Identification of factors required for m6A mRNA methylation in Arabidopsis reveals a role for the conserved E3 ubiquitin ligase HAKAI

Peer reviewe

Increased Expression of the Auxiliary β(2)-subunit of Ventricular L-type Ca(2+) Channels Leads to Single-Channel Activity Characteristic of Heart Failure

BACKGROUND: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary β-subunits as a possible explanation. METHODS AND RESULTS: By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC β-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac β-subunits: Unlike β(1) or β(3) isoforms, β(2a) and β(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, β(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal β(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing (“Adaptive Phase”), reveal the opposite phenotype, viz : reduced single-channel activity accompanied by lowered β(2) expression. Additional evidence for the cause-effect relationship between β(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible β(2) cardiac overexpression. Here in non-failing hearts induction of β(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. CONCLUSIONS: Our study presents evidence of the pathobiochemical relevance of β(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure

Playing stories? Narrative-dramatic agency in Disco Elysium (2019) and Astroneer (2019)

Drawing on Janet Murray (1997), Katie Salen and Eric Zimmerman (2004), and other previous proposals, this article conceptualizes player agency as the possibility space for “meaningful” choice expressed via player action that translates into avatar action, afforded and constrained by a videogame’s design. It further distinguishes between four core dimensions of agency thus conceptualized: First, spatial-explorative agency is afforded by those elements of a videogame’s design that determine the player’s ability to navigate and traverse the game spaces via their avatar. Second, temporal-ergodic agency is afforded by those elements of a videogame’s design that determine the player’s options for interacting with the videogame as a temporal system. Third, configurative-constructive agency is afforded by those elements of a videogame’s design that allow the player to configure their avatar and/or (re)construct the game spaces. Fourth, narrative-dramatic agency is afforded by those elements of a videogame’s design that determine the player’s “meaningful” impact on the unfolding story. The article then moves on to analyze two case studies of independently developed videogames: ZA/UM’s role-playing game Disco Elysium (2019), whose complex nonlinear narrative structure primarily affords configurative and narrative agency, and System Era Softworks’s sandbox adventure game Astroneer (2019), whose procedurally generated game spaces and “open” game mechanics primarily afford explorative, constructive, and dramatic agency

CCRP and adrenomedullin receptor populations in human cerebral arteries: in vitro pharmacological and molecular investigations in different artery sizes

The aim of the present study was to determine functional and molecular characteristics of receptors for calcitonin gene-related peptide (CGRP) and adrenomedullin in three different diameter groups of lenticulostriate arteries. Furthermore, the presence of perivascular neuronal sources of CGRP was evaluated in these arteries. In the functional studies, in vitro pharmacological experiments demonstrated that both CGRP and adrenomedullin induce alpha -CGRP-(8-37) sensitive vasodilation in artery segments of various diameters. The maximal amounts of vasodilation induced by CGRP and adrenomedullin were not different, whereas the potency of CGRP exceeded that of adrenomedullin by 2 orders of magnitude. Significant negative correlations between artery diameters and maximal responses were demonstrated for CGRP and adrenomedullin. In addition, the potency of both peptides tended to increase in decreasing artery diameter. In the molecular experiments, levels of mRNAs encoding CGRP receptors and receptor subunits were compared using reverse transcriptase polymerase chain reactions (RT-PCR). The larger the artery, the more mRNA encoding receptor activity-modifying proteins 1 and 2 (RAMP1 and RAMP2) was detected relative to the amount of mRNA encoding the calcitonin receptor-like receptor. By immunohistochemistry, perivascular CGRP containing nerve fibres were demonstrated in all the investigated artery sizes. In conclusion, both CGRP and adrenomedullin induced vasodilation via CGRP receptors in human lenticulostriate artery of various diameter. The artery responsiveness to the CGRP receptor agonists increased with smaller artery diameter, whereas the receptor-phenotype determining mRNA ratios tended to decrease. No evidence for CGRP and adrenomedullin receptor heterogeneity was present in lenticulostriate arteries of different diameters. (C) 2000 Elsevier Science B.V. All rights reserved

Histopathological findings in Vici syndrome

International audienc

High IgG1 Malaria Antibodies Level in Children is a Possible Risk Factor of Blackwater Fever: A Case-Control Study

peer reviewedContext: Pathogenesis of acute massive intravascular hemolysis in Blackwater fever is very complex. Mostly, Malaria immunity deficiency in expatriates, Quinine and Plasmodium are incriminated. The possible role of malaria IgG1 antibodies in BWF is not fully elucidated. Objectives: This study aimed to determine the profile of malaria IgG1 for malaria crude antigen in children developing blackwater fever compared to patients with uncomplicated malaria Methods: This case-control study was conducted in 4 medical institutions across Kinshasa. Cases were patients with Blackwater fever (BWF) whereas controls had uncomplicated Plasmodium falciparum malaria (UM). For each case, 2 controls were recruited and were matched for age, sex and the area of residence. Malaria IgG1 were assessed by standard ELISA and absorbance measured in an automated plate reader. Results: The majority of BWF cases (81.4%) were above 5 years old while only 18.6% were aged below 5 (OR: 1.33; 0.53-3.32). The level of malaria IgG antibodies in BWF children were significantly higher compared to uncomplicated malaria (p=0.002). Quinine was used by 95.3% of the BWF cases ([OR: 50.19 (10.75-234.42)] p<0.001) versus in uncomplicated malaria. There was no linear correlation between the age of patients and the logarithm of antibodies. R2 is totally null (p=0.335). Conclusion: Malaria IgG1 antibodies is significantly elevated in children with BWF and could trigger the occurrence of BWF. The absence of correlation with age suggests that BWF could not be age dependent

Prognostic Value of Microvascular Obstruction and Infarct Size, as Measured by CMR in STEMI Patients

International audienc