Saturated free fatty acids and apoptosis in microvascular mesangial cells: palmitate activates pro-apoptotic signaling involving caspase 9 and mitochondrial release of endonuclease G

BACKGROUND: In type 2 diabetes, free fatty acids (FFA) accumulate in microvascular cells, but the phenotypic consequences of FFA accumulation in the microvasculature are incompletely understood. Here we investigated whether saturated FFA induce apoptosis in human microvascular mesangial cells and analyzed the signaling pathways involved. METHODS: Saturated and unsaturated FFA-albumin complexes were added to cultured human mesangial cells, after which the number of apoptotic cells were quantified and the signal transduction pathways involved were delineated. RESULTS: The saturated FFA palmitate and stearate were apoptotic unlike equivalent concentrations of the unsaturated FFA oleate and linoleate. Palmitate-induced apoptosis was potentiated by etomoxir, an inhibitor of mitochondrial β-oxidation, but was prevented by an activator of AMP-kinase, which increases fatty acid β-oxidation. Palmitate stimulated an intrinsic pathway of pro-apoptotic signaling as evidenced by increased mitochondrial release of cytochrome-c and activation of caspase 9. A caspase 9-selective inhibitor blocked caspase 3 activation but incompletely blocked apoptosis in response to palmitate, suggesting an additional caspase 9-independent pathway. Palmitate stimulated mitochondrial release of endonuclease G by a caspase 9-independent mechanism, thereby implicating endonuclease G in caspase 9-indpendent regulation of apoptosis by saturated FFA. We also observed that the unsaturated FFA oleate and linoleate prevented palmitate-induced mitochondrial release of both cytochrome-c and endonuclease G, which resulted in complete protection from palmitate-induced apoptosis. CONCLUSIONS: Taken together, these results demonstrate that palmitate stimulates apoptosis by evoking an intrinsic pathway of proapoptotic signaling and identify mitochondrial release of endonuclease G as a key step in proapoptotic signaling by saturated FFA and in the anti-apoptotic actions of unsaturated FFA

Doctor of Philosophy

dissertationHumans have lived at high altitude for hundreds of generations despite unavoidable challenges imposed by hypobaric hypoxia. The lower barometric pressure at high altitude reduces the number of oxygen molecules available in each breath of air, yet oxygen-dependent physiological processes must be maintained for survival. Cellular and system responses to hypoxic stress can result in altitude illness and may prove fatal in a small proportion of maladapted individuals. Native high-altitude populations, however, exhibit a unique suite of heritable traits that afford tolerance to hypoxia. Compared to lowland visitors and Andean highlanders, Tibetans exhibit lower hemoglobin (Hb) levels at high altitude, which tend to be similar to those expected under sea-level conditions. Such differences suggest this population has unique adaptations to their native environment. It has been hypothesized that genes specifically involved in the hypoxia inducible factor (HIF) pathway could underlie adaptive changes in high-altitude populations. Genome-wide analyses provide the first lines of evidence in support of genetic adaptation to high altitude. Three regions of the genome that contain genes associated with the human response to hypoxia show evidence of selection and are associated with decreased Hb levels, and two of these are also associated with metabolite levels. These phenotypic associations provide corroborative evidence for adaptive roles of genomic regions targeted by strong positive selection in Tibetans. iv While many of the same selection candidate genes are reported by studies of different Tibetan populations, some signals of selection and association are unique to particular groups. The genetic makeup of Tibetan groups located throughout the plateau is therefore important to consider in studies of high-altitude adaptation. Taken together, the data presented in this dissertation demonstrate that multiple genes are involved in Tibetan adaptation to high altitude. Some of these genes have been linked to hematological and metabolic phenotypes characterized thus far, providing further support for roles in physiological adaptation to this extreme environment. Studies aimed to identify associations between specific genetic variants, mechanisms, and phenotypes will help bridge the gap between genetic variation and organismal responses to hypoxia, and will have important implications for understanding human health and disease

Geography

AbstractGeneralized Geography is an impartial two-person game played on a digraph G=(V,A). In impartial Arc (Vertex) Geography, a token is initially placed on a special start vertex, and the players alternately move the token along unused arcs (vertices) of G. The player first unable to move loses and his opponent wins. The question of who wins these games IAG and IVG is known to be PSPACE-complete.Both impartial versions with two tokens on special start vertices are proved PSPACE-complete even for DAGs but polynomial for directed trees. The partizan variations, PAG and PVG, with one token per player are PSPACE-complete even for bipartite degree-restricted digraphs. They are NP-hard for DAGs, but polynomial for directed trees

Violence à l’encontre du personnel des EMS et des CMS du Canton de Vaud

Présenté au Grand Conseil du Canton de Vaud lors de la séance du 30 juin 2015, le postulat « Philippe Vuillemin et consorts – Pour une meilleure protection du personnel soignant en EMS » part du constat que, si la maltraitance des personnes âgées est désormais reconnue et appréhendée par les différents acteurs concernés, celle à l’égard des soignant-e-s et des personnels travaillant en établissements médico-sociaux (EMS) et dans les centres médico-sociaux (CMS) est plus rarement évoquée publiquement

Violence à l’encontre du personnel des établissements médico-sociaux et des centres médico-sociaux du Canton de Vaud. Synthèse des résultats

Présenté au Grand Conseil du Canton de Vaud lors de la séance du 30 juin 2015, le postulat « Philippe Vuillemin et consorts – Pour une meilleure protection du personnel soignant en EMS » part du constat que, si la maltraitance des personnes âgées est désormais reconnue et appréhendée par les différents acteurs concernés, celle à l’égard des soignant-e-s et des personnels travaillant en établissements médico-sociaux (EMS) et dans les centres médico-sociaux (CMS) est plus rarement évoquée publiquement. Certain-e-s professionnel-le-s (par exemple : policier-ère-s, enseignant-e-s, personnels des établissements de santé) présentent des risques accrus d’être confrontés à des actes de violence à leur égard. Le travail isolé et le contact avec des clients, en particulier lorsque ces derniers sont sous l’emprise de la drogue ou de l’alcool, quand ils sont connus pour avoir eu un passé violent ou qu’ils souffrent de maladies pouvant être associées à des comportements agressifs constituent ainsi des facteurs de risque. Le risque d’être confronté à la violence ou à des comportements agressifs concerne aussi les professionnel-le-s en contact avec des personnes atteintes dans leur santé, à domicile ou en institution. Des enquêtes menées dans les établissements médico-sociaux (EMS) ou auprès des professionnel-le-s du maintien à domicile, à l’étranger et en Suisse rapportent des taux relativement élevés d’exposition à la violence chez les soignant-e-s. On ne dispose en revanche d’aucune donnée concernant cette problématique pour la Suisse Romande ou pour le Canton de Vaud

Giant Molecular Clouds are More Concentrated to Spiral Arms than Smaller Clouds

From our catalog of Milky Way molecular clouds, created using a temperature thresholding algorithm on the Bell Laboratories 13CO Survey, we have extracted two subsets:(1) Giant Molecular Clouds (GMCs), clouds that are definitely larger than 10^5 solar masses, even if they are at their `near distance', and (2) clouds that are definitely smaller than 10^5 solar masses, even if they are at their `far distance'. The positions and velocities of these clouds are compared to the loci of spiral arms in (l, v) space. The velocity separation of each cloud from the nearest spiral arm is introduced as a `concentration statistic'. Almost all of the GMCs are found near spiral arms. The density of smaller clouds is enhanced near spiral arms, but some clouds (~10%) are unassociated with any spiral arm. The median velocity separation between a GMC and the nearest spiral arm is 3.4+-0.6 km/s, whereas the median separation between smaller clouds and the nearest spiral arm is 5.5+-0.2 km/s.Comment: 11 pages, 3 figure

Evaluation de la formation PAPRICA (Physical Activity promotion in PRImary Care) : Petite enfance

L'activité physique des enfants est en baisse dans plusieurs pays développés comme en Suisse. En 2012, le programme cantonal "Ca marche!" et l'Hôpital de l'Enfance de Lausanne (HEL) ont lancé le projet "PAPRICA petite enfance", visant à former des professionnels des soins de la petite enfance issus de cinq disciplines (pédiatres, sages-femmes, infirmières de la petite enfance, infirmières scolaires et infirmières de soins à domicile) à la promotion de l'activité physique chez les enfants de 0 à 6 ans. Cette formation est donnée sur une demi-journée à des groupes transdisciplinaires et met l'accent sur le mouvement au quotidien pour les familles, ainsi que sur les techniques d'entretien motivationnel et de systémique familiale

Nanoelectromechanical Resonator Arrays for Ultrafast, Gas-Phase Chromatographic Chemical Analysis

Miniaturized gas chromatography (GC) systems can provide fast, quantitative analysis of chemical vapors in an ultrasmall package. We describe a chemical sensor technology based on resonant nanoelectromechanical systems (NEMS) mass detectors that provides the speed, sensitivity, specificity, and size required by the microscale GC paradigm. Such NEMS sensors have demonstrated detection of subparts per billion (ppb) concentrations of a phosphonate analyte. By combining two channels of NEMS detection with an ultrafast GC front-end, chromatographic analysis of 13 chemicals was performed within a 5 s time window