Merging Ring-Opening 1,2-Metallate Shift with Asymmetric C(sp3)-H Borylation of Aziridines.

Chiral secondary alkyl amines with a vicinal quaternary stereocenter are undoubtedly important and ubiquitous subunits in natural products and pharmaceuticals. However, their asymmetric synthesis remains a formidable challenge. Herein, we merge the ring-opening 1,2-metallate shift with iridium-catalyzed enantioselective C(sp3)-H borylation of aziridines to deliver these frameworks with high enantioselectivities. We also demonstrated the synthetic application by downstream transformations, including the total synthesis of two Amaryllidaceae alkaloids, (-)-crinane and (+)-mesmebrane.

Effect of acupuncture on post-stroke dysphagia: a randomized controlled trial.

Introduction: Post-stroke dysphagia (PSD) is associated with various complications that increase morbidity and mortality rates. Acupuncture has been used extensively in China to treat these complications; however, its therapeutic efficacy remains uncertain. We therefore aimed to study the clinical effects of acupuncture on PSD. Methods: Patients (n = 101) were randomly divided into acupuncture (n = 50) and rehabilitation training control (n = 51) groups based on the treatment used. Both groups were treated once daily, 6 days a week, for a total of 4 weeks. Pulse oxygen saturation (SpO2) and standardized swallowing assessment (SSA) were performed before the intervention, 2 weeks into treatment, after the intervention (4 weeks post-intervention), and at a 6-month follow-up (28 weeks). The levels of hemoglobin (Hb) and albumin (ALB), and 5-hydroxytryptamine (5-HT) and dopamine (DA) were measured before the intervention, 2 weeks into treatment, and after the intervention (4 weeks), as nutrition and swallowing function indices, respectively. Results: Following the intervention, significant differences were observed between the acupuncture and control groups. The acupuncture group exhibited considerably superior enhancements in SpO2 and SSA scores at 4 weeks (p < 0.001). Moreover, this group demonstrated significantly greater improvements in Hb, ALB, 5-HT, and DA values 4 weeks post-treatment (p < 0.001). However, sex-based differences were not observed (P > 0.005). Conclusion: Acupuncture treatment can improve the swallowing function and nutritional status of patients with PSD, and increase the levels of 5-HT and DA. These findings strongly support the efficacy of acupuncture as a therapeutic intervention in patients with PSD.Clinical trial registration: identifier, ChiCTR2100052201. (https://www.chictr.org.cn/).

Heterogeneous body compositions and all-cause mortality in acute coronary syndrome patients: a ten-year retrospective cohort study.

BACKGROUND: The association of different body components, including lean mass and body fat, with the risk of death in acute coronary syndrome (ACS) patients are unclear. METHODS: We enrolled adults diagnosed with ACS at our center between January 2011 and December 2012 and obtained follow-up outcomes via telephone questionnaires. We used restricted cubic splines (RCS) with the Cox proportional hazards model to analyze the associations between body mass index (BMI), predicted lean mass index (LMI), predicted body fat percentage (BF), and the value of LMI/BF with 10-year mortality. We also examined the secondary outcome of death during hospitalization. RESULTS: During the maximum 10-year follow-up of 1398 patients, 331 deaths (23.6%) occurred, and a U-shaped relationship was found between BMI and death risk (P nonlinearity = 0.03). After adjusting for age and history of diabetes, the overweight group (24 ≤ BMI < 28 kg/m2) had the lowest mortality (HR = 0.53, 95% CI: 0.29-0.99). Predicted LMI and LMI/BF had an inverse linear relationship with a 10-year death risk (P nonlinearity = 0.24 and P nonlinearity = 0.38, respectively), while an increase in BF was associated with increased mortality (P nonlinearity = 0.64). During hospitalization, 31 deaths (2.2%) were recorded, and the associations of the indicators with in-hospital mortality were consistent with the long-term outcome analyses. CONCLUSION: Our study provides new insight into the "obesity paradox" in ACS patients, highlighting the importance of considering body composition heterogeneity. Predicted LMI and BF may serve as useful tools for assessing nutritional status and predicting the prognosis of ACS, based on their linear associations with all-cause mortality.

U-Shaped Relationship Between Fibrinogen Level and 10-year Mortality in Patients With Acute Coronary Syndrome: Prospective Cohort Study.

This study demonstrated that fibrinogen is an independent risk factor for 10-year mortality in patients with acute coronary syndrome (ACS), with a U-shaped nonlinear relationship observed between the two. These findings underscore the importance of monitoring fibrinogen levels and the consideration of long-term anti-inflammatory treatment in the clinical management of patients with ACS.

Mining flotation reagents: Quantitative and robust analysis of metal-xanthate complexes in water.

Xanthates, common mining flotation reagents, strongly bind thiophilic metals such as copper (Cu), lead (Pb), cadmium (Cd), and zinc (Zn) and consequentially change their bioavailability and mobility upon their discharge into the environment. However, accurate quantification of the metal-xanthate complexes has remained elusive. This study develops a novel and robust method that realizes the accurate quantification of the metal-xanthate complexes resulted from single and multiple reactions of three typical xanthates (ethyl, isopropyl, and butyl xanthates) and four thiophilic metals (Cu, Pb, Cd, and Zn) in water samples. This method uses sulfur (S2-) dissociation, followed by tandem solid phase extraction of C18 + PWAX and subsequent LC-MS/MS analysis. It has a wide linearity range (1-1000 µg/L, R2 ≥ 0.995), low method detection limits (0.002-0.036 µg/L), and good recoveries (70.6-107.0 %) at 0.01-10 mg/L of xanthates. Applications of this method showed ubiquitous occurrence of the metal-xanthate complexes as the primary species in flotation wastewaters, which the concentrations were 4.6-28.9-fold higher than those previously determined. It is the first quantitative method established for the analysis of metal-xanthate complexes in water samples, which is of great importance to comprehensively understand the fate and risks of xanthates in the environment.

IPAD-DB: a manually curated database for experimentally verified inhibitors of proteins associated with Alzheimer's disease.

Alzheimer's disease (AD) is a universal neurodegenerative disease with the feature of progressive dementia. Currently, there are only seven Food and Drug Administration-approved drugs for the treatment of AD, which merely offer temporary relief from symptom deterioration without reversing the underlying disease process. The identification of inhibitors capable of interacting with proteins associated with AD plays a pivotal role in the development of effective therapeutic interventions. However, a vast number of such inhibitors are dispersed throughout numerous published articles, rendering it inconvenient for researchers to explore potential drug candidates for AD. In light of this, we have manually compiled inhibitors targeting proteins associated with AD and constructed a comprehensive database known as IPAD-DB (Inhibitors of Proteins associated with Alzheimer's Disease Database). The curated inhibitors within this database encompass a diverse range of compounds, including natural compounds, synthetic compounds, drugs, natural extracts and nano-inhibitors. To date, the database has compiled >4800 entries, each representing a correspondent relationship between an inhibitor and its target protein. IPAD-DB offers a user-friendly interface that facilitates browsing, searching and downloading of its records. We firmly believe that IPAD-DB represents a valuable resource for screening potential AD drug candidates and investigating the underlying mechanisms of this debilitating disease. Access to IPAD-DB is freely available at http://www.lamee.cn/ipad-db/ and is compatible with all major web browsers. Database URL: http://www.lamee.cn/ipad-db/.

Heterogenous Gene Expression of Bicellular and Tricellular Tight Junction-Sealing Components in the Human Intestinal Tract.

A major site for the absorption of orally administered drugs is the intestinal tract, where the mucosal epithelium functions as a barrier separating the inside body from the outer environment. The intercellular spaces between adjacent epithelial cells are sealed by bicellular and tricellular tight junctions (TJs). Although one strategy for enhancing intestinal drug absorption is to modulate these TJs, comprehensive gene (mRNA) expression analysis of the TJs components has never been fully carried out in humans. In this study, we used human biopsy samples of normal-appearing mucosa showing no endoscopically visible inflammation collected from the duodenum, jejunum, ileum, colon, and rectum to examine the mRNA expression profiles of TJ components, including occludin and tricellulin and members of the claudin family, zonula occludens family, junctional adhesion molecule (JAM) family, and angulin family. Levels of claudin-3, -4, -7, -8, and -23 expression became more elevated in each segment along the intestinal tract from the upper segments to the lower segments, as did levels of angulin-1 and -2 expression. In contrast, expression of claudin-2 and -15 was decreased in the large intestine compared to the small intestine. Levels of occludin, tricellulin, and JAM-B and -C expression were unchanged throughout the intestine. Considering their segment specificity, claudin-8, claudin-15, and angulin-2 appear to be targets for the development of permeation enhancers in the rectum, small intestine, and large intestine, respectively. These data on heterogenous expression profiles of intestinal TJ components will be useful for the development of safe and efficient intestinal permeation enhancers.

Impacts of mixed ferrous sulfate-biochar additives on humification and bacterial community during electric field-assisted aerobic composting.

This study assessed the impact of nine mixed ferrous sulfates and biochars on electric field-assisted aerobic composting (EAC), focusing on the spectroscopy of dissolved organic matter (DOM) and microbial communities. Adding 1.05% ferrous sulfate and 5.25% biochar to EAC increased the specific ultraviolet absorbances at 254 and 280 nm by 142.3% and 133.9% on day 35, respectively. This ratio accelerated the early response of carboxyl groups (-COOH) and lignin (CꘌC), enhancing the relative abundance of Thermobifida (4.0%) and Thermopolyspora (4.3%). The condition contributed to humus precursor formation on day 5, increasing the maximum fluorescence intensity of the humus-like component by 74.2% compared to the control on day 35. This study is the first to develop a combined and efficient organic and inorganic additive by multiple-variable experimentation for DOM humification. Consequently, it optimizes EAC for solid waste recycling.

A clinical-radiomics nomogram based on spectral CT multi-parameter images for preoperative prediction of lymph node metastasis in colorectal cancer.

To develop a clinical-radiomics nomogram based on spectral CT multi-parameter images for predicting lymph node metastasis in colorectal cancer. A total of 76 patients with colorectal cancer and 156 lymph nodes were included. The clinical data of the patients were collected, including gender, age, tumor location and size, preoperative tumor markers, etc. Three sets of conventional images in the arterial, venous, and delayed phases were obtained, and six sets of spectral images were reconstructed using the arterial phase spectral data, including virtual monoenergetic images (40 keV, 70 keV, 100 keV), iodine density maps, iodine no water maps, and virtual non-contrast images. Radiomics features of lymph nodes were extracted from the above images, respectively. Univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were used to select features. A clinical model was constructed based on age and carcinoembryonic antigen (CEA) levels. The radiomics features selected were used to generate a composed radiomics signature (Com-RS). A nomogram was developed using age, CEA, and the Com-RS. The models' prediction efficiency, calibration, and clinical application value were evaluated by the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis, respectively. The nomogram outperforms the clinical model and the Com-RS (AUC = 0.879, 0.824). It is well calibrated and has great clinical application value. This study developed a clinical-radiomics nomogram based on spectral CT multi-parameter images, which can be used as an effective tool for preoperative personalized prediction of lymph node metastasis in colorectal cancer.

Incidence, Predictors, and Outcomes of Paravalvular Regurgitation after TAVR in Sievers Type-1 Bicuspid Aortic Valves.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve (BAV) stenosis is technically challenging and is burdened by an increased risk of paravalvular regurgitation (PVR). OBJECTIVES: To identify the incidence, predictors, and clinical outcomes of PVR following TAVR in Sievers type 1 BAV stenosis. METHODS: Consecutive patients with severe Sievers type 1 BAV stenosis undergoing TAVR with current generation transcatheter heart valves (THVs) in 24 international centres were enrolled. PVR was graded as none/trace, mild, moderate, and severe according to echocardiographic criteria. The endpoint of major adverse events (MAE), defined as a composite of all-cause death, stroke, or hospitalization for heart failure, was assessed at the last available follow-up. RESULTS: A total of 946 patients were enrolled. PVR occurred in 423 patients (44.7%): mild, moderate, and severe in 387 (40.9%), 32 (3.4%), and 4 (0.4%) patients, respectively. Independent predictors of moderate or severe PVR were larger virtual raphe ring (VRR) perimeter (ORadj 1.07, 95% CI 1.02-1.13), severe annular or left ventricular outflow tract (LVOT) calcification (ORadj 5.21, 95% CI 1.45-18.77), self-expanding valve (ORadj 9.01, 95% CI 2.09-38.86), and intentional supra-annular THV positioning (ORadj 3.31, 95% CI 1.04-10.54). At a median follow-up of 1.3 [IQR 0.5-2.4] years, moderate or severe PVR was associated with an increased risk of MAE (HRadj 2.52, 95% CI 1.24-5.09). CONCLUSIONS: After TAVR with current-generation THVs in Sievers type 1 BAV stenosis, moderate or severe PVR occurred in about 4% of cases and was associated with an increased risk of MAE during follow-up.

Influencing Factors of Generic Prescribing Behavior of Physicians: A Structural Equation Model Based on the Theory of Planned Behavior.

Background: Although affordable generics could probably contribute to the solution of rapidly increasing pharmaceutical expenditure, those drugs are prescribed at a lower rate in China. Physicians' perception and knowledge of generics have a great influence on their prescribing behavior. Objective: This study aimed to identify factors that affect physicians' generic prescribing behavior based on the theory of planned behaviors (TPB). Methods: Data were collected by both electronic and paper-based surveys from 1297 Chinese physicians, and 1047 surveys were retained. The structural equation model (SEM) was employed to investigate the relationship between four behavioral constructs, namely, attitudes, subjective norms, perceived control of behaviors, and intentions. Results: About 50% of Chinese physicians had a positive attitude towards generic drugs that had passed the "Consistency Evaluation of Quality and Efficacy of Generic Drugs" (high-quality generic drugs), but their knowledge of generic drugs was relatively inadequate. The path coefficients for the effect of attitudes, subjective norms, and perceived behavioral control on behavioral intention were 0.285, 0.366, and 0.322 respectively. The path coefficients for the effect of behavioral intention and perceived behavioral control on prescribing behavior were 0.009 and 0.410 respectively. Conclusion: Physicians' attitudes, subjective norms, and perceived behavioral control were significant positive correlation predictors of behavioral intention. Subjective norms and perceived behavior control had a greater impact than attitude on physicians' prescribing intention. However, the generic prescribing behavior is not under the volitional control of Chinese physicians. Physicians' prescribing practice is likely affected by perceived strong control over prescribing generic drugs.

Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

GABAergic synapses from the ventral lateral septum to the paraventricular nucleus of hypothalamus modulate anxiety.

Emotional disorders, such as anxiety and depression, represent a major societal problem; however, the underlying neurological mechanism remains unknown. The ventral lateral septum (LSv) is implicated in regulating processes related to mood and motivation. In this study, we found that LSv GABAergic neurons were significantly activated in mice experiencing chronic social defeat stress (CSDS) after exposure to a social stressor. We then controlled LSv GABAergic neuron activity using a chemogenetic approach. The results showed that although manipulation of LSv GABAergic neurons had little effect on anxiety-like behavioral performances, the activation of LSv GABAergic neurons during CSDS worsened social anxiety during a social interaction (SI) test. Moreover, LSv GABAergic neurons showed strong projections to the paraventricular nucleus (PVN) of the hypothalamus, which is a central hub for stress reactions. Remarkably, while activation of GABAergic LSv-PVN projections induced social anxiety under basal conditions, activation of this pathway during CSDS alleviated social anxiety during the SI test. On the other hand, the chemogenetic manipulation of LSv GABAergic neurons or LSvGABA-PVN projections had no significant effect on despair-like behavioral performance in the tail suspension test. Overall, LS GABAergic neurons, particularly the LSv GABAergic-PVN circuit, has a regulatory role in pathological anxiety and is thus a potential therapeutic target for the treatment of emotional disorders.

Fungal Plasma Membrane H+-ATPase: Structure, Mechanism, and Drug Discovery.

The fungal plasma membrane H+-ATPase (Pma1) pumps protons out of the cell to maintain the transmembrane electrochemical gradient and membrane potential. As an essential P-type ATPase uniquely found in fungi and plants, Pma1 is an attractive antifungal drug target. Two recent Cryo-EM studies on Pma1 have revealed its hexameric architecture, autoinhibitory and activation mechanisms, and proton transport mechanism. These structures provide new perspectives for the development of antifungal drugs targeting Pma1. In this article, we review the history of Pma1 structure determination, the latest structural insights into Pma1, and drug discoveries targeting Pma1.

Congener-specific fate and impact of microcystins in the soil-earthworm system.

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services.

COAP-Pd Catalyzed Asymmetric Formal [3+2] Cycloaddition for Optically Active Multistereogenic Spiro Cyclopentane-Indandiones Bearing Cyclic N-Sulfonyl Ketimine Skeletons.

We reported a chiral oxamide-phosphine ligand (COAP-Ph)-Pd-catalyzed asymmetric [3+2] cycloaddition reaction between vinyl cyclopropane compounds derived from 1,3-indanedione and 2-vinylcyclopropane-1,1-dicarboxylates with cyclic sulfonyl 1-azadienes. The corresponding reactions provided a series of enantiomerically active spiro cyclopentane-indandione and cyclopentane structures bearing three consecutive stereogenic centers in good yields with good diastereo- and enantioselectivity. The COAP-Pd complex serves not only to promote generation of chiral π-allyl-palladium intermediates and induce the asymmetry of the reaction, but also depress the background reaction.

Genome assembly of autotetraploid Actinidia arguta highlights adaptive evolution and enables dissection of important economic traits.

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.

Chiral Phosphine Ligands of COAP and SKP Switched Regiodivergent Asymmetric Allylic Alkylation of MBH Adducts.

The palladium-catalyzed highly regioselective asymmetric allylic alkylation of 3'-indolyl-3-oxindole derivatives with Morita-Baylis-Hillman (MBH) carbonates was developed to facilely construct chiral 3,3'-bisindole derivatives under mild reaction conditions. The regioselectivity (α/γ) of MBH carbonates was efficiently switched in the presence of chiral oxalamide phosphine or spiroketal-based diphosphine/Pd(0) complexes as a chiral catalyst. A series of multifunctional 3,3'-bisindole derivatives with all-carbon quaternary stereogenic centers were obtained in high yields with good to excellent enantio-, diastereo-, and regioselectivity. The present process is endowed with some salient features such as broad substrate scope, N-protecting group-free, excellent stereoselectivity, as well as adjustable regioselectivity.