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Abstract Background Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis. Methods The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives. Results WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD. Conclusion The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.

Abstract Background Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules. Methods A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays. Results Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/β-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and β-catenin protein level, which negated the protective effects of USP2. Conclusion This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/β-catenin axis and alleviating cardiac hypertrophy-induced heart failure.

IntroductionDiabetic Retinopathy (DR) is a potentially blinding retinal disorder that develops through the pathogenesis of diabetes. The lack of disease predictors implies a poor prognosis with frequent irreversible retinal damage and vision loss. Extracellular Vesicles (EVs) present a novel opportunity for pre-symptomatic disease diagnosis and prognosis, both severely limited in DR. All biological fluids contain EVs, which are currently being studied as disease biomarkers. EV proteins derived from urine have emerged as potential noninvasive biomarkers.MethodsIn this study, we isolated EVs from DR retinal tissue explants and from DR patients’ urine, and characterized the vesicles, finding differences in particle number and size. Next, we performed proteomic analysis on human explanted DR retinal tissue conditioned media, DR retinal EVs and DR urinary EVs and compared to normal human retinal tissue, retinal EVs, and urinary EVs, respectivelyResultsOur system biology analysis of DR tissue and EV expression profiles revealed biological pathways related to cell-to-cell junctions, vesicle biology, and degranulation processes. Junction Plakoglobin (JUP), detected in DR tissue-derived EVs and DR urinary EVs, but not in controls, was revealed to be a central node in many identified pathogenic pathways. Proteomic results were validated by western blot. Urinary EVs obtained from healthy donors and diabetic patient without DR did not contain JUP.ConclusionThe absence of JUP in healthy urinary EVs provide the basis for development of a novel Diabetic Retinopathy biomarker, potentially facilitating diagnosis.

The Jamm’iyyat Ulama-i-Pakistan (abbreviated hereafter as JUP), in 1990s onwards was headed by dynamic reliogio-political echelon Moulana Shah Ahmad Nurani who believed in ‘constitutional rightism’ and didn’t believe in extra-constitutional maneuvers in order to with the game of power politics. He ran his political affairs under some set principles and abided by with them throughout his political career. His religio-political dynamism during Musharraf regime was the last but ever-glorious episode of his political strife for the enforcement of Islamic socio-economic system to which he termed as Nizam-e-Mustafa. Under his dynamic leadership the religio-political alliance, Mutahidda Majlis-i-Amal, popularly called as the ‘MMA’ showed one of the unprecedented performances the religio-political right ever showed. Up till his death in 2003, The MMA showed no compromise on the set principles, but later things went different. Among other measures of General Musharraf, his policy of so-called moderation of the society on allegedly US command was taken by the religious right of the country as ‘Command Enlightened Moderation’, hence reaction was inevitable. It flocked under the banner of MMA and tried its level best to cope with it. The research in hand highlights this interesting epoch of the history of Pakistan..

The Jamm’iyyat Ulama-i-Pakistan (abbreviated hereafter as JUP), in 1990s onwards was headed by dynamic reliogio-political echelon Moulana Shah Ahmad Nurani who believed in ‘constitutional rightism’ and didn’t believe in extra-constitutional maneuvers in order to with the game of power politics. He ran his political affairs under some set principles and abided by with them throughout his political career. His religio-political dynamism during Musharraf regime was the last but ever-glorious episode of his political strife for the enforcement of Islamic socio-economic system to which he termed as Nizam-e-Mustafa. Under his dynamic leadership the religio-political alliance, Mutahidda Majlis-i-Amal, popularly called as the ‘MMA’ showed one of the unprecedented performances the religio-political right ever showed. Up till his death in 2003, The MMA showed no compromise on the set principles, but later things went different. Among other measures of General Musharraf, his policy of so-called moderation of the society on allegedly US command was taken by the religious right of the country as ‘Command Enlightened Moderation’, hence reaction was inevitable. It flocked under the banner of MMA and tried its level best to cope with it. The research in hand highlights this interesting epoch of the history of Pakistan..

ABSTRACT Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated intestinal disease, resulting in severe diarrhea and fatal pseudomembranous colitis. TcdB, one of the essential virulence factors secreted by this bacterium, induces host cell apoptosis through a poorly understood mechanism. Here, we performed an RNA interference (RNAi) screen customized to Caco-2 cells, a cell line model of the intestinal epithelium, to discover host factors involved in TcdB-induced apoptosis. We identified plakoglobin, also known as junction plakoglobin (JUP) or γ-catenin, a member of the catenin family, as a novel host factor and a previously known cell death-related chromatin factor, high-mobility group box 1 (HMGB1). Disruption of those host factors by RNAi and CRISPR resulted in resistance of cells to TcdB-mediated and mitochondrion-dependent apoptosis. JUP was redistributed from adherens junctions to the mitochondria and colocalized with the antiapoptotic factor Bcl-XL. JUP proteins could permeabilize the mitochondrial membrane, resulting in the release of cytochrome c. Our results reveal a novel role of JUP in targeting the mitochondria to promote the mitochondrial apoptotic pathway. Treatment with glycyrrhizin, an HMGB1 inhibitor, resulted in significantly increased resistance to TcdB-induced epithelial damage in cultured cells and a mouse ligated colon loop model. These findings demonstrate the critical roles of JUP and HMGB1 in TcdB-induced epithelial cell apoptosis. IMPORTANCE Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea. Toxins, especially TcdB, cause epithelial cell apoptosis, but the underlying cell death mechanism is less clear. Through an apoptosis-focused RNAi screen using a bacterium-made small interfering (siRNA) library customized to a human colonic epithelial cell model, we found a novel host factor, plakoglobin (γ-catenin), as a key factor required for cell apoptosis induced by TcdB. Plakoglobin targets and permeabilizes mitochondria after stimulation by TcdB, demonstrating a hitherto underappreciated role of this catenin family member in the apoptosis of intestinal epithelial cells. We also found a previously known cell death-related chromatin factor, HMGB1, and explored the inhibition of HMGB1 for CDI therapy in vivo.

Introduction: JUP, a homologue of β-catenin, is a cell-cell junction protein involved in adhesion junction and desmosome composition. JUP may have a controversial role in different malignancies dependence of its competence with or collaboration with β-catenin as a transcription factor. Objective: In this study, we focused on the role of JUP in tumor progress and metastasis of GC. We investigated whether that the function of JUP is related to its cellular location in GC development process from epithelium-like, low malignant GC to advanced EMT-phenotypic GC. Conclusion: Gradual loss of membrane and/or cytoplasm JUP was closely correlated with GC malignancy and poor prognostics. Knockdown of JUP in epithelium-like GC cells causes EMT and promotes GC cell migration and invasion. Ectopic expression of wild JUP in malignant GC cells led to an attenuated malignant phenotype such as reduced cell invasive potential. In mechanism, loss of membrane and/or cytoplasm JUP abolished the restrain of JUP to EGFR at cell membrane and resulted in increased p-AKT levels and AKT/GSK3β/β-catenin signaling activity. In addition, nuclear JUP interacts with nuclear β-catenin and TCF4 and played a synergistic role with β-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion.

La relación entre el peronismo y la universidad fue estudiada a partir de un conjunto de prejuicios que afirmaban su total antagonismo. Con el fin de poner en tela de juicio a los mismos, analizaremos el discurso sobre la universidad de la revista 4161; la misma se autodenominada órgano de la Juventud Universitaria Peronista y sus dos números aparecieron entre 1963 y 1964. A nuestro juicio, la relevancia de la revista radica en que fue una aparición temprana de un conjunto de universitarios dados a la tarea de construir una identidad universitaria peronista. La idea que guía nuestra pesquisa es que la revista ensaya un sincretismo que, partiendo del peronismo, busca converger con diversas corrientes como el reformismo o el marxismo. Este proceso es de vital importancia para dar cuenta de la posterior masividad que adquiere el peronismo en las universidades en la década del ´70 y, hacia el ´73 y cómo aquellas concepciones influyeron en los proyectos de reforma institucional de las universidades argentinas. Por este sendero, podemos pensar que 4161 fue el inicio de una cultura política universitaria del peronismo.