Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH.

Advancing Guideline-Directed Medical Therapy in Heart Failure: Overcoming Challenges and Maximizing Benefits.

The delayed titration of guideline-directed drug therapy (GDMT) is a complex event influenced by multiple factors that often result in poor prognosis for patients with heart failure (HF). Individualized adjustments in GDMT titration may be necessary based on patient characteristics, and every clinician is responsible for promptly initiating GDMT and titrating it appropriately within the patient's tolerance range. This review examines the current challenges in GDMT implementation and scrutinizes titration considerations within distinct subsets of HF patients, with the overarching goal of enhancing the adoption and effectiveness of GDMT. The authors also underscore the significance of establishing a novel management strategy that integrates cardiologists, nurse practitioners, pharmacists, and patients as a unified team that can contribute to the improved promotion and implementation of GDMT.

Overcoming barriers for left atrial appendage thrombus: a systematic review of left atrial appendage closure.

BACKGROUND: Approximately 90% of intracardial thrombi originate from the left atrial appendage in non-valvular atrial fibrillation patients. Even with anticoagulant therapy, left atrial appendage thrombus (LAAT) still occurs in 8% of patients. While left atrial appendage closure (LAAC) could be a promising alternative, the current consensus considers LAAT a contraindication to LAAC. However, the feasibility and safety of LAAC in patients with LAAT have yet to be determined. METHODS: This systematic review synthesizes published data to explore the feasibility and safety of LAAC for patients with LAAT. RESULTS: This study included a total of 136 patients with LAATs who underwent successful LAAC. The Amulet Amplatzer device was the most frequently utilized device (48.5%). Among these patients, 77 (56.6%) had absolute contraindications to anticoagulation therapy. Cerebral protection devices were utilized by 47 patients (34.6%). Transesophageal echocardiography (TEE) is the primary imaging technique used during the procedure. Warfarin and novel oral anticoagulants were the main anticoagulant medications used prior to the procedure, while dual antiplatelet therapy was primarily used post-procedure. During a mean follow-up period of 13.2 ± 11.5 months, there was 1 case of fatality, 1 case of stroke, 3 major bleeding events, 3 instances of device-related thrombus, and 8 cases of peri-device leakage. CONCLUSIONS: This review highlights the preliminary effectiveness and safety of the LAAC procedure in patients with persistent LAAT. Future large-scale RCTs with varied LAAT characteristics and LAAC device types are essential for evidence-based decision-making in clinical practice.

Amino acid profile alteration in age-related atrial fibrillation.

BACKGROUND: Amino acids (AAs) are one of the primary metabolic substrates for cardiac work. The correlation between AAs and both atrial fibrillation (AF) and aging has been documented. However, the relationship between AAs and age-related AF remains unclear. METHODS: Initially, the plasma AA levels of persistent AF patients and control subjects were assessed, and the correlations between AA levels, age, and other clinical indicators were explored. Subsequently, the age-related AF mouse model was constructed and the untargeted myocardial metabolomics was conducted to detect the level of AAs and related metabolites. Additionally, the gut microbiota composition associated with age-related AF was detected by a 16S rDNA amplicon sequencing analysis on mouse fecal samples. RESULTS: Higher circulation levels of lysine (Student's t-test, P = 0.001), tyrosine (P = 0.002), glutamic acid (P = 0.008), methionine (P = 0.008), and isoleucine (P = 0.014), while a lower level of glycine (P = 0.003) were observed in persistent AF patients. The feature AAs identified by machine learning algorithms were glutamic acid and methionine. The association between AAs and age differs between AF and control subjects. Distinct patterns of AA metabolic profiles were observed in the myocardial metabolites of aged AF mice. Aged AF mice had lower levels of Betaine, L-histidine, L-alanine, L-arginine, L-Pyroglutamic acid, and L-Citrulline compared with adult AF mice. Aged AF mice also presented a different gut microbiota pattern, and its functional prediction analysis showed AA metabolism alteration. CONCLUSION: This study provided a comprehensive network of AA disturbances in age-related AF from multiple dimensions, including plasma, myocardium, and gut microbiota. Disturbances of AAs may serve as AF biomarkers, and restoring their homeostasis may have potential benefits for the management of age-related AF.

Pulsed field ablation: A promising approach for ventricular tachycardia ablation.

Radiofrequency ablation (RFA) has been a central therapeutic strategy for ventricular tachycardia (VT). However, concerns about its long-term effectiveness and complications have arisen. Pulsed field ablation (PFA), characterized by its nonthermal, highly tissue-selective ablation technique, has emerged as a promising alternative. This comprehensive review delves into the potential advantages and opportunities presented by PFA in the realm of VT, drawing insights from both animal experimentation and clinical case studies. PFA shows promise in generating superior lesions within scarred myocardial tissue, and its inherent repetition dependency holds the potential to enhance therapeutic outcomes. Clinical cases underscore the promise of PFA for VT ablation. Despite its promising applications, challenges such as catheter maneuverability and proarrhythmic effects require further investigation. Large-scale, long-term studies are essential to establish the suitability of PFA for VT treatment.

Physical activity, sedentary behavior, and the risk of frailty and falling: A Mendelian randomization study.

BACKGROUND: Due to inconclusive evidence from observational studies regarding the impact of physical activity (PA) and sedentary behavior on frailty and falling risk, we conducted a two-sample Mendelian randomization analysis to investigate the causal associations between PA, sedentary behavior, and frailty and falls. METHODS: We extracted summary data from genome-wide association studies conducted among individuals of European ancestry, encompassing PA (n = 90 667-608 595), sedentary behavior (n = 372 609-526 725), frailty index (n = 175 226), and falling risk (n = 451 179). Single nucleotide polymorphisms associated with accelerometer assessed fraction >425 milligravities, self-reported vigorous activity, moderate to vigorous physical acticity (MVPA), leisure screen time (LST), and sedentary behavior at work were taken as instrumental variables. The causal effects were primarily estimated using inverse variance weighted methods, complemented by several sensitivity and validation analyses. RESULTS: Genetically predicted higher levels of PA were significantly associated with a reduction in the frailty index (accelerometer assessed fraction >425 milligravities: ß = -0.25, 95% CI = -0.36 to -0.14, p = 1.27 × 10-5 ; self-reported vigorous activity: ß = -0.13, 95% CI = -0.20 to -0.05, p = 7.9 × 10-4 ; MVPA: ß = -0.28, 95% CI = -0.40 to -0.16, p = 9.9 × 10-6 ). Besides, LST was significantly associated with higher frailty index (ß = 0.18, 95% CI = 0.14-0.22, p = 5.2 × 10-20 ) and higher odds of falling (OR = 1.13, CI = 1.07-1.19, p = 6.9 × 10-6 ). These findings remained consistent throughout sensitivity and validation analyses. CONCLUSIONS: Our study offers evidence supporting a causal relationship between PA and a reduced risk of frailty. Furthermore, it underscores the association between prolonged LST and an elevated risk of frailty and falls. Therefore, promoting PA and reducing sedentary behavior may be an effective strategy in primary frailty and falls prevention.

Novel Drug Targets for Atrial Fibrillation Identified Through Mendelian Randomization Analysis of the Blood Proteome.

PURPOSE: Novel, effective, and safe preventive therapy targets for AF are still needed. Circulating proteins with causal genetic evidence are promising candidates. We aimed to systematically screen circulating proteins for AF drug targets and determine their safety and efficacy using genetic methods. METHODS: The protein quantitative trait loci (pQTL) of up to 1949 circulating proteins were retrieved from nine large genome-proteome-wide association studies. Two-sample Mendelian Randomization (MR) and colocalization analyses were used to estimate the causal effects of proteins on the risk of AF. Furthermore, phenome-wide MR was conducted to depict side effects and the drug-target databases were searched for drug validation and repurposing. RESULTS: Systematic MR screen identified 30 proteins as promising AF drug targets. Genetically predicted 12 proteins increased AF risk (TES, CFL2, MTHFD1, RAB1A, DUSP13, SRL, ANXA4, NEO1, FKBP7, SPON1, LPA, MANBA); 18 proteins decreased AF risk (PMVK, UBE2F, SYT11, CHMP3, PFKM, FBP1, TNFSF12, CTSZ, QSOX2, ALAD, EFEMP1, FLRT2, LRIG1, OLA1, SH3BGRL3, IL6R, B3GNT8, FCGR2A). DUSP13 and TNFSF12 possess strong colocalization evidence. For the proteins that were identified, extended phe-MR analysis was conducted to assess their side-effect profiles, while drug-target databases provided information on their approved or investigated indications. CONCLUSION: We identified 30 circulating proteins as potential preventive targets for AF.

The impact of the establishment of carbon emission trade exchange on carbon emission efficiency.

The China government focuses on changes in carbon emission efficiency with establishing carbon emission trade exchange (CETE). It is meaningful to study whether the pilot CETEs can facilitate the betterment of carbon emission efficiency. Using the data of 283 cities in China within 2006-2019, this article gauges the carbon emission efficiency with the SBM-DEA model. This paper analyzes the impact of China's pilot CETEs, which was gradually launched from 2013 to 2014, on carbon emission efficiency through the time-varying difference-in-difference (DID) model. Finally, the mediating effect model is further used to analyze the impact mechanism of the pilot CETEs on carbon emission efficiency from the perspectives of innovation investment and pollution control investment. The results reveal that the carbon emission efficiency of each city from 2006 to 2019 is not very ideal. All cities have some room to facilitate the carbon emission efficiency. The pilot CETEs have increased the carbon emission efficiency and reduced carbon dioxide emission. The policy influences the carbon emission efficiency through innovation investment and pollution control investment, which represent long-run and short-run mechanism respectively.

Human early syncytiotrophoblasts are highly susceptible to SARS-CoV-2 infection.

Direct in vivo investigation of human placenta trophoblast's susceptibility to SARS-CoV-2 is challenging. Here we report that human trophoblast stem cells (hTSCs) and their derivatives are susceptible to SARS-CoV-2 infection, which reveals heterogeneity in hTSC cultures. Early syncytiotrophoblasts (eSTBs) generated from hTSCs have enriched transcriptomic features of peri-implantation trophoblasts, express high levels of angiotensin-converting enzyme 2 (ACE2), and are productively infected by SARS-CoV-2 and its Delta and Omicron variants to produce virions. Antiviral drugs suppress SARS-CoV-2 replication in eSTBs and antagonize the virus-induced blockage of STB maturation. Although less susceptible to SARS-CoV-2 infection, trophoblast organoids originating from hTSCs show detectable viral replication reminiscent of the uncommon placental infection. These findings implicate possible risk of COVID-19 infection in peri-implantation embryos, which may go unnoticed. Stem cell-derived human trophoblasts such as eSTBs can potentially provide unlimited amounts of normal and genome-edited cells and facilitate coronavirus research and antiviral discovery.

Comparison between High-Power Short-Duration and Conventional Ablation Strategy in Atrial Fibrillation: An Updated Meta-Analysis.

High-power short-duration (HPSD) setting during radiofrequency ablation has become an attempt to improve atrial fibrillation (AF) treatment outcomes. This study ought to compare the efficacy, safety, and effectiveness between HPSD and conventional settings. PubMed, Embase, and Cochrane Library were searched. Studies that compared HPSD and conventional radiofrequency ablation settings in AF patients were included while studies performed additional ablations on nonpulmonary vein targets without clear recording were excluded. Data were pooled with random-effect model. Efficacy endpoints include first-pass pulmonary vein isolation (PVI), acute pulmonary vein (PV) reconnection, free from AF, and free from atrial tachycardia (AT) during follow-up. Safety endpoints include esophagus injury rate and major complication rate. Effectiveness endpoints include complete PVI rate, total procedure time, PVI time, and PVI radiofrequency ablation (PVI RF) time. We included 22 studies with 3867 atrial fibrillation patients in total (2393 patients received HPSD radiofrequency ablation). Perioperatively, the HPSD group showed a higher first-pass PVI rate (risk ratio, RR = 1.10, P = 0.0001) and less acute PV reconnection rate (RR = 0.56, P = 0.0004) than the conventional group. During follow-up, free from AF (RR = 1.11, P = 0.16) or AT (RR = 1.06, P = 0.24) rate did not differ between HPSD and conventional groups 6-month postsurgery. However, the HPSD group showed both higher free from AF (RR = 1.17, P = 0.0003) and AT (RR = 1.11, P < 0.0001) rate than the conventional group 12-month postsurgery. The esophagus injury (RR = 0.99, P = 0.98) and major complications (RR = 0.76, P = 0.70) rates did not differ between the two groups. The HPSD group took shorter total procedure time (MD = -33.71 95% CI: -43.10 to -24.33, P < 0.00001), PVI time (MD = -21.60 95% CI: -25.00 to -18.21, P < 0.00001), and PVI RF time (MD = -13.72, 95% CI: -14.45 to -13.00, P < 0.00001) than conventional groups while complete procedure rate did not differ between two groups (RR = 1.00, P = 0.93). HPSD setting during AF radiofrequency ablation has better effectiveness, efficacy, and similar safety compared with the conventional setting.

YAP Inhibition by Verteporfin Causes Downregulation of Desmosomal Genes and Proteins Leading to the Disintegration of Intercellular Junctions.

The Hippo-YAP pathway serves as a central signalling hub in epithelial tissue generation and homeostasis. Yes-associated protein (YAP) is an essential downstream transcription cofactor of this pathway, with its activity being negatively regulated by Hippo kinase-mediated phosphorylation, leading to its cytoplasmic translocation or degradation. Our recent study showed phospho-YAP complexes with Desmoglein-3 (Dsg3), the desmosomal cadherin known to be required for junction assembly and cell-cell adhesion. In this study, we show that YAP inhibition by Verteporfin (VP) caused a significant downregulation of desmosomal genes and a remarkable reduction in desmosomal proteins, including the Dsg3/phospho-YAP complex, resulting in attenuation of cell cohesion. We also found the desmosomal genes, along with E-cadherin, were the YAP-TEAD transcriptional targets and Dsg3 regulated key Hippo components, including WWTR1/TAZ, LATS2 and the key desmosomal molecules. Furthermore, Dsg3 and phospho-YAP exhibited coordinated regulation in response to varied cell densities and culture durations. Overexpression of Dsg3 could compensate for VP mediated loss of adhesion components and proper architecture of cell junctions. Thus, our findings suggest that Dsg3 plays a crucial role in the Hippo network and regulates junction configuration via complexing with phospho-YAP.

Associations of Visceral Adipose Tissue, Circulating Protein Biomarkers, and Risk of Cardiovascular Diseases: A Mendelian Randomization Analysis.

Aim: To evaluate the genetic associations of visceral adipose tissue (VAT) mass with metabolic risk factors and cardiovascular disease (CVD) endpoints and to construct a network analysis about the underlying mechanism using Mendelian randomization (MR) analysis. Methods and Results: Using summary statistics from genome-wide association studies (GWAS), we conducted the two-sample MR to assess the effects of VAT mass on 10 metabolic risk factors and 53 CVD endpoints. Genetically predicted VAT mass was associated with metabolic risk factors, including triglyceride (odds ratio, OR, 1.263 [95% confidence interval, CI, 1.203-1.326]), high-density lipoprotein cholesterol (OR, 0.719 [95% CI, 0.678-0.763]), type 2 diabetes (OR, 2.397 [95% CI, 1.965-2.923]), fasting glucose (OR, 1.079 [95% CI, 1.046-1.113]), fasting insulin (OR, 1.194 [95% CI, 1.16-1.229]), and insulin resistance (OR, 1.204 [95% CI, 1.16-1.25]). Genetically predicted VAT mass was associated with CVD endpoints, including atrial fibrillation (OR, 1.414 [95% CI, 1.332 = 1.5]), coronary artery disease (OR, 1.573 [95% CI, 1.439 = 1.72]), myocardial infarction (OR, 1.633 [95% CI, 1.484 =1.796]), heart failure (OR, 1.711 [95% CI, 1.599-1.832]), any stroke (OR, 1.29 [1.193-1.394]), ischemic stroke (OR, 1.292 [1.189-1.404]), large artery stroke (OR, 1.483 [1.206-1.823]), cardioembolic stroke (OR, 1.261 [1.096-1.452]), and intracranial aneurysm (OR, 1.475 [1.235-1.762]). In the FinnGen study, the relevance of VAT mass to coronary heart disease, stroke, cardiac arrhythmia, vascular diseases, hypertensive heart disease, and cardiac death was found. In network analysis to identify the underlying mechanism between VAT and CVDs, VAT mass was positively associated with 23 cardiovascular-related proteins (e.g., Leptin, Hepatocyte growth factor, interleukin-16), and inversely with 6 proteins (e.g., Galanin peptides, Endothelial cell-specific molecule 1). These proteins were further associated with 32 CVD outcomes. Conclusion: Mendelian randomization analysis has shown that VAT mass was associated with a wide range of CVD outcomes including coronary heart disease, cardiac arrhythmia, vascular diseases, and stroke. A few circulating proteins may be the mediators between VAT and CVDs.

Identification of Methylation Immune Subtypes and Establishment of a Prognostic Signature for Gliomas Using Immune-Related Genes.

DNA methylation patterns are essential in understanding carcinogenesis. However, the relationship between DNA methylation and the immune process has not been clearly established-this study aimed at elucidating the interaction between glioma and DNA methylation, consolidating glioma classification and prognosis. A total of 2,483 immune-related genes and 24,556 corresponding immune-related methylation probes were identified. From the Cancer Genome Atlas (TCGA) glioma cohort, a total of 683 methylation samples were stratified into two different clusters using unsupervised clustering, and eight types of other cancer samples from the TCGA database were shown to exhibit excellent distributions. A total of 3,562 differentially methylated probes (DMPs) were selected and used for machine learning. A five-probe signature was established to evaluate the prognosis of glioma as well as the potential benefits of radiotherapy and Procarbazine, CCNU, Vincristine (PCV) treatment. Other prognostic clinical models, such as nomogram and decision tree, were also evaluated. Our findings confirmed the interactions between immune-related methylation patterns and glioma. This novel approach for cancer molecular characterization and prognosis should be validated in further studies.

fMRI neurofeedback in the motor system elicits bidirectional changes in activity and in white matter structure in the adult human brain.

White matter (WM) plasticity supports skill learning and memory. Up- and downregulation of brain activity in animal models lead to WM alterations. But can bidirectional brain-activity manipulation change WM structure in the adult human brain? We employ fMRI neurofeedback to endogenously and directionally modulate activity in the sensorimotor cortices. Diffusion tensor imaging is acquired before and after two separate conditions, involving regulating sensorimotor activity either up or down using real or sham neurofeedback (n = 20 participants × 4 scans). We report rapid opposing changes in corpus callosum microstructure that depend on the direction of activity modulation. Our findings show that fMRI neurofeedback can be used to endogenously and directionally alter not only brain-activity patterns but also WM pathways connecting the targeted brain areas. The level of associated brain activity in connected areas is therefore a possible mediator of previously described learning-related changes in WM.

Defining the Cholesterol Lowering Mechanism of Bergamot (Citrus bergamia) Extract in HepG2 and Caco-2 Cells.

Bergamot, a Mediterranean citrus fruit native to southern Italy, has been reported to have cholesterol-lowering properties; however, the mechanism of action is not well understood. Due to structural similarities with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, it has been proposed that the phenolic compounds in bergamot may also inhibit HMGCR. Statins are widely used for their cholesterol-lowering properties; however, they are not universally well tolerated, suggesting there is a need to identify novel cholesterol-lowering strategies. In the present study, we investigated bergamot fruit extract (BFE) and its principal components (neoeriocitrin, naringin, neohesperidin, melitidin, and brutieridin) for their ability to regulate cholesterol levels in HepG2 and Caco-2 cells. BFE at increasing concentrations decreased the levels of total and free cholesterol in HepG2 cells. BFE and its constituents did not directly inhibit HMGCR activity. However, BFE and neohesperidin decreased HMGCR levels in HepG2 cells, suggesting that neohesperidin and BFE may downregulate HMGCR expression. An increase in AMP-kinase phosphorylation was observed in BFE and neohesperidin-treated cells. In Caco-2 cells, brutieridin exhibited a significant reduction in cholesterol uptake and decreased the level of Niemann-Pick C1 Like 1, an important cholesterol transporter. Taken together, our data suggest that the cholesterol-lowering activity of bergamot is distinct from statins. We hypothesize that BFE and its principal constituents lower cholesterol by inhibiting cholesterol synthesis and absorption.

Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein.

The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. There is still no cure to the disease apart from the use of corticosteroids and immunosuppressive agents. Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. Thus, further understanding of the molecular basis underlying this disease process is vital to develop targeted therapies. Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. DSG3 is a pivotal player in mediating outside-in signaling involved in cell junction remodeling, cell proliferation, differentiation, migration or apoptosis, thus validating its biological function in tissue integrity and homeostasis beyond desmosome adhesion. Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. The purpose of this review is to summarize the earlier and recent advances highlighting our recent findings related to PV pathogenesis that may pave the way for future research to develop novel specific therapies in curing this disease.

Effect of overlying water pH, temperature, and hydraulic disturbance on heavy metal and nutrient release from drinking water reservoir sediments.

How environmental factors impact the release of pollutants from sediment is critical to ensure the safety of drinking water, especially when the seasons change. Here, we investigated the effect of water pH, temperature, and hydraulic disturbance on the release of heavy metals and nutrients from the sediment of drinking water reservoir. The results show that lower initial water pH promoted the Zn release, while low temperature enhanced the Mn flux after 15 days. Meanwhile, continuous disturbance caused more metals releasing from sediment than intermittent disturbance due to greater shear stress and turbulence effect. However, intermittent high-speed disturbance greatly altered the dynamic release of Zn from L-shaped curve to U-shape in water column. Moreover, lower water pH caused higher ammonium in water but lower nitrate since H+ restrained the nitrification. Yet, higher temperature inhibited the release of ammonium from sediment, which might relate to the accelerated mineralization of organic nitrogen and elevated dissolved oxygen caused by the algae growth. Notably, hydraulic disturbance with various intensity and duration greatly influenced the fluxes of various species of nitrogen and soluble phosphate in water column, because the disturbance facilitated the nitrogen and phosphorus exchanges between sediment-water and water-air interfaces. PRACTITIONER POINTS: Lower water pH induced Zn release, while low temperature gradually enhanced Mn level. More metals were released from sediment under continuous disturbance than intermittent disturbance. Lower water pH caused higher ammonium nitrogen in water but lower nitrate nitrogen. Higher temperature inhibited the release of ammonium nitrogen from sediment. Hydraulic disturbance greatly changed the release of different species of nitrogen and soluble phosphate from sediment.

Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris.

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.

Mendelian Randomization Integrating GWAS, eQTL, and mQTL Data Identified Genes Pleiotropically Associated With Atrial Fibrillation.

Background: Atrial fibrillation (AF) is the most common arrhythmia. Genome-wide association studies (GWAS) have identified more than 100 loci associated with AF, but the underlying biological interpretation remains largely unknown. The goal of this study is to identify gene expression and DNA methylation (DNAm) that are pleiotropically or potentially causally associated with AF, and to integrate results from transcriptome and methylome. Methods: We used the summary data-based Mendelian randomization (SMR) to integrate GWAS with expression quantitative trait loci (eQTL) studies and methylation quantitative trait loci (mQTL) studies. The HEIDI (heterogeneity in dependent instruments) test was introduced to test against the null hypothesis that there is a single causal variant underlying the association. Results: We prioritized 22 genes by eQTL analysis and 50 genes by mQTL analysis that passed the SMR & HEIDI test. Among them, 6 genes were overlapped. By incorporating consistent SMR associations between DNAm and AF, between gene expression and AF, and between DNAm and gene expression, we identified several mediation models at which a genetic variant exerted an effect on AF by altering the DNAm level, which regulated the expression level of a functional gene. One example was the genetic variant-cg18693985-CPEB4-AF axis. Conclusion: In conclusion, our integrative analysis identified multiple genes and DNAm sites that had potentially causal effects on AF. We also pinpointed plausible mechanisms in which the effect of a genetic variant on AF was mediated by genetic regulation of transcription through DNAm. Further experimental validation is necessary to translate the identified genes and possible mechanisms into clinical practice.