scHiCStackL: a stacking ensemble learning-based method for single-cell Hi-C classification using cell embedding.

Single-cell Hi-C data are a common data source for studying the differences in the three-dimensional structure of cell chromosomes. The development of single-cell Hi-C technology makes it possible to obtain batches of single-cell Hi-C data. How to quickly and effectively discriminate cell types has become one hot research field. However, the existing computational methods to predict cell types based on Hi-C data are found to be low in accuracy. Therefore, we propose a high accuracy cell classification algorithm, called scHiCStackL, based on single-cell Hi-C data. In our work, we first improve the existing data preprocessing method for single-cell Hi-C data, which allows the generated cell embedding better to represent cells. Then, we construct a two-layer stacking ensemble model for classifying cells. Experimental results show that the cell embedding generated by our data preprocessing method increases by 0.23, 1.22, 1.46 and 1.61$\%$ comparing with the cell embedding generated by the previously published method scHiCluster, in terms of the Acc, MCC, F1 and Precision confidence intervals, respectively, on the task of classifying human cells in the ML1 and ML3 datasets. When using the two-layer stacking ensemble framework with the cell embedding, scHiCStackL improves by 13.33, 19, 19.27 and 14.5 over the scHiCluster, in terms of the Acc, ARI, NMI and F1 confidence intervals, respectively. In summary, scHiCStackL achieves superior performance in predicting cell types using the single-cell Hi-C data. The webserver and source code of scHiCStackL are freely available at http://hww.sdu.edu.cn:8002/scHiCStackL/ and https://github.com/HaoWuLab-Bioinformatics/scHiCStackL, respectively.

Clinical Characteristics and Comparative Proteomics Analysis of COVID-19-Related Atrioventricular Block.

Background: Atrioventricular block (AVB) is thought to be a rare cardiovascular complication of the coronavirus disease 2019 (COVID-19), though limited data are available beyond case reports. We aim to describe the baseline characteristics, proteomics profile, and outcomes for patients with COVID-19-related AVB. Methods: We prospectively recruited patients diagnosed with COVID-19-related AVB between November 2022 and March, 2023. Inclusion criteria were hospitalization for COVID-19 with the diagnosis of AVB. A total of 24 patients diagnosed with COVID-19 without AVB were recruited for control. We analyzed patient characteristics and outcomes and performed a comparative proteomics analysis on plasma samples of those patients and controls. Results: A total of 17 patients diagnosed with COVID-19-related AVB and 24 individuals diagnosed with COVID-19 infection without AVB were included. Among patients with COVID-19-related AVB, the proportion of concurrent pneumonia was significantly higher than controls (7/17 versus 2/24, p < 0.05). All 17 AVB patients (9 of permanent AVB, 8 of paroxysmal AVB) received permanent pacemaker implantation. No procedural-related complication occurred. In laboratory tests, the level of biomarkers indicating myocardial damage were substantially higher than controls, including high-sensitivity cardiac troponin-I (median 0.005 versus 0.002 ng/mL, p < 0.05), myoglobulin (median 39.0 versus 27.6 ng/mL, p < 0.05), and MB isoenzyme of creatine kinase (median 1.2 versus 0.8 U/L, p < 0.05). The level of N-terminal pro-b-type natriuretic peptide (median 241.0 versus 33.5 pg/mL, p < 0.05), C-reactive protein (median 4.8 versus 2.0 mg/L, p < 0.05), D-dimer (median 1.2 versus 0.2 µg/mL, p < 0.05), left ventricular end-diastolic diameter (median 49.3 versus 45.7 mm, p < 0.05) in patients with COVID-19-related AVB were significantly higher than controls. The level of albumin (median 41.9 versus 44.5 g/L, p < 0.05) was significantly lower than controls. In comparative proteomics analysis, we identified 397 human proteins. Several significantly altered plasma proteins related to inflammatory response (Serum amyloid A protein, C-reactive protein, Protein Adenosine 5'-monophosphate-activated protein kinase (AMPK), Alpha-2-macroglobulin), complement and coagulation cascades (Tetranectin, haptoglobin), and immune response (Neutrophil defensin 3, Fibrinogen beta chain) may contribute to the pathogenesis of COVID-19-related AVB. Conclusions: Patients with COVID-19-related AVB are more prone to have myocardial damage and concurrent pneumonia. Through laboratory tests and comparative proteomics analysis, we identified several differential expressed proteins (Serum amyloid A protein, Tetranectin, Neutrophil defensin 3) releated to the inflammatory response, complement and coagulation cascades, and immune response, which provides evidence of potential biomarkers and sheds light on the pathogenesis of COVID-19-related AVB.

Prognostic implications of premature ventricular contractions and non-sustained ventricular tachycardia in light-chain cardiac amyloidosis.

AIMS: Premature ventricular contractions (PVC) and non-sustained ventricular tachycardia (NSVT) are commonly observed in light chain cardiac amyloidosis (AL-CA), but their association with prognosis is still unclear. We aimed to evaluate the prognostic value of PVCs and NSVT in patients with moderate-to-advanced AL-CA. METHODS AND RESULTS: We retrospectively included patients with AL-CA at modified 2004 Mayo stages II-IIIb between February 2014 and December 2020. Twenty-four-hour Holter recordings were assessed on admission. The outcomes included (i) new onset of adverse ventricular arrhythmia (VA) or sudden cardiac death (SCD) and (ii) cardiac death during follow-up. Of the 143 patients studied (60.41 ± 11.06 years, male 64.34%), 132 (92.31%) had presence of PVC, and 50 (34.97%) had NSVT on Holter. Twelve (8.4%) patients died in hospital and 131 patients were followed up (median 24.4 months), among whom 71 patients had cardiac death, and 15 underwent adverse VA/SCD. NSVT [hazard ratio (HR): 13.57, 95% confidence interval (CI): 3.06-60.18, P < 0.001], log-transformed PVC counts (HR: 1.46, 95%CI: 1.15-1.86, P = 0.002) and PVC burden (HR: 1.43 95%CI:1.14-1.80, P = 0.002) were predictive of new onset of adverse VA/SCD. The highest tertile of PVC counts (HR: 2.33, 95%CI: 1.27-4.28, P = 0.006) and PVC burden (HR: 2.58, 95%CI: 1.42-4.69, P = 0.002), rather than NSVT (HR: 1.16, 95%CI: 0.67-1.98, P = 0.603), was associated with cardiac death. Higher PVC counts/burden provided incremental value on modified 2004 Mayo stage in predicting cardiac death, with C index increasing from 0.681 to 0.712 and 0.717, respectively (P values <0.05). CONCLUSION: PVC count, burden, and NSVT significantly correlated with adverse VA/SCD during follow-up in patients with AL-CA. Higher PVC counts/burdens added incremental value for predicting cardiac death.

Two novel in vitro assays to screen chemicals for their capacity to inhibit thyroid hormone transmembrane transporter proteins OATP1C1 and OAT4.

Early brain development depends on adequate transport of thyroid hormones (THs) from the maternal circulation to the fetus. To reach the fetal brain, THs have to cross several physiological barriers, including the placenta, blood-brain-barrier and blood-cerebrospinal fluid-barrier. Transport across these barriers is facilitated by thyroid hormone transmembrane transporters (THTMTs). Some endocrine disrupting chemicals (EDCs) can interfere with the transport of THs by THTMTs. To screen chemicals for their capacity to disrupt THTMT facilitated TH transport, in vitro screening assays are required. In this study, we developed assays for two THTMTs, organic anion transporter polypeptide 1C1 (OATP1C1) and organic anion transporter 4 (OAT4), both known to play a role in the transport of THs across barriers. We used overexpressing cell models for both OATP1C1 and OAT4, which showed an increased uptake of radiolabeled T4 compared to control cell lines. Using these models, we screened various reference and environmental chemicals for their ability to inhibit T4 uptake by OATP1C1 and OAT4. Tetrabromobisphenol A (TBBPA) was identified as an OATP1C1 inhibitor, more potent than any of the reference chemicals tested. Additionally perfluorooctanesulfonic acid (PFOS), perfluoroctanic acid (PFOA), pentachlorophenol and quercetin were identified as OATP1C1 inhibitors in a similar range of potency to the reference chemicals tested. Bromosulfophthalein, TBBPA, PFOA and PFOS were identified as potent OAT4 inhibitors. These results demonstrate that EDCs commonly found in our environment can disrupt TH transport by THTMTs, and contribute to the identification of molecular mechanisms underlying TH system disruption chemicals.

Etiology Distribution, Clinical Characteristics, and Suboptimal Pacing Outcome of Atrioventricular Block in Young Patients.

Background: The causes of atrioventricular block (AVB) are different and diverse young patients, as compared to the old. However, little is known about the etiology distribution and clinical characteristics of AVB in the young group. Methods: We retrospectively analyzed clinical information for AVB patients under 50 years of age. We summarized clinical phenotypes for patients with undetermined AVB etiology, according to AVB type and cardiac-structural change, whereas those who received pacing therapy were followed up for suspected heart failure events (HFEs). Results: AVB etiology was identified in only 289 (61.4%) patients, while 38.6% still have undertermined etiology for AVB. Non-ischemic cardiomyopathy (16.6%) and complication of cardiac surgery (13.4%) were the top two etiologies. In addition, four distinct phenotypes were identified in AVB patients with undetermined etiology, of which the severe phenotype (both borderline/elevated left ventricular diameter or abnormal left ventricular ejection fraction and advanced AVB) accounted for 17%. Notably, 80.7% of patients with severe phenotype received pacing therapy. Based on a median follow-up time of 17.5 months, we found the occurrence of 16 suspected HFEs in 110 pacemaker receivers (12 were lost to follow up). Notably, the severe phenotype was associated with a higher risk of heart failure (HF) symptoms. Conclusions: AVB etiology in young patients under 50 years of age is complex and underdiagnosed. In patients with undetermined etiology, severe phenotype featuring advanced AVB and abnormal Left ventricle (LV) structure/function is associated with a higher rate of HF symptoms even after pacing therapy.

Long-Term Outcomes of Bioprosthetic and Mechanical Valve Replacement for Patients Aged between 50 and 70 Years.

Background: The choice between bioprosthetic and mechanical valves for aortic valve replacement (AVR) and mitral valve replacement (MVR) among patients aged 50-70 years is controversial. We compared the long-term outcomes of patients using bioprosthetic or mechanical valves to provide clinical evidence for valve selection. Methods: From 2002 to 2007, patients aged 50-70 years who underwent isolated AVR or MVR at the Fuwai Hospital were enrolled. After inverse probability-weighted (IPW) propensity balancing, we evaluated long-term mortality, stroke, and bleeding events between patients receiving mechanical and biological prostheses for MVR or AVR. Results: A total of 1639 patients were included in the study, including 1181 patients undergoing MVR (median follow-up: 11.6 years) and 458 patients undergoing AVR (median follow-up: 11.4 years). After IPW adjustment, there was no significant difference in long-term mortality and stroke rate between patients using bioprosthetic and mechanical valves for MVR [mortality: log-rank p = 0.802; stroke: log-rank p = 0.983] and AVR [mortality: log-rank p = 0.815; stroke: log-rank p = 0.537]. Landmark analysis at 12.5 years yielded significantly lower mortality in the patients receiving mechanical valves compared with bioprosthetic valves in the MVR cohort (p = 0.028). Patients receiving mechanical aortic valves displayed an increased risk of bleeding compared with those who received bioprosthetic aortic valves [Hazard Ratio (95% Confidence interval): 2.51 (1.06-5.93) p = 0.036]. Conclusions: For patients aged 50-70, there was no significant difference in overall long-term mortality between mechanical and bioprosthetic valve recipients. Patients receiving mechanical valves for MVR displayed lower mortality after 12.5 years follow-up. For AVR, bioprosthetic valves were associated with a lower risk of bleeding.

Left Bundle Branch Area Pacing Contributes to a Greater Acute Blood Pressure Reduction Compared to Right Ventricular Pacing.

Background: Several previous studies have explored the potential arterial blood pressure (BP) changes in patients undergoing right ventricular pacing (RVP), however, the relationship between left bundle branch area pacing (LBBAP) and BP variations remains unknown. This study aimed to examine the acute BP variations following LBBAP and RVP implantation in patients with bradycardia. Methods: We conducted a single-center retrospective study including all patients who underwent de-novo dual-chamber pacemaker implantation between January 2019 and June 2021. Patients were divided into two groups, LBBAP and RVP, and propensity score-matching (PSM) was used to balance confounding factors. Three time periods were defined according to the timing of the implant: baseline (within 24 hours before implantation), hyper-acute period (0-24 hours post-implantation), and acute period (24-48 hours post-implantation). BP was measured at least three times per period using an arm pressure cuff and then averaged for analysis, which allowed us to determine the acute impact of pacemaker implantation on BP. Results: From a cohort of 898 patients, 193 LBBAP receivers were matched to 193 RVP receivers. A significant decrease in systolic BP (SBP) after the implantation was observed in the study cohort, from baseline 137.3 ± 9.2 mmHg to the acute period of 127.7 ± 9.4 mmHg (p < 0.001). The LBBAP group exhibited a greater SBP reduction than the RVP group ( Δ 11.6 ± 6.2 mmHg vs. Δ 7.6 ± 5.8 mmHg, p < 0.001). In further subgroup analysis, LBBAP receivers who had high baseline SBP (p < 0.001) and those without using anti-hypertensive drugs (p = 0.045) appeared to have a higher magnitude of SBP reduction. Conclusions: Permanent pacemaker implantation may contribute to an acute decrease in systolic BP, which was more pronounced in LBBAP receivers. Future experimental and clinical investigations are necessary to explore the underlying mechanisms and the long-term hemodynamic effects of LBBAP versus RVP.

Cardiac magnetic resonance-derived myocardial scar is associated with echocardiographic response and clinical prognosis of left bundle branch area pacing for cardiac resynchronization therapy.

AIMS: Left bundle branch area pacing (LBBAP) is a novel approach for cardiac resynchronization therapy (CRT), but the impact of myocardial substrate on its effect is poorly understood. This study aims to assess the association of cardiac magnetic resonance (CMR)-derived scar burden and the response of CRT via LBBAP. METHODS AND RESULTS: Consecutive patients with CRT indications who underwent CMR examination and successful LBBAP-CRT were retrospectively analysed. Cardiac magnetic resonance late gadolinium enhancement was used for scar assessment. Echocardiographic reverse remodelling and composite outcomes (defined as all-cause death or heart failure hospitalization) were evaluated. The echocardiographic response was defined as a ≥15% reduction of left ventricular end-systolic volume. Among the 54 patients included, LBBAP-CRT resulted in a 74.1% response rate. The non-responders had higher global, septal, and lateral scar burden (all P < 0.001). Global, septal, and lateral scar percentage all predicted echocardiographic response [area under the curve (AUC): 0.857, 0.864, and 0.822; positive likelihood ratio (+LR): 9.859, 5.594, and 3.059; and negative likelihood ratio (-LR): 0.323, 0.233, and 0.175 respectively], which was superior to QRS morphology criteria (Strauss left bundle branch abnormality: AUC: 0.696, +LR 2.101, and -LR 0.389). After a median follow-up time of 20.3 (11.5-38.7) months, higher global, lateral and septal scar burdens were all predictive of the composite outcome (hazard ratios: 4.996, 7.019, and 4.741, respectively; P's < 0.05). CONCLUSION: Lower scar burden was associated with higher response rate of LBBAP-CRT. The pre-procedure CMR scar evaluation provides further useful information to identify potential responders and clinical outcomes.

Screening of Endocrine Disrupting Potential of Surface Waters via an Affinity-Based Biosensor in a Rural Community in the Yellow River Basin, China.

Overcoming the limitations of traditional analytical methods and developing technologies to continuously monitor environments and produce a comprehensive picture of potential endocrine-disrupting chemicals (EDCs) has been an ongoing challenge. Herein, we developed a portable nuclear receptor (NR)-based biosensor within 90 min to perform highly sensitive analyses of a broad range of EDCs in environmental water samples. Based on the specific binding of the fluorescence-labeled NRs with their ligands, the receptors were attached to the EDC-functionalized fiber surface by competing with EDCs in the samples. The biosensor emitted fluorescence due to the evanescent wave excitation, thereby resulting in a turn-off sensing mode. The biosensor showed a detection limit of 5 ng/L E2-binding activity equivalent (E2-BAE) and 93 ng/L T3-BAE. As a case study, the biosensor was used to map the estrogenic binding activities of surface waters obtained from a rural community in the Yellow River basin in China. When the results obtained were compared with those from the traditional yeast two-hybrid bioassay, a high correlation was observed. It is anticipated that the good universality and versatility exhibited by this biosensor for various EDCs, which is achieved by using different NRs, will significantly promote the continuous assessment of global EDCs.

Freeze-thaw alternations accelerate plasticizers release and pose a risk for exposed organisms.

The application of plastic mulch films brings convenience to agricultural production, but also causes plastic waste that can be degraded into microplastics (MPs). However, little is known about the fate of plastic waste in agricultural ecosystem under freeze-thaw alternation in middle and high latitudes, as well as in highlands around the world. Whether the release of plasticizers, i.e. phthalate esters (PAEs), under such conditions would pose a potential risk to exposed organisms due to bioaccumulation is also unknown. To fill these data gaps, the agricultural fields in Liaoning of China with typical freeze-thaw alternation was selected as the study area. The transformation of plastic film was demonstrated by simulation freeze-thaw alternating from -30 to 20 â„ƒ. Soil samples were collected to investigate the patterns of MP composition, abundance, and distribution. Concurrently, the concentrations of two PAEs including bis(2-ethylhexyl) phthalate (DEHP) and diethyl phthalate (DEP) in soils were analyzed to provide information on the correlation between MPs abundance and PAEs concentrations as well as potential risks. The results showed that freeze-thaw alternating can accelerate the formation of MPs and release of PAEs from plastic waste. The abundance of MPs was positively correlated with the concentration of PAEs. Soil PAEs ranged from 3268 ± 213-6351 ± 110 µg/kg, indicating that over 40 % of the PAEs were transferred from plastic films to soils. Such residual amounts could pose risk for exposed organisms. Hence, the current study suggested that special concerns should be given to the release plasticizers in plastic waste of agricultural soils.

Thyroid Hormone Transporters in Pregnancy and Fetal Development.

Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis.

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway.

Oxidized low-density lipoprotein (oxLDL) induced a foam-cell-like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression.

Association of carbamylated high-density lipoprotein with coronary artery disease in type 2 diabetes mellitus: carbamylated high-density lipoprotein of patients promotes monocyte adhesion.

BACKGROUND: Increasing evidence showed that carbamylated lipoprotein accelerated atherosclerosis. However, whether such modification of high-density lipoprotein (HDL) particles alters in type 2 diabetes mellitus (T2DM) patients and facilitates vascular complications remains unclear. We aimed to investigate the alteration of the carbamylation in HDL among T2DM patients and clarify its potential role in atherogenesis. METHODS: A total of 148 consecutive T2DM patients undergoning angiography and 40 age- and gender-matched control subjects were included. HDL was isolated from plasma samples, and the concentration of HDL carbamyl-lysine (HDL-CBL) was measured. Furthermore, the HDL from subjects and in-vitro carbamylated HDL (C-HDL) was incubated with endothelial cells and monocyte to endothelial cell adhesion. Adhesion molecule expression and signaling pathway were detected. RESULTS: Compared with the control group, the HDL-CBL level was remarkably increased in T2DM patients (6.13 ± 1.94 vs 12.00 ± 4.06 (ng/mg), P < 0.001). Of note, HDL-CBL demonstrated a more significant increase in T2DM patients with coronary artery disease (CAD) (n = 102) than those without CAD (n = 46) (12.75 ± 3.82 vs. 10.35 ± 4.11(ng/mg), P = 0.001). Multivariate logistic regression analysis demonstrated that higher HDL-CBL level was independently associated with a higher prevalence of CAD in diabetic patients after adjusting for established cofounders (adjusted odds ratio 1.174, 95% confidence Interval 1.045-1.319, p = 0.017). HDL from diabetic patients with CAD enhanced greater monocyte adhesion than that from the non-CAD or the control group (P < 0.001). Such pro-atherogenic capacity of diabetic HDL positively correlated with HDL-CBL level. Furthermore, in-vitro incubation of carbamylated HDL (C-HDL) with endothelial promoted monocyte to endothelial cell adhesion, induced upregulation of cell adhesion molecules expression, and activated NF-κB/p65 signaling in endothelial cells. Inhibiting carbamylation of HDL or NF-κB activation attenuated the monocyte to endothelial cell adhesion and cell surface adhesion molecules expression. CONCLUSIONS: Our study identified elevated carbamylation modification of HDL from T2DM patients, especially in those with concomitant CAD. We also evidenced that C-HDL enhanced monocyte to endothelial cell adhesion, indicating a potential pro-atherogenic role of C-HDL in atherosclerosis among T2DM patients. Trial registration https://register.clinicaltrials.gov , NCT04390711 Registered on 14 May 2020; Retrospectively registered.

Single-cell RNA Sequencing: In-depth Decoding of Heart Biology and Cardiovascular Diseases.

BACKGROUND: The cardiac system is a combination of a complex structure, various cells, and versatile specified functions and sophisticated regulatory mechanisms. Moreover, cardiac diseases that encompass a wide range of endogenous conditions, remain a serious health burden worldwide. Recent genome-wide profiling techniques have taken the lead in uncovering a new realm of cell types and molecular programs driving physiological and pathological processes in various organs and diseases. In particular, the emerging technique single-cell RNA sequencing dominates a breakthrough in decoding the cell heterogeneity, phenotype transition, and developmental dynamics in cardiovascular science. CONCLUSION: Herein, we review recent advances in single cellular studies of cardiovascular system and summarize new insights provided by single-cell RNA sequencing in heart developmental sciences, stem-cell researches as well as normal or disease-related working mechanisms.

The fate of the herbicide propanil in plants of the littoral zone of the Three Gorges Reservoir (TGR), China.

The anti-seasonal hydrology with 30m water fluctuations in the Three Gorges Reservoir (TGR) of China attracts growing environmental and ecological concerns. We investigated the biotransformation of the herbicide propanil in plants dominating in the littoral zone of the TGR by applying the 14C-ring-labeled herbicide into non-aseptic hydroponic plant systems (Cynodon dactylon, Nelumbo nucifera and Bidens pilosa), aseptic plants (Lemna minor and Lemna gibba) and cell suspension cultures (C. dactylon and L. minor). (1) Propanil absorbed in plants of the hydroponic systems was (12.46±1.63)% of applied radioactivity (AR) (C. dactylon), (52.36±6.38)% (N. nucifera) and (76.55±6.07)% (B. pilosa), respectively. The 14C-residues in the plant extractable fractions and the corresponding media were confirmed by radio-Thin Layer Chromatography (TLC), radio-High Performance Liquid Chromatography (HPLC) and Gas Chromatography-Electron Ionization Mass Spectrometry (GC-EIMS) as propanil, 3,4-dichloroaniline (DCA) and N-(3,4-dichlorophenyl)-ß-d-glucopyranosylamine (Glu-DCA). (2) About 8% of AR was taken up by both aseptic plants, from which 7.0% of AR was extracted and identified also as propanil, DCA and Glu-DCA. (3) Concerning cell suspension cultures, (39.22±9.39)% of AR was absorbed by C. dactylon after 72hr, whereas the accumulated 14C-propanil by L. minor cell suspension culture amounted to (65.04±1.72)% after 7days. The identified compounds in cell cultures are consistent with those in the tested plants. Most of the pesticide residues in the intact plants were un-extractable, which are recognized as the end of the detoxification process. We therefore consider these plants as suitable for the phytoremediation of the herbicide propanil in the TGR region.

Identification of Diagnostic Genes of Aortic Stenosis That Progresses from Aortic Valve Sclerosis.

Background: Aortic valve sclerosis (AVS) is a pathological state that can progress to aortic stenosis (AS), which is a high-mortality valvular disease. However, effective medical therapies are not available to prevent this progression. This study aimed to explore potential biomarkers of AVS-AS advancement. Methods: A microarray dataset and an RNA-sequencing dataset were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened from AS and AVS samples. Functional enrichment analysis, protein-protein interaction (PPI) network construction, and machine learning model construction were conducted to identify diagnostic genes. A receiver operating characteristic (ROC) curve was generated to evaluate diagnostic value. Immune cell infiltration was then used to analyze differences in immune cell proportion between tissues. Finally, immunohistochemistry was applied to further verify protein concentration of diagnostic factors. Results: A total of 330 DEGs were identified, including 92 downregulated and 238 upregulated genes. The top 5% of DEGs (n = 17) were screened following construction of a PPI network. IL-7 and VCAM-1 were identified as the most significant candidate genes via least absolute shrinkage and selection operator (LASSO) regression. The diagnostic value of the model and each gene were above 0.75. Proportion of anti-inflammatory M2 macrophages was lower, but the fraction of pro-inflammatory gamma-delta T cells was elevated in AS samples. Finally, levels of IL-7 and VCAM-1 were validated to be higher in AS tissue than in AVS tissue using immunohistochemistry. Conclusion: IL-7 and VCAM-1 were identified as biomarkers during the disease progression. This is the first study to analyze gene expression differences between AVS and AS and could open novel sights for future studies on alleviating or preventing the disease progression.

Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian randomization study.

Background: Systemic inflammation has been proposed to be associated with the incidence of atrial fibrillation (AF), but whether it is a cause or a consequence of AF remains uncertain. We sought to explore the causal associations between systemic inflammation and AF using bidirectional Mendelian randomization (MR) analysis. Methods: Independent genetic variants strongly associated with AF were selected as instrumental variables from the largest genome-wide association study (GWAS) with up to 1,030,836 individuals. Regarding inflammation traits, genetic associations with 41 inflammatory cytokines and 5 inflammatory biomarkers were obtained from their corresponding GWASs databases. Effect estimates were primarily evaluated using the inverse-variance weighted (IVW) method, supplemented by sensitivity analyses using MR-Egger, weighted median, and MR-PRESSO methods. Results: In our initial MR analyses, we observed suggestive associations of genetically predicted interleukin-17 (IL-17), interleukin-2 receptor subunit alpha (IL-2rα), and procalcitonin (PCT) with AF. One standard deviation (SD) increase in IL-17, IL-2rα, and PCT caused an increase in AF risk by 6.3 % (OR 1.063, 95 %CI 1.011---1.118, p = 0.018), 4.9 % (OR 1.049, 95 %CI 1.007---1.094, p = 0.023) and 3.4 % (OR 1.034, 95 %CI 1.005---1.064, p = 0.022), respectively. Furthermore, our reverse MR analyses indicated that genetically predicted AF contributed to a suggestive increase in the levels of macrophage inflammatory protein-1ß (MIP1ß) (ß 0.055, 95 %CI 0.006 to 0.103, p = 0.028), while a decrease in the levels of fibrinogen (Fbg) (ß -0.091, 95 %CI -0.140 to -0.041, p < 0.001), which remained significant after multiple test correction. Conclusions: Our MR study identified several inflammatory biomarkers with suggestive causal associations regarding the upstream and downstream regulation of AF occurrence, offering new insights for therapeutic exploitation of AF. Further research is required to validate the underlying link between systemic inflammation and AF in larger cohorts.

A Comparison of the Association of Septal Scar Burden on Responses to LBBAP-CRT and BVP-CRT.

BACKGROUND: Left bundle branch area pacing (LBBAP) is an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). However, despite the presence of left bundle branch block, whether cardiac substrate may influence the effect between the 2 strategies is unclear. OBJECTIVES: This study aims to assess the association of septal scar on reverse remodeling and clinical outcomes of LBBAP compared with BVP. METHODS: We analyzed patients with nonischemic cardiomyopathy who had CRT indications undergoing preprocedure cardiac magnetic resonance examination. Changes in left ventricular ejection fraction (LVEF) and echocardiographic response (ER) (≥5% absolute LVEF increase) were assessed at 6 months. The clinical outcome was the composite of all-cause mortality, heart failure hospitalization, or major ventricular arrhythmia. RESULTS: There were 147 patients included (51 LBBAP and 96 BVP). Among patients with low septal scar burden (below median 5.7%, range: 0% to 5.3%), LVEF improvement was higher in the LBBAP than the BVP group (17.5% ± 10.9% vs 12.3% ± 11.8%; P = 0.037), with more than 3-fold increased odds of ER (OR: 4.35; P = 0.033). In high sepal scar subgroups (≥5.7%, range: 5.7%-65.9%), BVP trended towards higher LVEF improvement (9.2% ± 9.4% vs 6.4% ± 12.4%; P = 0.085). Interaction between septal scar burden and pacing strategy was significant for ER (P = 0.002) and LVEF improvement (P = 0.011) after propensity score adjustment. During median follow-up of 33.7 (Q1-Q3: 19.8-42.1) months, the composite clinical outcome occurred in 34.7% (n = 51) of patients. The high-burden subgroups had worse clinical outcomes independent of CRT method. CONCLUSIONS: Remodeling response to LBBAP and BVP among nonischemic cardiomyopathy patients is modified by septal scar burden. High septal scar burden was associated with poor clinical prognosis independent of CRT methods.

Combined simulation on pesticides fate, toxicities and ecological risk in rice paddies for Sustainable Development Goals achievements.

In order to assess the risk of pesticides to aquatic ecosystems, five single-dose pesticides including chlorpyrifos, pymetrozine, dinotefuran, azoxystrobin, and acetochlor that are frequently used in developing countries, were selected. Based on the principle of conservative risk assessment, application amounts for different dosage forms were recommended, the Top-Rice model and risk quotient method were used to evaluate the aquatic ecological risk of the aforementioned single-dose pesticide products. The results showed that predicted peak environmental concentration ranges after application on rice were 110.52-564.25 µg/L for chlorpyrifos, 20.79-114.6 µg/L for pymetrozine, 21.81-114.02 µg/L for dinotefuran, 16.52-56.94 µg/L for azoxystrobin, and 167.22-2184.01 µg/L for acetochlor in different seasons of Changsha, Hangzhou, Nanning in China, and Lahore and Faisalabad in Pakistan. Under the current conditions of registered administration, the acute and chronic risks posed by chlorpyrifos to fish and invertebrates were deemed alarming, and those by pymetrozine and dinotefuran were considered acceptable. The acute risk of exposure of azoxystrobin to vertebrates such as fish, and invertebrates such as daphnia and shrimp is alarming, whereas the chronic risk to vertebrates, invertebrates, and algae was acceptable. The acute exposure risk posed by acetochlor was deemed worrying, and in the case of chronic exposure, only 36 % of the simulation group exhibited a risk quotient below 1, indicating no risk. These findings imply that the ecological risks of using registered chlorpyrifos and acetochlor products on rice cannot be ignored. It should be noted that the analysis method and model employed in this study were intentionally conservative to ensure a comprehensive assessment of the potential risks associated with the use of registered pesticide products. However, the model failed to consider influential factors like photolysis of pesticides on the soil surface, thereby introducing a certain degree of conservativeness in the evaluation results.

3,3',5-Triiodothyroacetic Acid Transporters.

Introduction: Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter (MCT) 8 is a key transporter and is expressed at the blood-brain barrier (BBB), in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays because of cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3',5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human BBB and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and Methods: Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate-buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization in brain sections from wild-type and Mct8/Oatp1c1 knockout mice at postnatal days 12, 21, and 120. Results: In total, 59 plasma membrane transporters were selected for screening of TRIAC accumulation (n = 40 based on expression at the human BBB and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n = 19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6, and SLC22A24 (in DMEM). The zebrafish and mouse orthologs of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but was reduced at P120. Conclusions: Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8, and SLC22A24 as well as their mouse and zebrafish orthologs are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.