Single-cell sequencing combined with machine learning reveals the mechanism of interaction between epilepsy and stress cardiomyopathy

BackgroundEpilepsy is a disorder that can manifest as abnormalities in neurological or physical function. Stress cardiomyopathy is closely associated with neurological stimulation. However, the mechanisms underlying the interrelationship between epilepsy and stress cardiomyopathy are unclear. This paper aims to explore the genetic features and potential molecular mechanisms shared in epilepsy and stress cardiomyopathy.MethodsBy analyzing the epilepsy dataset and stress cardiomyopathy dataset separately, the intersection of the two disease co-expressed differential genes is obtained, the co-expressed differential genes reveal the biological functions, the network is constructed, and the core modules are identified to reveal the interaction mechanism, the co-expressed genes with diagnostic validity are screened by machine learning algorithms, and the co-expressed genes are validated in parallel on the epilepsy single-cell data and the stress cardiomyopathy rat model.ResultsEpilepsy causes stress cardiomyopathy, and its key pathways are Complement and coagulation cascades, HIF-1 signaling pathway, its key co-expressed genes include SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3. The key immune cell subpopulations localized by single-cell data are the T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup, and Oligodendrocytes subgroup.ConclusionWe believe epilepsy causing stress cardiomyopathy results from a multi-gene, multi-pathway combination. We identified the core co-expressed genes (SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3) and the pathways that function in them (Complement and coagulation cascades, HIF-1 signaling pathway, JAK-STAT signaling pathway), and finally localized their key cellular subgroups (T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup, and Oligodendrocytes subgroup). Also, combining cell subpopulations with hypercoagulability as well as sympathetic excitation further narrowed the cell subpopulations of related functions

Hepatic Autophagy Deficiency Compromises FXR Functionality and Causes Cholestatic Injury

Autophagy is important for hepatic homeostasis, nutrient regeneration and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy due to the lack of Atg7 or Atg5, key autophagy‐related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of TMCA/TCA in the bile, increased hepatic bile acid load, abnormal bile canaliculi and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and upregulated expression of Fxr in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly Bsep, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy‐deficient livers. In addition, co‐deletion of Nrf2 in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy‐deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion

The Role of Sleep Deprivation in Arrhythmias

Sleep is essential to the normal psychological and physiological activities of the human body. Increasing evidence indicates that sleep deprivation is associated with the occurrence, development, and poor treatment effects of various arrhythmias. Sleep deprivation affects not only the peripheral nervous system but also the central nervous system, which regulates the occurrence of arrhythmias. In addition, sleep deprivation is associated with apoptotic pathways, mitochondrial energy metabolism disorders, and immune system dysfunction. Although studies increasingly suggest that pathological sleep patterns are associated with various atrial and ventricular arrhythmias, further research is needed to identify specific mechanisms and recommend therapeutic interventions. This review summarizes the findings of sleep deprivation in animal experiments and clinical studies, current challenges, and future research directions in the field of arrhythmias

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Validation of American Joint Committee on Cancer 8th edition of TNM staging in resected distal pancreatic cancer

BACKGROUND In order to improve risk stratification and clinical management of the pancreatic ductal adenocarcinoma (PDAC), the American Joint Committee on Cancer (AJCC) has published its eighth edition staging manual. Some major changes have been introduced in the new staging system for both T and N categories. Given the rarity of resectable disease, distal pancreatic cancer is likely underrepresented in the published clinical studies, and how the impact of the staging system actually reflects on to clinical outcomes remain unclear. AIM To validate the AJCC 8th edition of TNM staging in distal PDAC. METHODS A retrospective cohort study was performed in seven academic medical centers in the United States. Clinicopathological prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated through univariate and multivariate analyses. RESULTS Overall, 454 patients were enrolled in the study, and were divided into 2 subgroups: Invasive intraductal papillary mucinous neoplasms (IPMN) (115 cases) and non-IPMN associated adenocarcinoma (339 cases). Compared to invasive IPMN, non-IPMN associated adenocarcinomas are more common in relatively younger patients, have larger tumor size, are more likely to have positive lymph nodes, and are associated with a higher tumor (T) stage and nodal (N) stage, lymphovascular invasion, perineural invasion, tumor recurrence, and a worse PFS and OS. The cohort was predominantly categorized as stage 3 per AJCC 7th edition staging manual, and it’s more evenly distributed based on 8th edition staging manual. T and N staging of both 7th and 8th edition sufficiently stratify PFS and OS in the entire cohort, although dividing into N1 and N2 according to the 8th edition does not show additional stratification. For PDAC arising in IPMN, T staging of the 7th edition and N1/N2 staging of the 8th edition appear to further stratify PFS and OS. For PDAC without an IPMN component, T staging from both versions fails to stratify PFS and OS. CONCLUSION The AJCC 8th edition TNM staging system provides even distribution for the T staging, however, it does not provide better risk stratification than previous staging system for distal pancreatic cancer

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Funder: Funding details are provided in the Supplementary MaterialAbstractPolygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.</jats:p

Computational and experimental research on mechanism of cis/trans isomerization of oleic acid

The harm of trans-fatty acids to health has aroused public concern. It is believed that the main source of trans-fatty acids in diets is the isomerization of unsaturated fatty acids in edible oils during cooking. However, the information on the isomerization mechanism is very limited. In this paper, we used oleic acid, an unsaturated fatty acid, as a simplified model for edible oil and investigated the mechanism of cis/trans isomerization by computation and experiments. The computational results show that Rc-O-O-H is a very important intermediate, and the cleavage of O-O bond in Rc-O-O-H is the rate-controlling step during the cis/trans isomerization. Using the ATR-FTIR measurements, the contents of elaidic acid were measured quantitatively in sites. The experimental results indicate that the cis/trans isomerization of oleic acid can occur obviously only under oxidizing condition when the temperature is higher than 120 °C

Deep desulfurization performance of thiophene with deep eutectic solvents loaded carbon nanotube composites

One source of air pollution is the combustion of sulfur compounds in fuel oil. Reducing sulfur content in fuel oil has become a hot issue demanding timely solutions. Using ionic liquids and deep eutectic solvents (DESs) to remove sulfides in fuel oil has achieved good results presently. However, since DESs are liquid and their transportation and separation are inconvenient, a new way is proposed that the DESs are loaded on the carbon nanotubes (CNTs) with large specific surface area and good chemical stability. A series of composites materials (DESs/CNTs) were prepared. Finally, they are applied to the removal of sulfides in fuel oil. This loading method, which imparts introduced unique physico-chemical properties of the DESs to the carrier materials, preserves both advantages while overcoming some of the problems with DESs. The interaction between DESs and CNTs is mutual promotion. Therefore, this study has important theoretical significance and industrial application value. Under optimal conditions, when the reagent ChCl/p-TsOH (1 : 2) was loaded on multi-walled CNTs (OD = 30–60 nm) to prepare the composite material (ChCl/p-TsOH)/CNTs, the single desulfurization rate of the composite material was 95.8%. Finally, the catalytic/oxidation mechanism was studied systematically and this work would provide a green route for the desulfurization of fuels