Atrial-selective block of sodium channels by acehytisine in rabbit myocardium

AbstractAcehytisine, a multi-ion channel blocker, can markedly inhibit INa, ICa, IKur, If at various concentrations and effectively terminate and prevent atrial fibrillation (AF) in patients and animal models, but the molecular mechanism underlying its blockage remains elusive. In this study, we investigated the effects of acehytisine on action potentials and sodium channels of atrial and ventricular myocytes isolated from rabbit, using whole-cell recording system. We found that acehytisine exerted stronger blocking effects on sodium channels in atria than in ventricles, especially at depolarization (IC50: 48.48 ± 7.75 μmol/L in atria vs. 560.17 ± 63.98 μmol/L in ventricles). It also significantly shifted steady state inactivation curves toward negative potentials in atrial myocytes, without affecting the recovery kinetics from inactivation of sodium channels in the same cells. In addition, acehytisine inhibited INa in a use-dependent manner and regulated slow inactivation kinetics by different gating configurations. These findings indicate that acehytisine selectively blocks atrial sodium channels and possesses affinity to sodium channel in certain states, which provides additional evidence for the anti-AF of acehytisine

Maximizing temporal quantum correlation by approaching an exceptional point

Quantum correlations, both spatial and temporal, are the central pillars of quantum mechanics. Over the last two decades, a big breakthrough in quantum physics is its complex extension to the non-Hermitian realm, and dizzying varieties of novel phenomena and applications beyond the Hermitian framework have been uncovered. However, unique features of non-Hermitian quantum correlations, especially in the time domain, still remain to be explored. Here, for the first time, we experimentally achieve this goal by using a parity-time (PT )-symmetric trapped-ion system. The upper limit of temporal quantum correlations, known as the algebraic bound, which has so far not been achieved in the standard measurement scenario, is reached here by approaching the exceptional point (EP), thus showing the unexpected ability of EPs in tuning temporal quantum correlation effects. Our study, unveiling the fundamental interplay of non-Hermiticity, nonlinearity, and temporal quantum correlations, provides the first step towards exploring and utilizing various non-Hermitian temporal quantum effects by operating a wide range of EP devices, which are important for both fundamental studies and applications of quantum EP systems.Comment: 4 figures and 8 page

Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction

A comparative photocatalytic study of TiO2 loaded on three natural clays with different morphologies

[EN] In this work, a sol-gel method was used to load TiO2 nanoparticles on three clays (kaolinite, halloysite and palygorskite) with different morphologies (plates, tubes, and rods with micro tunnels), and then the photocatalytic performance of obtained clay-TiO2 composites for degradation of methyl orange was comparatively investigated. The results surprisingly show that the trend of photocatalytic performance of composites is opposite to that of special surface area of corresponding clays. By concentrated analysis of the loading status of TiO2, the lowest photocatalytic efficiency of palygorskite-TiO2 composite is mainly ascribed to (1) the aggregation of TiO2 nanoparticles on Pal surface, not the amount of TiO2 and (2) the relatively weak adsorption of Pal to methyl orange. The additional adsorption of hydroxyl surface of Kaol to methyl orange and little TiO2 in the lumen of Hal tube leads to the better photocatalytic performance of kaolinite-TiO2 composite than halloysite-TiO2 composite. Finally, kaolinite is proved to be an excellent carrier to support nano TiO2 resulting in a good photocatalytic performance and cycle stability, and the study can provide a direct guidance to select appropriate clay-photocatalyst composites for different practical applications.This work is supported by the National Natural Science Foundation of China (41502032) and the Fundamental Research Funds for the Central Universities (2019XKQYMS76).Wu, A.; Wang, D.; Wei, C.; Zhang, X.; Liu, Z.; Feng, P.; Ou, X.... (2019). A comparative photocatalytic study of TiO2 loaded on three natural clays with different morphologies. Applied Clay Science. 183:1-12. https://doi.org/10.1016/j.clay.2019.105352S11218

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe