Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells

Objectives.The present work was designed to provide an initial characterization of M cells in the normal human heart.Background.Recent studies have uncovered a unique population of cells in the midmyocardial region of the canine ventricle. These cells, named M cells, were found to possess electrophysiologic features and a pharmacologic responsiveness different from those of other myocardial cells. Although well characterized in the dog, their presence or absence in the human heart is unknown.Methods.Standard microelectrode techniques were used to map slices of ventricular free wall obtained from normal human hearts (n = 4). Preparations were paced at cycle lengths ranging from 1 to 10 s.Results.We identified three cell subtypes: endocardial, subepicardial (M cells) and epicardial cells. The principal features differentiating M cells from the other cell subtypes were their longer action potential duration, more accentuated action potential duration rate relations and greater maximal rate of increase in action potential upstroke (Vmax). Our findings suggest that M cells represent ∼ 30% of the cellular mass of the left ventricular wall. Concordance between changes in their repolarization and changes in QTU interval provide support for the role of M cells in the generation of the electrocardiographic (ECG) U wave.Conclusions.This study provides evidence for the existence of M cells in the human heart that contribute to heterogeneity of repolarization within the ventricular wall. Our findings provide strong support for the hypothesis that M cells contribute importantly to the manifestation of the U wave on the ECG

Differential binding of the transcription factors Sp1, AP-1, and NFI to the promoter of the human α5 integrin gene dictates its transcriptional activity

Purpose. Damage to the corneal epithelium results in the massive secretion of fibronectin (FN) shortly after injury and induces the expression of its integrin receptor α5β1. The authors reported previously that FN induces α5 expression in human corneal epithelial cells and rabbit corneal epithelial cells by altering the binding of the transcription factor (TF) Sp1 to a regulatory element from the α5 promoter that it is also flanked by binding sites for the TFs NFI and AP-1. Here, they assessed the function of NFI and AP-1 on α5 gene expression and evaluated the contribution of FN to their overall regulatory influence. Methods. TF binding to the α5 promoter was evaluated in vitro by electrophoretic mobility shift assays and in vivo by ligation-mediated PCR or chromatin immunoprecipitation. TFs expression was monitored by Western blot, whereas their influence was assessed by transfection and RNAi analyses. Results. Coexpression of Sp1, NFI, and AP-1 was demonstrated in all cell types, and each TF was shown to bind efficiently to the α5 promoter. Whereas both AP-1 and Sp1 activated expression directed by the α5 promoter, NFI functioned as a potent repressor of that gene. Interestingly, FN could either promote or repress α5 promoter activity in a cell density–dependent manner by differentially altering the ratio of these TFs. Conclusions. These results suggest that α5 gene expression is likely dictated by subtle alterations in the nuclear ratio of TFs that either repress (NFI) or activate (Sp1 and AP-1) α5 transcription in corneal epithelial cells

Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Improvement of the Trivalent Inactivated Flu Vaccine Using PapMV Nanoparticles

Commercial seasonal flu vaccines induce production of antibodies directed mostly towards hemaglutinin (HA). Because HA changes rapidly in the circulating virus, the protection remains partial. Several conserved viral proteins, e.g., nucleocapsid (NP) and matrix proteins (M1), are present in the vaccine, but are not immunogenic. To improve the protection provided by these vaccines, we used nanoparticles made of the coat protein of a plant virus (papaya mosaic virus; PapMV) as an adjuvant. Immunization of mice and ferrets with the adjuvanted formulation increased the magnitude and breadth of the humoral response to NP and to highly conserved regions of HA. They also triggered a cellular mediated immune response to NP and M1, and long-lasting protection in animals challenged with a heterosubtypic influenza strain (WSN/33). Thus, seasonal flu vaccine adjuvanted with PapMV nanoparticles can induce universal protection to influenza, which is a major advancement when facing a pandemic

La diversité de genre s’invite au Musée de la civilisation de Québec (note de recherche)

Les musées ont un rôle important à jouer dans la diffusion et la légitimation de représentations de la diversité sociale auprès d’un large public bien souvent néophyte, ce qui contribue à structurer les rapports qu’entretient la population majoritaire avec des populations souvent minorisées. Cette note de recherche porte sur le processus d’élaboration d’une exposition sur la diversité de genre au Musée de la civilisation de Québec débuté en 2021, à partir des documents de travail du comité de spécialistes, de l’expérience de deux universitaires trans ayant travaillé à la scénarisation, et de discussions avec la chargée du projet. L’objectif de cet article est de situer cette expérience collaborative dans le cadre des développements récents dans le domaine de la diversité du genre dans la société québécoise au niveau politique et institutionnel, et des politiques de la représentation des personnes et communautés LGBTQ+ dans le monde muséal.Museums have an important role to play in disseminating and legitimizing representations of social diversity to a large, often neophyte public, which contributes to structuring the relationships between the majority population and groups who have been marginalized. This research note focuses on the development of an exhibition on gender diversity at the Musée de la civilisation de Québec, from the beginning of the process in 2021 to the inauguration of the exhibit in 2023. It is based on the working documents of the committee of experts, the experience of two trans researchers hired by the museum to work on the script, and discussions with the person in charge of the project. The objective of this article is to situate this collaborative experience within the framework of recent developments in the field of gender diversity in Quebec society at the political and institutional level, and the politics of the representation of LGBTQ+ people and communities in the museum world.Los museos desempeñan un papel importante en la difusión y la legitimación de las representaciones de la diversidad social ante un público amplio y a menudo no iniciado, lo que contribuye a estructurar la relación entre la población mayoritaria y los grupos que a menudo son minorías. Esta nota de investigación examina el desarrollo de una exposición sobre la diversidad de género en el Musée de la civilisation de Québec, desde el inicio del proceso en 2021 hasta la inauguración de la exposición en 2023. Se basa en los documentos de trabajo del comité de expertos, en la experiencia de dos personas trans contratadas por el museo para trabajar en el diseño de la exposición y en las conversaciones con la responsable del proyecto. El objetivo de este artículo es situar esta experiencia de colaboración en el contexto de la evolución reciente en el ámbito de la diversidad de género en la sociedad quebequense a nivel político e institucional, y de las políticas de representación de las personas y comunidades LGBTQ+ en el mundo de los museos

CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia

The most common rearrangement in childhood precursor B-cell acute lymphoblastic leukemia is the t(12;21)(p13;q22) translocation resulting in the ETV6-AML1 fusion gene. A frequent concomitant event is the loss of the residual ETV6 allele suggesting a critical role for the ETV6 transcriptional repressor in the etiology of this cancer. However, the precise mechanism through which loss of functional ETV6 contributes to disease pathogenesis is still unclear. To investigate the impact of ETV6 loss on the transcriptional network and to identify new transcriptional targets of ETV6, we used whole transcriptome analysis of both pre-B leukemic cell lines and patients combined with chromatin immunoprecipitation. Using this integrative approach, we identified 4 novel direct ETV6 target genes: CLIC5, BIRC7, ANGPTL2 and WBP1L. To further evaluate the role of chloride intracellular channel protein CLIC5 in leukemogenesis, we generated cell lines overexpressing CLIC5 and demonstrated an increased resistance to hydrogen peroxide-induced apoptosis. We further described the implications of CLIC5’s ion channel activity in lysosomal-mediated cell death, possibly by modulating the function of the transferrin receptor with which it colocalizes intracellularly. For the first time, we showed that loss of ETV6 leads to significant overexpression of CLIC5, which in turn leads to decreased lysosome-mediated apoptosis. Our data suggest that heightened CLIC5 activity could promote a permissive environment for oxidative stress-induced DNA damage accumulation, and thereby contribute to leukemogenesis