Identification and characterisation of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier

AbstractTwo novel thiazolidine compounds, GW604714X and GW450863X, were found to be potent inhibitors of mitochondrial respiration supported by pyruvate but not other substrates. Direct measurement of pyruvate transport into rat liver and yeast mitochondria confirmed that these agents inhibited the mitochondrial pyruvate carrier (MPC) with Ki values <0.1 μM. Inhibitor titrations of pyruvate-dependent respiration by heart mitochondria gave values (±S.E.) for the concentration of inhibitor binding sites (pmol per mg protein) and their Ki (nM) of 56.0±0.9 and 0.057±0.010 nM for the more hydrophobic GW604714X; for GW450863X the values were 59.9±4.6 and 0.60±0.12 nM. [3H]-methoxy-GW450863X binding was also used to determine the MPC content of the heart, kidney, liver and brain mitochondria giving values of 56, 40, 26 and 20 pmol per mg protein respectively. Binding to yeast mitochondria was <10% of that in rat liver mitochondria, consistent with the slow rate of pyruvate transport into yeast mitochondria. [3H]-methoxy-GW450863X binding was inhibited by GW604714X and by the established MPC inhibitor, UK5099. The absorbance spectra of GW450863X and GW604714X were markedly changed by the addition of β-mercaptoethanol suggesting that the novel inhibitors, like α-cyanocinnamate, possess an activated double bond that attacks a critical cysteine residue on the MPC. However, no labelled protein was detected following SDS-PAGE suggesting that the covalent modification is reversible. GW604714X and GW450863X inhibited l-lactate transport by the plasma membrane monocarboxylate transporter MCT1, but at concentrations more than four orders of magnitude greater than the MPC

Professional educators in the Circumpolar North: A model for the digital competence of future teachers

Source at https://arcticyearbook.com/arctic-yearbook/2023-special-issue/2023-special-scholarly-papers/477-professional-educators-in-the-circumpolar-north-a-model-for-the-digital-competence-of-future-teachers.This article is based on a study that considers future teachers’ digital competencies in the Arctic education context with special attention to the necessary cultural and contextual dimensions of teachers’ work. This study explored the professional competencies teachers require when teaching diverse and multicultural pupils in the Circumpolar North drawing on the multiple affordances offered by the digital world. Previous research draws attention to specific teaching and teacher competencies required for rural schools in the Circumpolar North considering the unique assets and characteristics of rural places in this region. This study presents a model of Digital Competence for Future Teachers (DCFT) that illustrates the competencies required by teachers in rural schools in the Arctic. Within the proposed model, four types of digital knowledge-based competencies necessary for holistic education were identified: techno-cultural, intercultural, self-cultural, and micro-cultural. The model was created through a process of analysis of existing models of teachers’ digital competencies: MAP-, TPACK- and PEAT-models which are then reflected on the findings of an earlier international comparative multiple-case study by the same authors examining the sudden change to remote online teaching during the COVID-19 pandemic, and the Cultural Competence for Equity and Inclusion (CCEI) framework. Although the presented study focused on the Circumpolar North, the findings have implications for teacher education and policy production more widely in national and international educational environments

Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes.

Type I diabetes [insulin-dependent diabetes mellitus (IDDM)] is an autoimmune disease associated with the destruction of pancreatic beta cells. Serum from patients with IDDM increased L-type calcium channel activity of insulin-producing cells and of GH3 cells derived from a pituitary tumor. The subsequent increase in the concentration of free cytoplasmic Ca2+ ([Ca2+]i) was associated with DNA fragmentation typical of programmed cell death or apoptosis. These effects of the serum were prevented by adding a blocker of voltage-activated L-type Ca2+ channels. When the serum was depleted of immunoglobulin M (IgM), it no longer affected [Ca2+]i. An IgM-mediated increase in Ca2+ influx may thus be part of the autoimmune reaction associated with IDDM and contribute to the destruction of beta cells in vivo

Professional educators in the Circumpolar North:a model for the digital competence of future teachers

Abstract This article is based on a study that considers future teachers’ digital competencies in the Arctic education context with special attention to the necessary cultural and contextual dimensions of teachers’ work. This study explored the professional competencies teachers require when teaching diverse and multicultural pupils in the Circumpolar North drawing on the multiple affordances offered by the digital world. Previous research draws attention to specific teaching and teacher competencies required for rural schools in the Circumpolar North considering the unique assets and characteristics of rural places in this region. This study presents a model of Digital Competence for Future Teachers (DCFT) that illustrates the competencies required by teachers in rural schools in the Arctic. Within the proposed model, four types of digital knowledge-based competencies necessary for holistic education were identified: techno-cultural, intercultural, self-cultural, and micro-cultural. The model was created through a process of analysis of existing models of teachers’ digital competencies: MAP-, TPACK- and PEAT-models which are then reflected on the findings of an earlier international comparative multiple-case study by the same authors examining the sudden change to remote online teaching during the COVID-19 pandemic, and the Cultural Competence for Equity and Inclusion (CCEI) framework. Although the presented study focused on the Circumpolar North, the findings have implications for teacher education and policy production more widely in national and international educational environments