99; P = 0.042), 0.63 (95%CI, 0.47 ~ 0.83; P = 0.001), 0.55（95%CI, 0.40 ~ 0.76; P < 0.001）, and 0.52 (95%CI, 0.37 ~ 0.74; P < 0.001)，0.39 (95%CI, 0.27 ~ 0.58; P < 0.001), 0.33 (95%CI, 0.22 ~ 0.51; P < 0.001) LIPA is beneficial for reducing mortality, but the shape of the association depends on cardiovascular health status.

Effect of omega-3 fatty acids supplementation on the prognosis of coronary artery disease: A meta-analysis of randomized controlled trials.

AIMS: To evaluate whether omega-3 fatty acids (É·-3 FAs) supplementation can improve cardiovascular outcomes in patients with established coronary artery disease (CAD). DATA SYNTHESIS: Five electronic databases were searched for randomized controlled trials that evaluated the effect of É·-3 FAs on cardiovascular outcomes in patients with CAD. The language was restricted to English. The risk ratio was pooled. Subgroup analyses were conducted to evaluate whether study-level variables might act as effect modifiers. A total of 12 studies involving 29913 patients were included. É·-3 FAs had no effects on major adverse cardiovascular events (MACEs) (RR, 0.93; 95 % CI: 0.85 to 1.01, P = 0.09). While É·-3 FAs reduced the incidences of all-cause death (RR, 0.90; 95 % CI: 0.83 to 0.97, P = 0.005), cardiovascular death (RR, 0.82; 95 % CI: 0.75 to 0.90, P < 0.0001), myocardial infarction (RR, 0.77; 95 % CI: 0.68 to 0.86, P < 0.0001), revascularization (RR, 0.80; 95 % CI: 0.69 to 0.93, P = 0.003), sudden cardiac death (RR, 0.67; 95 % CI: 0.52 to 0.86, P = 0.002) and hospitalization for heart failure or unstable angina pectoris (RR, 0.75; 95 % CI: 0.58 to 0.97, P = 0.03) in CAD. It did not statistically reduce the risk of stroke (RR, 0.96; 95 % CI: 0.77 to 1.21, P = 0.76). The favorable effects of É·-3 FAs on MACEs were significant in subgroups of intervention with EPA and baseline triglyceride ≥1.7 mmol/L. CONCLUSION: É·-3 FAs supplementation, especially EPA, appears to be an effective adjunct therapy for improving the prognosis of CAD. REGISTRATION NUMBER: PROSPERO CRD42022311237.

Highly Diastereo- and Enantioselective Synthesis of Chiral Cyclohexylphosphines by Cu-Catalyzed Phosphination-Aldol Cyclization of Ketone-Enamides.

A highly diastereo- and enantioselective phosphinative cyclization of ketone-enamides with secondary diarylphosphines enabled by copper catalysis is reported, providing a range of chiral tertiary cyclohexylphosphines bearing three contiguous stereogenic centers in high yields. This asymmetric phosphination-aldol cyclization protocol can also be extended to desymmetrization of dione-enamides to create four contiguous stereogenic centers in a highly selective manner.

A pan-cancer analysis of TNFAIP8L1 in human tumors.

TNFAIP8L1, as a recently identified member in TNFAIP8 family, plays an important role in tumorigenesis. However, a pan-cancer analysis of TNFAIP8L1 in human tumors has not been conducted until now. The main purpose of study is to investigate TNFAIP8L1 during 33 different types of human tumors by using TCGA and GTEx. The pan-cancer analysis showed that TNFAIP8L1 was significantly over-expressed in 15 cancers and low-expressed in 9 cancers. There were distinct relations between TNFAIP8L1 expression and prognosis of patients with cancer. Furthermore, we also found that DNA methylation and RNA modification of TNFAIP8L1 were associated with many cancers. And then, we detected that TNFAIP8L1 level was positively associated with cancer-associated fibroblasts (CAFs) in many tumors. And, we obtained that TNFAIP8L1 expression was related with most of immune inhibitory and stimulatory genes in multiple types of tumors. We also found TNFAIP8L1 expression was correlated with most of chemokine, receptor, MHC, immunoinhibitor and immunostimulator gens in most of cancers. Moreover, we detected TNFAIP8L1 expression was associated with TMB and MSI in several tumors. Finally, TNFAIP8L1 gene had a significant positive association with 5 genes including BCL6B, DLL4, PCDH12, COL4A1 and DLL4 in the majority of tumors. GO enrichment and KEGG pathway analyses showed that TNFAIP8L1 in thepathogenesis of cancer may be related to "purine nucleoside binding," "purine ribonucleoside binding," "ECM-receptor interaction," etc. Our first pan-cancer study may provide a deep comprehending of TNFAIP8L1 in tumoeigenesis from different tumors.

Dithiolation of Alkenyl Sulfonium Salts with Arylthiols to Access 1,2-Dithioalkanes.

A dithiolation of alkenyl sulfonium salts with arylthiols is described, affording a series of 1,2-dithioalkanes in high yields. This protocol features mild and catalyst-free conditions and involves the formation of two C-S bonds sequentially via the regioselective addition of an arylthiol to the unsaturated C═C bonds, followed by the attack of another arylthiol to form 1,2-dithioalkanes exclusively.

Efficacy and safety of Qixue Tongzhi Granule in improving the exercise capacity of stable coronary artery disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

Background: Despite optimal medical therapy, patients with stable coronary artery disease (SCAD) still have a high risk of recurrent cardiovascular events. Exercise capacity measured by cardiopulmonary exercise testing (CPET) is a good surrogate marker for the long-term prognosis of SCAD. Qixue Tongzhi Granule (QTG) is created by academician Chen Keji and has the function of tonifying qi, promoting blood circulation, and regulating qi-flowing. This trial aims to investigate the efficacy and safety of QTG in improving exercise tolerance, alleviating angina pectoris and anxiety/depression symptoms, promoting health-related quality of life, and reducing the risk of adverse cardiovascular events in subjects with SCAD. Methods: This is a randomized, double-blind, placebo-controlled trial. 150 SCAD patients with qi deficiency, blood stasis, and liver qi stagnation syndrome are enrolled. Patients will be randomly allocated to the QTG or placebo groups at a 1:1 ratio. QTG and placebo will be added to the modern guideline-directed medical therapy for 12 weeks and patients will be followed up for another 24 weeks. The primary outcome is the improvement of metabolic equivalents measured by CPET. The secondary outcomes are cumulative incidence of composite endpoint events, other indicators in CPET, changes in the Seattle Angina Questionnaire, traditional Chinese medicine syndrome scale, 12 items of Short Form Health Survey Questionnaire, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7, changes of ST-T segment in the electrocardiogram, improvement of left ventricular ejection fraction and left ventricular end-diastolic diameter in echocardiography. In addition, metabolomics analysis will be performed based on blood samples. Adverse events and safety evaluations will also be documented. A full analysis set, per protocol set, and safety analysis set will be conducted. Discussion: This clinical trial can enrich treatment options for CHD patients with low cardiorespiratory fitness and psychological imbalance, and it may also create a new situation for promoting the application of traditional Chinese medicine in cardiac rehabilitation.Clinical Trial Registration: [http://www.chictr.org.cn], identifier: [ChiCTR2200058988].

Highly Regioselective Dichalcogenation of Alkenyl Sulfonium Salts to Access 1,1-Dichalcogenalkenes.

An unprecedented geminal olefinic dichalcogenation of alkenyl sulfonium salts with dichalcogenides ArYYAr (Y = S, Se, Te) is reported, providing various trisubstituted 1,1-dichalcogenalkenes [Ar1CH = C(YAr2)2] in a highly selective manner under mild and catalyst-free conditions. The key process involves the formation of two geminal olefinic C-Y bonds via sequential C-Y cross-coupling and C-H chalcogenation. A mechanistic rationale is further supported by control experiments and density functional theory calculations.