Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes.

AIMS/HYPOTHESIS: MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesity-associated type 2 diabetes and to assess their potential contribution to the development of the disease. METHODS: MicroRNA profiling of pancreatic islets isolated from prediabetic and diabetic db/db mice and from mice fed a high-fat diet was performed by microarray. The functional impact of the changes in microRNA expression was assessed by reproducing them in vitro in primary rat and human beta cells. RESULTS: MicroRNAs differentially expressed in both models of obesity-associated type 2 diabetes fall into two distinct categories. A group including miR-132, miR-184 and miR-338-3p displays expression changes occurring long before the onset of diabetes. Functional studies indicate that these expression changes have positive effects on beta cell activities and mass. In contrast, modifications in the levels of miR-34a, miR-146a, miR-199a-3p, miR-203, miR-210 and miR-383 primarily occur in diabetic mice and result in increased beta cell apoptosis. These results indicate that obesity and insulin resistance trigger adaptations in the levels of particular microRNAs to allow sustained beta cell function, and that additional microRNA deregulation negatively impacting on insulin-secreting cells may cause beta cell demise and diabetes manifestation. CONCLUSIONS/INTERPRETATION: We propose that maintenance of blood glucose homeostasis or progression toward glucose intolerance and type 2 diabetes may be determined by the balance between expression changes of particular microRNAs.

Generic approach for the sensitive absolute quantification of large undigested peptides in plasma using a particular liquid chromatography-mass spectrometry setup.

A generic LC-MS approach for the absolute quantification of undigested peptides in plasma at mid-picomolar levels is described. Nine human peptides namely, brain natriuretic peptide (BNP), substance P (SubP), parathyroid hormone 1-34 (PTH), C-peptide, orexines A and B (Orex-A and -B), oxytocin (Oxy), gonadoliberin-1 (gonadothropin releasing-hormone or luteinizing hormone-releasing hormone, LHRH) and α-melanotropin (α-MSH) were targeted. Plasma samples were extracted via a 2-step procedure: protein precipitation using 1vol of acetonitrile followed by ultrafiltration of supernatants on membranes with a MW cut-off of 30 kDa. By applying a specific LC-MS setup, large volumes of filtrates (e.g., 2×750 μL) were injected and the peptides were trapped on a 1mm i.d.×10 mm length C8 column using a 10× on-line dilution. Then, the peptides were back-flushed and a second on-line dilution (2×) was applied during the transfer step. The refocalized peptides were resolved on a 0.3mm i.d. C18 analytical column. Extraction recovery, matrix effect and limits of detection were evaluated. Our comprehensive protocol demonstrates a simple and efficient sample preparation procedure followed by the analysis of peptides with limits of detection in the mid-picomolar range. This generic approach can be applied for the determination of most therapeutic peptides and possibly for endogenous peptides with latest state-of-the-art instruments.

Apoplastic polyesters in Arabidopsis surface tissues--a typical suberin and a particular cutin.

Cutinized and suberized cell walls form physiological important plant-environment interfaces as they act as barriers limiting water and nutrient loss and protect from radiation and invasion by pathogens. Due to the lack of protocols for the isolation and analysis of cutin and suberin in Arabidopsis, the model plant for molecular biology, mutants and transgenic plants with a defined altered cutin or suberin composition are unavailable, causing that structure and function of these apoplastic barriers are still poorly understood. Transmission electron microscopy (TEM) revealed that Arabidopsis leaf cuticle thickness ranges from only 22 nm in leaf blades to 45 nm on petioles, causing the difficulty in cuticular membrane isolation. We report the use of polysaccharide hydrolases to isolate Arabidopsis cuticular membranes, suitable for depolymerization and subsequent compositional analysis. Although cutin characteristic omega-hydroxy acids (7%) and mid-chain hydroxylated fatty acids (8%) were detected, the discovery of alpha,omega-diacids (40%) and 2-hydroxy acids (14%) as major depolymerization products reveals a so far novel monomer composition in Arabidopsis cutin, but with chemical analogy to root suberin. Histochemical and TEM analysis revealed that suberin depositions were localized to the cell walls in the endodermis of primary roots and the periderm of mature roots of Arabidopsis. Enzyme digested and solvent extracted root cell walls when subjected to suberin depolymerization conditions released omega-hydroxy acids (43%) and alpha,omega-diacids (24%) as major components together with carboxylic acids (9%), alcohols (6%) and 2-hydroxyacids (0.1%). This similarity to suberin of other species indicates that Arabidopsis roots can serve as a model for suberized tissue in general.

Role of substrate utilization and thermogenesis on body-weight control with particular reference to alcohol.

Alcohol (ethanol; EtOH) provides fuel energy to the body (29.7 kJ (7. 1 kcal)/g, 23.4 kJ (5.6 kcal)/ml), as do other macronutrients, but no associated essential nutrients. The thermogenic effect of EtOH (on average 15 % of its metabolizable value) is much greater than that of the main substrates utilized by the body, i.e. fat and carbohydrates (CHO), suggesting a lower net efficiency of energy utilization for EtOH than for fat and CHO. EtOH cannot be stored in the body and is toxic, so that there is an obligatory continuous oxidation of EtOH and it becomes the priority fuel to be metabolized. In contrast to CHO, its rate of oxidation does not depend on the dose ingested. As with CHO intake, it engenders a shift in postprandial substrate utilization (decrease in fat oxidation), but by a non-insulin-mediated mechanism. A limited amount of EtOH can be converted to fatty acids by hepatic de novo lipogenesis (as occurs with high levels of CHO feeding) from acetate production, which inhibits lipolysis in peripheral tissues. There is no evidence that EtOH consumed under normoenergetic conditions (i.e. isoenergetically replacing CHO or fat) leads to greater body fat storage than fat or CHO. However, there is still a lack of experimental studies on the influence of EtOH on the level of spontaneous physical activity in man. This effect may well depend on the dose of EtOH consumed as well as other intrinsic factors.

Pure monoparesis: a particular stroke subgroup?

BACKGROUND: Acute stroke presenting as monoparesis is rare, with a pure motor deficit in the arm or leg extending to an isolated facial paresis. OBJECTIVE: To raise the question if acute stroke presenting as monoparesis is a different entity from stroke with a more extensive motor deficit. PATIENTS: In the Lausanne Stroke Registry (1979-2000), 195 (4.1%) of 4802 patients met the clinical criteria for pure monoparesis involving the face (22%), arm (63%), or leg (15%). RESULTS: In the vast majority of cases (> 95%), monoparesis corresponded to ischemic stroke with a favorable outcome, with initial computed tomography scans or magnetic resonance images showing no signs of hemorrhage. The lesion for a facial deficit was most frequently located subcortically (internal capsule); for an arm deficit, in the superficial middle cerebral artery; and for a leg deficit, in the anterior cerebral artery territory. In pure monoparesis, only 17% of the patients had more than 1 risk factor as compared with 26% of those with bimodal and trimodal hemiparesis and with 46% of all patients with stroke other than those with pure motor stroke. The only frequent risk factor was hypertension (53%); however, this frequency was no different from that in other patients with stroke. No major stroke etiology could be identified in any of the 3 subgroups of monoparesis. CONCLUSION: Our finding of a wide range of stroke localization and etiology in monoparesis without any particular subgroup suggests that no specific plan of investigation can be recommended for these patients.

Valoriser le géopatrimoine par la médiation indirecte et la visualisation des objets géomorphologiques

Résumé: Valoriser le géopatrimoine par la médiation indirecte et la visualisation des objets géomorphologiques Le géopatrimoine regroupe des objets géologiques lato sensu auxquels certaines valeurs sont attribuées, en fonction de leur intérêt pour la science, de leur rareté, de leurs particularités culturelles ou écologiques, etc. Valoriser le géopatrimoine signifie avant tout faire partager cette approche aux non-spécialistes, en expliquant ce qui fait la valeur de ces objets. Cette valorisation peut s'effectuer, entre autres, sous la forme d'une activité touristique et contribuer ainsi au développement régional. Faire comprendre l'origine, la singularité et la valeur des formes du relief implique le recours à une communication éducative, désignée par le terme de médiation. Les implications de la dimension éducative du processus, comme la prise en compte des connaissances et attentes du public, la création d'un environnement favorable à l'apprentissage ou l'attractivité du contenu, sont souvent négligées. Du point de vue conceptuel, un modèle de la médiation indirecte (c'est-à-dire au moyen de supports médiatiques) a été proposé et appliqué au développement empirique de produits de médiation et à leur évaluation. Ce modèle ne garantit pas la réussite de la communication éducative, mais contribue à créer un cadre favorable au processus. De plus, plusieurs lignes directrices pour le choix du type de média et sa mise en forme ont été définies sur la base d'une compilation de résultats de la psychologie cognitive sur l'usage des médias pour l'apprentissage. Des méthodes qualitatives et quantitatives variées ont été mobilisées : enquêtes par questionnaire ex situ et in situ, auprès des visiteurs de géomorphosites de montagne, réalisation de médias interactifs testés ensuite auprès de divers publics (parcours enregistré, pré- et post-questionnaires) et entretiens collectifs. Les résultats obtenus éclairent divers aspects de la problématique. L'étude du public a montré, par exemple, que le géotourisme possède un réel public parmi les visiteurs des sites de montagnes : trois-quarts d'entre eux expriment de l'intérêt pour des explications sur la géologie et l'évolution du paysage. Cette thèse a exploré ces aspects liés au processus d'apprentissage en se focalisant sur les médias visuels, surtout interactifs. La plupart des médias visuels couramment utilisés en géomorphologie ont été considérés. Le développement de versions interactives de ces médias sous forme d'applications web a fourni un aperçu concret des possibilités des nouvelles technologies. Les utilisateurs apprécient en particulier a richesse du contenu, le haut degré d'interactivité et la variété de ces applications. De tels médias incitent à visiter le site naturel et semblent aussi répondre aux intérêts de publics variés. Abstract: Geoheritage promotion through non-personal interpretation and visualisation of geomorphological features Geoheritage concerns all geological features lato sensu to which some values are attributed, according to their scientific interest, their rarity, their cultural or ecological dimensions, etc. Geoheritage promotion implies sharing this point of view with non-specialists, explaining what gives value to those objects. Geotourism is one of the many ways to achieve geoheritage promotion, while contributing also to regional development. In order to make non-specialists understand the origin, the specificity and the value of landforms, educational communication is needed, that is called interpretation (French: médiation). This education dimension has several, and often neglected, implications, like taking into account public's knowledge and expectations, creating a favourable learning environment, attractive design, etc. From the conceptual point of view, a model for non-personal interpretation has been proposed and applied for the empirical development and for the assessment of interpretive products. This model does not guarantee success of educational communication, but help creating a favourable environment for this process. Moreover, some guidelines were defined from a compilation of several results of cognitive psychology on media use for learning. They guide the choice of the kind of media and its design. Several qualitative and quantitative methods were applied: survey questionnaires ex situ and in situ by mountain geomorphosites visitors, interactive medias developed and then tested by different kinds of users (with usertracking, pre- and post-survey questionnaires), group interviews. The results answered different aspects of the research questions. Visitor surveys revealed for example that geotourism could attract many visitors of mountain areas: three quarters of them say they are interested in getting explanations about geology and landscape (in particular its dynamic dimensions). This thesis examined those aspects with a focus on visual medias, both statics and interactive. Most of currently used medias in geomorphology were considered. Interactive versions of those medias were developed in web applications; they gave a concrete overview on the opportunities that new technologies offer. The content richness, the high interaction level and the diversity of the applications are the most liked aspects by the users. Such medias drive to visit the natural site and seem to correspond to the interests of various kinds of publics. Zusammenfassung: Aufwertung des erdwissenschaftlichen Erbes durch mediale Vermittlung und Visualisierung von geomorphologischen Objekten Das erdwissenschaftliche Erbe besteht aus geologischen Gegebenheiten lato sensu, denen entsprechend ihrer Bedeutung für die Wissenschaft, ihrer Seltenheit, ihrer kulturellen oder ökologischen Besonderheiten usw. bestimmte Werte zugeordnet werden. Das erdwissenschaftliche Erbe aufzuwerten bedeutet in erster Linie, diesen Ansatz Nichtspezialisten näher zu bringen, indem ihnen erklärt wird, was den Wert dieser Gegebenheiten ausmacht. Dies kann etwa im Rahmen eines touristischen Angebots geschehen und so die regionale Entwicklung unterstützen. Um Entstehung, Besonderheit und Wert von Geländeformen verständlich zu machen, wird eine pädagogische Kommunikationsform verwendet, die als mediale Vermittlung (franz. médiation) bezeichnet wird. Die Bedeutung der pädagogischen Dimension des Vermittlungsprozesses wie etwa der Einbezug des Wissens und der Erwartungen des Publikums, die Gestaltung eines positiven Lernklimas oder die Attraktivität des Inhalts wird oft vernachlässigt. Auf konzeptueller Ebene wurde ein Modell der indirekten Interpretation erarbeitet (d. h. anhand von Medien), das bei der empirischen Entwicklung der Interpretationsprodukte und ihrer Evaluation Anwendung fand. Dieses Modell garantiert zwar nicht den Erfolg der pädagogischen Kommunikation. Es trägt aber dazu bei, einen für den Prozess günstigen Kontext zu schaffen. Des Weiteren wurden mehrere Richtlinien für die Wahl des Medientyps und dessen Ausgestaltung anhand einer Zusammenstellung von Resultaten der kognitiven Psychologie über den Gebrauch von Medien in Lernprozessen definiert. Es wurden verschiedene qualitative und quantitative Methoden eingesetzt: Befragung mittels Fragebogen der Besucher von geomorphologischen Geotopen im Gebirge - ex situ und in situ -, Erarbeitung von interaktiven Medien, die anschliessend anhand verschiedener Zielgruppen gestestet wurden (Aufnahme des Besuchparcours, Vor- und Nachfragebögen) sowie kollektive Interviews. Die Ergebnisse geben Aufschluss zu verschiedenen Aspekten der Fragestellung. Die Befragung des Publikums hat zum Beispiel deutlich gemacht, dass der Geotourismus unter den Besuchern von Berggebieten tatsächlich auf eine Nachfrage stösst: drei Viertel von ihnen zeigen ein Interesse für Erläuterungen zur Geologie und der Landschaftsentwicklung. Die vorliegende Doktorarbeit hat die genannten Aspekte der Lernprozesse untersucht, wobei der Fokus auf visuellen, insbesondere interaktiven Medien lag. Die meisten gängigen visuellen Medien der Geomorphologie wurden berücksichtigt. Die Entwicklung von interaktiven Versionen dieser Medien in Form von Web-Anwendungen hat die Möglichkeiten der neuen Technologien veranschaulicht. Die Benutzer schätzten insbesondere die Vielfalt des Inhalts, die hohe Interaktivität und die Diversität dieser Anwendungen. Solche Medien laden dazu ein, ein Naturgebiet zu besuchen und scheinen den Interessen der verschiedenen Publikumsgruppen entgegenzukommen.

Il voto ticinese sull'iniziativa 'contro l'immigrazione di massa' del 9 febbraio 2014

Riassunto Il presente studio verte sull'analisi del voto relativo all'iniziativa popolare 'contro l'immigrazione di massa' del 9 febbraio 2014. In particolare, l'analisi si concentra sul voto avvenuto nel Ticino, il cantone svizzero in cui l'iniziativa ha avuto maggiore sostegno. Lo studio si è avvalso di un'inchiesta d'opinione rappresentativa realizzata dall'Osservatorio della vita politica regionale dell'Università di Losanna presso 1.429 cittadini ticinesi nei giorni successivi allo scrutinio. Dopo una contestualizzazione del voto del 9 febbraio rispetto alla storia delle votazioni sui temi di politica estera e migratoria, l'analisi si è concentrata sulla partecipazione al voto. Il ricorso a tre modelli interpretativi (delle risorse, della competenza e della mobilitazione) ha permesso di mostrare come il voto del 9 febbraio sia caratterizzato in particolare modo dal senso del dovere, dall'interesse per la politica e dal legame di partito. L'analisi dell'orientamento di voto evidenzia l'influenza delle dimensioni economiche, politiche, identitarie, e soprattutto, alla stregua di altri voti nel passato recente di questo cantone, una forte tensione tra centro e periferia. Dall'analisi del voto del 9 febbraio emerge un forte timore che vede nel Ticino una 'doppia periferia', verso Berna e in relazione alla vicina Lombardia. Parole chiave: iniziativa popolare, partecipazione, orientamento di voto, centro-periferia. Résumé Cette étude porte sur l'analyse du vote sur l'initiative populaire 'contre l'immigration de masse' du 9 février 2014 et, plus précisément, sur le vote qui s'est déroulé au Tessin, canton suisse dans lequel l'initiative a obtenu le plus large soutien. L'étude a été menée à l'aide d'une enquête d'opinion représentative réalisée par l'Observatoire de la vie politique régionale de l'Université de Lausanne auprès de 1.429 citoyens tessinois dans les jours suivant le scrutin. Après une contextualisation du vote du 9 février par rapport à l'histoire des votations sur les thèmes de la politique étrangère et de l'immigration, l'analyse a porté sur la participation au vote. À ce propos, l'utilisation de trois modèles explicatifs (des ressources, de la compétence et de la mobilisation) a permis de dévoiler que le vote a été caractérisé plus particulièrement par le sens du devoir (habitus du vote), par l'intérêt pour la politique et par le lien avec un parti. L'analyse de l'orientation du vote montre l'influence des aspects économiques, politiques et identitaire ainsi que, à l'instar d'autres votations récemment passées dans le canton italophone, des raisons qui mettent en évidence une vision contrastée du Tessin et notamment le risque de devenir une 'double périphérie' par rapport à Berne et à la Lombardie. Mots-clés: initiative populaire, participation, choix du vote, centre-périphérie. Zusammenfassung Die vorliegende Studie analysiert das Abstimmungsverhalten anlässlich der eidgenössischen Volksinitiative 'Gegen Masseneinwanderung' vom 9. Februar 2014. Die Analyse beschränkt sich auf die Abstimmung im Kanton Tessin, wo die Initiative am stärksten unterstützt wurde. Die Studie wurde vom Observatorium des regionalen politischen Lebens der Universität Lausanne durchgeführt und basiert auf einer repräsentativen Umfrage, bei welcher 1429 Bürger des Kantons Tessin in den Tagen nach der Abstimmung teilnahmen. Zunächst wird die Abstimmung vom 9. Februar in Bezug auf die Geschichte verschiedener anderer Abstimmungen zum Thema Aussen- und Immigrationspolitik kontextualisiert. Die Analyse analysiert dann als erstes die Wahlbeteiligung: Der Gebrauch von drei Erklärungsmodellen (Ressourcen, Kompetenz und Mobilisierung) zeigt auf, dass der Entscheid, an der Abstimmung vom 9. Februar überhaupt teilzunehmen, vor allem von Pflichtbewusstsein, politischem Interesse und Parteibindung geprägt war. Das Abstimmungsverhalten selber war dann von ökonomischen und politischen Faktoren, von der eigenen Identität sowie insbesondere - und wie auch schon andere Abstimmungen in der jüngsten Vergangenheit des italienisch-sprechenden Kantons -von einer grossen Angst geprägt, dass das Tessin eine 'doppelte Peripherie' zwischen Bern und der Lombardei werden könnte. Stichwörter: Volksinitiative, Teilnahme, Abstimmungsverhalten, Zentrum-Peripherie Abstract This study focuses on the analysis of the federal vote on the popular initiative 'against mass immigration' of 9 February 2014. More precisely, the analysis focuses on the vote that took place in Ticino, the Swiss canton in which the popular initiative has received the widest support. The study was carried out by the Research Observatory for Regional Politics at the University of Lausanne using a representative survey among 1.429 citizens of Ticino during the days following the vote. After a contextualization of the vote of 9 February with respect to the history of referenda about foreign policy and immigration issues, the analysis first discusses voter turnout. In this regard, the use of three explanatory models (resources, expertise and mobilisation) reveals that participation in the vote of 9 February was especially characterized by one's sense of duty, political interest, and links with a political party. The decision how to vote was then influenced by economic, political and identity factors as well as - like other votes in the recent past in the Italian-speaking canton - the particular fear that Ticino would become a 'double periphery' vis-à-vis both Berne and Lombardy. Keywords: popular initiative, participation, vote, centre-periphery.

Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis.

The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes.