Establishment success and resulting fitness consequences for vole dispersers

Dispersal is one of the most important, yet least understood phenomena of evolutionary ecology. Triggers and consequences of dispersal are difficult to study in natural populations since dispersers can typically only be identified a posteriori. Therefore, a lot of work on dispersal is either of a theoretical nature or based on anecdotal observation. This is especially true for cryptic species such as small mammals. We conducted an experiment on the common vole, Microtus arvalis, in semi-natural enclosures and investigated the spatial and genetic establishment success of residents and dispersers in their natal and new populations. Our study uses genetic data on the reproductive success of 1255 individuals to measure the fitness trajectories of the residents and dispersing individuals. In agreement with past studies, we found that dispersal was highly male-biased, and was most probably induced by the agonistic encounters with conspecifics, suggesting it could act as an inbreeding avoidance mechanism. There was low breeding success of dispersers into new populations. Although nearly 26% of identified dispersers reproduced in their natal populations, only seven percent reproduced in the new populations. Settlement appeared to be a pre-requisite for reproduction in both sexes, and animals that did not spatially settle into a new population dispersed again, usually on the same day of immigration. In the event that dispersers reproduced in the new population, they did so at relatively low population densities. We also found age-related differences between the sexes in breeding success, and male dispersers that subsequently established in the new population were young individuals that had not reproduced in their natal population, whereas successful females had already reproduced in their natal population. In conclusion, with our detailed field data on establishment and substantial parentage assignments to understand breeding success, we were able to gain an insight into the fitness of dispersers, and how the two sexes optimise their fitness. Taken together, our results help to further understand the relative advantages and costs of dispersal in the common vole.

Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis.

Recent findings have implicated Fas/Fas ligand (FasL) in mediating the death of keratinocytes in spongiotic lesions. We asked whether dying keratinocytes could potentially initiate a protective response of the skin to limit the destruction of the epidermis in the spongiotic areas. In addition to apoptosis, treatment of keratinocyte cultures in vitro with FasL triggers a profound phoshorylation of the epidermal growth factor receptor (EGFR) and of its downstream effectors ERK and protein kinase B (PKB/Akt). Using a variety of inhibitors and blocking antibodies, we demonstrated that: (i) apoptosis is required for the generation of the signal(s) leading to the activation of EGFR, ERK, and Akt; (ii) the activation of EGFR, ERK, and Akt by FasL is indeed mediated by its bona fide receptor Fas; (iii) the activation of EGFR is essential for the subsequent activation of ERK and Akt; and (iv) apoptotic keratinocytes secrete soluble EGFR ligands (including amphiregulin) that are processed from membrane-bound proligand forms by metalloproteinase(s). Our findings demonstrate a potential mechanism for the restriction and repair of spongiotic damage in eczemas.

High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.

BACKGROUND: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect. OBJECTIVE: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome. DESIGN: Cross-sectional comparison. SETTING: University hospital in Lausanne, Switzerland. PARTICIPANTS: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated. MEASUREMENTS: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype. RESULTS: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene. CONCLUSION: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland.

The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor alpha (ERalpha) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-kappaB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR(-/-) phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.

Signaling pathways controlling induced resistance to insect herbivores in Arabidopsis.

Insect attack triggers changes in transcript level in plants that are mediated predominantly by jasmonic acid (JA). The implication of ethylene (ET), salicylic acid (SA), and other signals in this response is less understood and was monitored with a microarray containing insect- and defense-regulated genes. Arabidopsis thaliana mutants coi1-1, ein2-1, and sid2-1 impaired in JA, ET, and SA signaling pathways were challenged with the specialist small cabbage white (Pieris rapae) and the generalist Egyptian cotton worm (Spodoptera littoralis). JA was shown to be a major signal controlling the upregulation of defense genes in response to either insect but was found to suppress changes in transcript level only in response to P. rapae. Larval growth was affected by the JA-dependent defenses, but S. littoralis gained much more weight on coi1-1 than P. rapae. ET and SA mutants had an altered transcript profile after S. littoralis herbivory but not after P. rapae herbivory. In contrast, both insects yielded similar transcript signatures in the abscisic acid (ABA)-biosynthetic mutants aba2-1 and aba3-1, and ABA controlled transcript levels both negatively and positively in insect-attacked plants. In accordance with the transcript signature, S. littoralis larvae performed better on aba2-1 mutants. This study reveals a new role for ABA in defense against insects in Arabidopsis and identifies some components important for plant resistance to herbivory.

Proinflammatory activity of cell-wall constituents from gram-positive bacteria.

Innate immunity reacts to conserved bacterial molecules. The outermost lipopolysaccharide (LPS) of Gram-negative organisms is highly inflammatory. It activates responsive cells via specific CD14 and toll-like receptor-4 (TLR4) surface receptor and co-receptors. Gram-positive bacteria do not contain LPS, but carry surface teichoic acids, lipoteichoic acids and peptidoglycan instead. Among these, the thick peptidoglycan is the most conserved. It also triggers cytokine release via CD14, but uses the TLR2 co-receptor instead of TLR4 used by LPS. Moreover, whole peptidoglycan is 1000-fold less active than LPS in a weight-to-weight ratio. This suggests either that it is not important for inflammation, or that only part of it is reactive while the rest acts as ballast. Biochemical dissection of Staphylococcus aureus and Streptococcus pneumoniae cell walls indicates that the second assumption is correct. Long, soluble peptidoglycan chains (approximately 125 kDa) are poorly active. Hydrolysing these chains to their minimal unit (2 sugars and a stem peptide) completely abrogates inflammation. Enzymatic dissection of the pneumococcal wall generated a mixture of highly active fragments, constituted of trimeric stem peptides, and poorly active fragments, constituted of simple monomers and dimers or highly polymerized structures. Hence, the optimal constraint for activation might be 3 cross-linked stem peptides. The importance of structural constraint was demonstrated in additional studies. For example, replacing the first L-alanine in the stem peptide with a D-alanine totally abrogated inflammation in experimental meningitis. Likewise, modifying the D-alanine decorations of lipoteichoic acids with L-alanine, or deacylating them from their diacylglycerol lipid anchor also decreased the inflammatory response. Thus, although considered as a broad-spectrum pattern-recognizing system, innate immunity can detect very subtle differences in Gram-positive walls. This high specificity underlines the importance of using well-characterized microbial material in investigating the system.

Nitric oxide and the release of lipoprotein lipase from white adipose tissue

Background/Aim: Lipoprotein lipase (LPL) is the main enzyme responsible for the distribution of circulating triacylglycerides in tissues. Its regulation via release from active sites in the vascular endothelium is poorly understood. In a previous study we reported that in response to acute immobilization (IMMO), LPL activity rapidly increases in plasma and decreases in white adipose tissue (WAT) in rats. In other stress situations IMMO triggers a generalized increase in nitric oxide (NO) production. Methods/Results: Here we demonstrate that in rats: 1) in vivo acute IMMO rapidly increases NO concentrations in plasma 2) during acute IMMO the WAT probably produces NO via the endothelial isoform of nitric oxide synthase (eNOS) from vessels, and 3) epididymal WAT perfused in situ with an NO donor rapidly releases LPL from the endothelium. Conclusion: We propose the following chain of events: stress stimulus / rapid increase of NO production in WAT (by eNOS) / release of LPL from the endothelium in WAT vessels. This chain of events could be a new mechanism that promotes the rapid decrease of WAT LPL activity in response to a physiological stimulus.

Persistent unequal sex ratio in a population of grayling (salmonidae) and possible role of temperature increase.

In some fishes, water chemistry or temperature affects sex determination or creates sex-specific selection pressures. The resulting population sex ratios are hard to predict from laboratory studies if the environmental triggers interact with other factors, whereas in field studies, singular observations of unusual sex ratios may be particularly prone to selective reporting. Long-term monitoring largely avoids these problems. We studied a population of grayling (Thymallus thymallus) in Lake Thun, Switzerland, that has been monitored since 1948. Samples of spawning fish have been caught about 3 times/week around spawning season, and water temperature at the spawning site has been continuously recorded since 1970. We used scale samples collected in different years to determine the average age of spawners (for life-stage specific analyses) and to identify the cohort born in 2003 (an extraordinarily warm year). Recent tissue samples were genotyped on microsatellite markers to test for genetic bottlenecks in the past and to estimate the genetically effective population size (N(e) ). Operational sex ratios changed from approximately 65% males before 1993 to approximately 85% males from 1993 to 2011. Sex ratios correlated with the water temperatures the fish experienced in their first year of life. Sex ratios were best explained by the average temperature juvenile fish experienced during their first summer. Grayling abundance is declining, but we found no evidence of a strong genetic bottleneck that would explain the apparent lack of evolutionary response to the unequal sex ratio. Results of other studies show no evidence of endocrine disruptors in the study area. Our findings suggest temperature affects population sex ratio and thereby contributes to population decline. Persistencia de Proporción de Sexos Desigual en una Población de Tímalos (Salmonidae) y el Posible Papel del Incremento de la Temperatura.

Metabolic alterations in the cortex of a mouse model with glutathione deficit - relevance to schizophrenia

Background: Glutathione (GSH) is a major redox regulator and antioxidant and is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients [Do et al. (2000) Eur J Neurosci 12:3721]. The genes of the key GSH-synthesizing enzyme, glutamate- cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, are associated with schizophrenia, suggesting that the deficit in GSH synthesis is of genetic origin [Gysin et al. (2007) PNAS 104:16621]. GCLM knock-out (KO) mice, which display an 80% decrease in brain GSH levels, have abnormal brain morphology and function [Do et al. (2009) Curr Opin Neurobiol 19:220]. Developmental redox deregulation by impaired GSH synthesis and environmental risk factors generating oxidative stress may have a central role in schizophrenia. Here, we used GCLM KO mice to investigate the impact of a genetically dysregulated redox system on the neurochemical profile of the developing brain. Methods: The neurochemical profile of the anterior and posterior cortical areas of male and female GCLM KO and wild-type mice was determined by in vivo 1H NMR spectroscopy on postnatal days 10, 20, 30, 60 and 90, under 1 to 1.5% isoflurane anaesthesia. Localised 1H NMR spectroscopy was performed on a 14.1 T, 26 cm VNMRS spectrometer (Varian, Magnex) using a home-built 8 mm diameter quadrature surface coil (used both for RF excitation and signal reception). Spectra were acquired using SPECIAL with TE of 2.8 ms and TR of 4 s from VOIs placed in anterior or posterior regions of the cortex [Mlynárik et al. (2006) MRM 56:965]. LCModel analysis allowed in vivo quantification of a neurochemical profile composed of 18 metabolites. Results: GCLM KO mice displayed nearly undetectable GSH levels as compared to WT mice, demonstrating their drastic redox deregulation. Depletion of GSH triggered alteration of metabolites related to its synthesis, namely increase of glycine and glutamate levels during development (P20 and P30). Concentrations of glutamine and aspartate that are produced from glutamate were also increased in GCLM KO animals relative to WT. In addition, GCLM KO mice also showed higher levels of N-acetylaspartate that originates from the acetylation of aspartate. These metabolites are particularly implicated in neurotransmission processes and in mitochondrial oxidative metabolism. Their increase may indicate impaired mitochondrial metabolism with concomitant accumulation of lactate in the adult mice (P60 and P90). In addition, the GSH depletion triggers reduction of GABA concentration in anterior cortex of the P60 mice, which is in accordance with known impairment of GABAergic interneurons in that area. Changes were generally more pronounced in males than in females at P60, which is consistent with earlier disease onset in male patients. Discussion: In conclusion, the observed metabolic alterations in the cortex of a mouse model of redox deregulation suggest impaired mitochondrial metabolism and altered neurotransmission. The results also highlight the age between P20 and P30 as a sensitive period during the development for these alterations.

Functions of the peroxisome proliferator-activated receptor (PPAR) alpha and beta in skin homeostasis, epithelial repair, and morphogenesis.

The three peroxisome proliferator-activated receptors (PPAR alpha, PPAR beta, and PPAR gamma) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. They are regarded as being sensors of physiological levels of fatty acids and fatty acid derivatives. In the adult mouse skin, they are found in hair follicle keratinocytes but not in interfollicular epidermis keratinocytes. Skin injury stimulates the expression of PPAR alpha and PPAR beta at the site of the wound. Here, we review the spatiotemporal program that triggers PPAR beta expression immediately after an injury, and then gradually represses it during epithelial repair. The opposing effects of the tumor necrosis factor-alpha and transforming growth factor-beta-1 signalling pathways on the activity of the PPAR beta promoter are the key elements of this regulation. We then compare the involvement of PPAR beta in the skin in response to an injury and during hair morphogenesis, and underscore the similarity of its action on cell survival in both situations.

Characterization of GLUT8 and GLUT9, two novel glucose transporter isoforms

Summary Prevalence of type 2 diabetes is increasing worldwide at alarming rates, probably secondarily to that of obesity. As type 2 diabetes is characterized by blood hyperglycemia, controlling glucose entry into tissues from the bloodstream is key to maintain glycemia within acceptable ranges. In this context, several glucose transporter isoforms have been cloned recently and some of them have appeared to play important regulatory roles. Better characterizing two of them (GLUT8 and GLUT9) was the purpose of my work. The first part of my work was focused on GLUT8, which is mainly expressed in the brain and is able to transport glucose with high affinity. GLUT8 is retained intracellularly at basal state depending on an N-terminal dileucine motif, thus implying that cell surface expression may be induced by extracellular triggers. In this regard, I was interested in better defining GLUT8 subcellular localization at basal state and in finding signals promoting its translocation, using an adenoviral vector expressing a myc epitope-tagged version of the transporter, thus allowing expression and detection of cell-surface GLUT8 in primary hippocampal neurons and PC 12 cells. This tool enabled me to found out that GLUT8 resides in a unique compartment different from lysosomes, endoplasmic reticulum, endosomes and the Golgi. In addition, absence of GLUT8 translocation following pharmacological activation of several signalling pathways suggests that GLUT8 does not ever translocate to the cell surface, but would rather fulfill its role in its unique intracellular compartment. The second part of my work was focused on GLUT9, which -contrarily to GLUT8 - is unable to transport glucose, but retains the ability to bind glucose-derived cross-linker molecules, thereby suggesting that it may be a glucose sensor rather than a true glucose transporter. The aim of the project was thus to define if GLUT9 triggers intracellular signals when activated. Therefore, adenoviral vectors expressing GLUTS were used to infect both ßpancreatic and liver-derived cell lines, as GLUTS is endogenously expressed in the liver. Comparison of gene expression between cells infected with the GLUTS-expressing adenovirus and cells infected with a GFP-expressing control adenovirus ended up in the identification of the transcription factor HNF4α as being upregulated in aGLUT9-dependent manner. Résumé La prévalence du diabète de type 2 augmente de façon alarmante dans le monde entier, probablement secondairement à celle de l'obésité. Le diabète de type 2 étant caractérisé par une glycémie sanguine élevée, l'entrée du glucose dans les tissus depuis la circulation sanguine constitue un point de contrôle important pour maintenir la glycémie à des valeurs acceptables. Dans ce contexte, plusieurs isoformes de transporteurs au glucose ont été clonées récemment et certaines d'entre elles sont apparues comme jouant d'importants rôles régulateurs. Mieux caractériser deux d'entre elles (GLUT8 et GLUT9) était le but de mon travail. La première partie de mon travail a été centrée sur GLUT8, qui est exprimé principalement dans le cerveau et qui peut transporter le glucose avec une haute affinité. GLUT8 est retenu intracellulairement à l'état basal de façon dépendante d'un motif dileucine N-terminal, ce qui implique que son expression à la surface cellulaire pourrait être induite par des stimuli extracellulaires. Dans cette optique, je me suis intéressé à mieux définir la localisation subcellulaire de GLUT8 à l'état basal et à trouver des signaux activant sa translocation, en utilisant comme outil un vecteur adénoviral exprimant une version marquée (tag myc) du transporteur, me permettant ainsi d'exprimer et de détecter GLUT8 à la surface cellulaire dans des neurones hippocampiques primaires et des cellules PC12. Cet outil m'a permis de montrer que GLUT8 réside dans un compartiment unique différent des lysosomes, du réticulum endoplasmique, des endosomes, ainsi que du Golgi. De plus, l'absence de translocation de GLUT8 à la suite de l'activation pharmacologique de plusieurs voies de signalisation suggère que GLUT8 ne transloque jamais à la membrane plasmique, mais jouerait plutôt un rôle au sein même de son compartiment intracellulaire unique. La seconde partie de mon travail a été centrée sur GLUT9, lequel -contrairement à GLUT8 -est incapable de transporter le glucose, mais conserve la capacité de se lier à des molécules dérivées du glucose, suggérant que ce pourrait être un senseur de glucose plutôt qu'un vrai transporteur. Le but du projet a donc été de définir si GLUT9 active des signaux intracellulaires quand il est lui-même activé. Pour ce faire, des vecteurs adénoviraux exprimant GLUT9 ont été utilisés pour infecter des lignées cellulaires dérivées de cellules ßpancréatiques et d'hépatocytes, GLUT9 étant exprimé de façon endogène dans le foie. La comparaison de l'expression des gènes entre des cellules infectées avec l'adénovirus exprimant GLUT9 et un adénovirus contrôle exprimant la GFP a permis d'identifier le facteur de transcription HNF4α comme étant régulé de façon GLUT9-dépendante. Résumé tout public Il existe deux types bien distincts de diabète. Le diabète de type 1 constitue environ 10 des cas de diabète et se déclare généralement à l'enfance. Il est caractérisé par une incapacité du pancréas à sécréter une hormone, l'insuline, qui régule la concentration sanguine du glucose (glycémie). Il en résulte une hyperglycémie sévère qui, si le patient n'est pas traité à l'insuline, conduit à de graves dommages à divers organes, ce qui peut mener à la cécité, à la perte des membres inférieurs, ainsi qu'à l'insuffisance rénale. Le diabète de type 2 se déclare plus tard dans la vie. Il n'est pas causé par une déficience en insuline, mais plutôt par une incapacité de l'insuline à agir sur ses tissus cibles. Le nombre de cas de diabète de type 2 augmente de façon dramatique, probablement à la suite de l'augmentation des cas d'obésité, le surpoids chronique étant le principal facteur de risque de diabète. Chez l'individu sain, le glucose sanguin est transporté dans différents organes (foie, muscles, tissu adipeux,...) où il est utilisé comme source d'énergie. Chez le patient diabétique, le captage de glucose est altéré, expliquant ainsi l'hyperglycémie. Il est ainsi crucial d'étudier les mécanismes permettant ce captage. Ainsi, des protéines permettant l'entrée de glucose dans la cellule depuis le milieu extracellulaire ont été découvertes depuis une vingtaine d'années. La plupart d'entre elles appartiennent à une sous-famille de protéines nommée GLUT (pour "GLUcose Transporters") dont cinq membres ont été caractérisés et nommés selon l'ordre de leur découverte (GLUT1-5). Néanmoins, la suppression de ces protéines chez la souris par des techniques moléculaires n'affecte pas totalement le captage de glucose, suggérant ainsi que des transporteurs de glucose encore inconnus pourraient exister. De telles protéines ont été isolées ces dernières années et nommées selon l'ordre de leur découverte (GLUT6-14). Durant mon travail de thèse, je me suis intéressé à deux d'entre elles, GLUT8 et GLUT9, qui ont été découvertes précédemment dans le laboratoire. GLUT8 est exprimé principalement dans le cerveau. La protéine n'est pas exprimée à la surface de la cellule, mais est retenue à l'intérieur. Des mécanismes complexes doivent donc exister pour déplacer le transporteur à la surface cellulaire, afin qu'il puisse permettre l'entrée du glucose dans la cellule. Mon travail a consisté d'une part à définir où se trouve le transporteur à l'intérieur de la cellule, et d'autre part à comprendre les mécanismes capables de déplacer GLUT8 vers la surface cellulaire, en utilisant des neurones exprimant une version marquée du transporteur, permettant ainsi sa détection par des méthodes biochimiques. Cela m'a permis de montrer que GLUT8 est localisé dans une partie de la cellule encore non décrite à ce jour et qu'il n'est jamais déplacé à la surface cellulaire, ce qui suggère que le transporteur doit jouer un rôle à l'intérieur de la cellule et non à sa surface. GLUT9 est exprimé dans le foie et dans les reins. Il ressemble beaucoup à GLUT8, mais ne transporte pas le glucose, ce qui suggère que ce pourrait être un récepteur au glucose plutôt qu'un transporteur à proprement parler. Le but de mon travail a été de tester cette hypothèse, en comparant des cellules du foie exprimant GLUT9 avec d'autres n'exprimant pas la protéine. Par des méthodes d'analyses moléculaires, j'ai pu montrer que la présence de GLUT9 dans les cellules du foie augmente l'expression de HNF4α, une protéine connue pour réguler la sécrétion d'insuline dans le pancréas ainsi que la production de glucose dans le foie. Des expériences complémentaires seront nécessaires afin de mieux comprendre par quels mécanismes GLUT9 influence l'expression de HNF4α dans le foie, ainsi que de définir l'importance de GLUT9 dans la régulation de la glycémie chez l'animal entier.

The effect of virtual reality on visual vertigo symptoms in patients with peripheral vestibular dysfunction: a pilot study.

Individuals with vestibular dysfunction may experience visual vertigo (VV), in which symptoms are provoked or exacerbated by excessive or disorientating visual stimuli (e.g. supermarkets). VV can significantly improve when customized vestibular rehabilitation exercises are combined with exposure to optokinetic stimuli. Virtual reality (VR), which immerses patients in realistic, visually challenging environments, has also been suggested as an adjunct to VR to improve VV symptoms. This pilot study compared the responses of sixteen patients with unilateral peripheral vestibular disorder randomly allocated to a VR regime incorporating exposure to a static (Group S) or dynamic (Group D) VR environment. Participants practiced vestibular exercises, twice weekly for four weeks, inside a static (Group S) or dynamic (Group D) virtual crowded square environment, presented in an immersive projection theatre (IPT), and received a vestibular exercise program to practice on days not attending clinic. A third Group D1 completed both the static and dynamic VR training. Treatment response was assessed with the Dynamic Gait Index and questionnaires concerning symptom triggers and psychological state. At final assessment, significant betweengroup differences were noted between Groups D (p = 0.001) and D1 (p = 0.03) compared to Group S for VV symptoms with the former two showing a significant 59.2% and 25.8% improvement respectively compared to 1.6% for the latter. Depression scores improved only for Group S (p = 0.01) while a trend towards significance was noted for Group D regarding anxiety scores (p = 0.07). Conclusion: Exposure to dynamic VR environments should be considered as a useful adjunct to vestibular rehabilitation programs for patients with peripheral vestibular disorders and VV symptoms.

Role for JIP-1/IB1 in pancreatic β-cell and adipocyte dysfunctions in type 2 diabetes and obesity

L'insuline, produite par les cellules β du pancréas, joue un rôle central dans le contrôle de la glycémie. Un manque d'insuline entraine le diabète de type 2, une maladie répandue au stade d'épidémie au niveau mondial. L'augmentation du nombre de personnes obèses est une des causes principales du développement de la maladie. Avec l'obésité les tissus tels que le foie, le muscle, et le tissu adipeux deviennent résistants à l'insuline. En général, cette résistance est équilibrée par une augmentation de la sécrétion d'insuline. De ce fait, un grand nombre d'individus obèses ne deviennent pas diabétiques. Lorsque les cellules β ne produisent plus suffisamment d'insuline, alors le diabète se développe. Dans l'obésité, les cellules graisseuses sont résistantes à l'insuline et relâchent des lipides et autres produits qui affectent le bon fonctionnement et la vie des cellules β. «c-Jun Ν terminal Kinase» (JNK) est une enzyme qui joue un rôle important dans la résistance de l'insuline des cellules graisseuses. Cette même en2yme contribue aussi au déclin de la cellule β dans les conditions diabétogènes, et représente ainsi une cible thérapeutique potentielle du diabète. L'objectif de cette thèse a été de comprendre le mécanisme conduisant à l'activité de JNK dans les adipocytes et cellules β, dans l'obésité et le diabète de type 2. Nous montrons que les variations de JNK sont la conséquence de taux anormaux de JIP-1/EB1, une protéine qui a été impliquée dans certaines formes génétiques de diabète de type 2. En outre nous décrivons le mécanisme responsable des anomalies de JIP1/IB1 dans les adipocytes et cellules β. La restauration des taux de JIP-1/EB1 dans les deux types cellulaires pourrait être un objectif des thérapeutiques antidiabétiques actuelles et futures. - Le nombre d'individus touchés par le diabète de type 2 atteint aujourd'hui des proportions épidémiques à l'échelle mondiale. L'augmentation de la prévalence de l'obésité est la cause principale du développement de la maladie, qui, en général, survient suite à une perte de la sensibilité à l'insuline des tissus périphériques. Dans un grand nombre des cas, l'insulino-résistance est compensée par une augmentation de la sécrétion de l'insuline par les cellules β pancréatiques. Le diabète apparaît lorsque l'insuline n'est plus produite en quantité suffisante pour contrecarrer la résistance à l'insuline des tissus. Le défaut de production de l'insuline résulte du dysfonctionnement et de la réduction massive des cellules β. Les acides gras libres non estérifiés, en particulier le palmitate, provenant d'une alimentation riche en lipides et libérés par les adipocytes insulino-résistants contribuent au déclin de la cellule β en activant la voie de signalisation «cJun N-terminal kinase» (JNK). L'activation de JNK contribue aussi à la résistance à l'insuline des adipocytes dans l'obésité, soulignant ainsi l'importance de cette voie de signalisation dans la pathophysiologie du diabète. L'objectif de cette thèse a été de comprendre les mécanismes qui régulent JNK dans les cellules β et les adipocytes. Nous montrons que l'activation de JNK dans ces deux types cellulaires est la conséquence de la variation des taux de «JNK interacting protein 1» appelé aussi «islet brain 1» (JEP-1/ΓΒΙ), une protéine qui attache les kinases de la signalisation de JNK et dont des variations génétiques ont été associées avec le diabète de type 2. Dans les cellules β cultivées avec du palmitate, ainsi que dans les adipocytes dans l'obésité, l'expression de JEP-l/BBl est modifiée. Les modulations de l'expression de JEP-1/ΓΒΙ sont réalisées par le facteur de transcription «inducible cAMP early repressor» (ICER). L'expression d'ICER dans les adipocytes est diminuée dans l'obésité, et corrèle avec l'augmentation des niveaux de JEP-1/IB1. A l'inverse, le niveau d'expression d'ICER est augmenté dans les cellules β cultivées avec du palmitate, et cette augmentation perturbe le bon fonctionnement des cellules en réduisant les niveaux de JEP-l/IBl. Comme le palmitate, les particules pro-athérogéniques LDL-cholesterol oxydés, sont élevées chez les personnes obèses et diabétiques et sont délétères aux cellules β. Ces particules modifiées activent JNK dans les cellules β en diminuant l'expression de JIP-1/IB1 via ICER. Tous ces résultats montrent que le dérèglement de l'expression de JIP-l/EBl par ICER joue un rôle central dans l'activation de JNK dans les adipocytes et cellules β en souffrance dans l'obésité et le diabète de type 2. La restauration appropriée des niveaux de JEPl/IBl et d'ICER pourrait être considérée comme un objectif pour mesurer l'efficacité des traitements antidiabétiques actuels et futurs. - Type 2 diabetes has reached epidemic proportions worldwide, and poses a major socio-economic burden on developed and developing societies. The disease is often accompanied by obesity, and arises when β-cells produce insufficient insulin to meet the increased hormone demand, caused by insulin resistance. In obesity, enlargement of adipocytes contribute to their dysfunction, which is characterized by the abnormal release of some bioactive products such as non-esterified free fatty acids (NEF As). Chronic plasma elevation of NEF As elicits β-cell dysfunction and death, thereby, representing a key feature for development of diabetes in obesity (diabesity). Palmitate is the most abundant circulating NEF As in obesity, which triggers adipocytes and β-cell dysfunction. The effects of palmitate rely on the induction of the cJun N-terminal kinase (JNK) pathway. Activation of JNK promotes both β-cells dysfunction and insulin resistance in adipocytes. This thesis was undertaken to investigate the mechanisms accounting for the induction of the JNK pathway caused by palmitate. JNK is regulated by the scaffold protein JNK interacting protein-1, also called islet brain 1 (JIP-1/IB1). The levels of JDM/IB1 are critical for glucose homeostasis, as genetic variations within the gene were associated with diabetes. We found that activation of JNK in both, β-cells exposed to palmitate, and in adipocytes of obese mice, results from variations in the expression of JIP-l/EBl. Modifications in the JIP-1/IB1 levels were the consequence of abnormal expression of the inducible cAMP early repressor (ICER) in the two cell types. In addition, our data show that this repressor plays a key role in abnormal production of adipocyte hormones and β-cell dysfunction evoked by the pro-atherogenic oxidized LDL. Taken together, this study proposes that fine-tuning of appropriate levels of JIP-l/EBl, and ICER could circumvent β-cell failure, adipocyte dysfunction, and thereby, development of diabesity.

Risk and global change : developing scientific methods for advocacy and awareness raising

Les catastrophes sont souvent perçues comme des événements rapides et aléatoires. Si les déclencheurs peuvent être soudains, les catastrophes, elles, sont le résultat d'une accumulation des conséquences d'actions et de décisions inappropriées ainsi que du changement global. Pour modifier cette perception du risque, des outils de sensibilisation sont nécessaires. Des méthodes quantitatives ont été développées et ont permis d'identifier la distribution et les facteurs sous- jacents du risque.¦Le risque de catastrophes résulte de l'intersection entre aléas, exposition et vulnérabilité. La fréquence et l'intensité des aléas peuvent être influencées par le changement climatique ou le déclin des écosystèmes, la croissance démographique augmente l'exposition, alors que l'évolution du niveau de développement affecte la vulnérabilité. Chacune de ses composantes pouvant changer, le risque est dynamique et doit être réévalué périodiquement par les gouvernements, les assurances ou les agences de développement. Au niveau global, ces analyses sont souvent effectuées à l'aide de base de données sur les pertes enregistrées. Nos résultats montrent que celles-ci sont susceptibles d'être biaisées notamment par l'amélioration de l'accès à l'information. Elles ne sont pas exhaustives et ne donnent pas d'information sur l'exposition, l'intensité ou la vulnérabilité. Une nouvelle approche, indépendante des pertes reportées, est donc nécessaire.¦Les recherches présentées ici ont été mandatées par les Nations Unies et par des agences oeuvrant dans le développement et l'environnement (PNUD, l'UNISDR, la GTZ, le PNUE ou l'UICN). Ces organismes avaient besoin d'une évaluation quantitative sur les facteurs sous-jacents du risque, afin de sensibiliser les décideurs et pour la priorisation des projets de réduction des risques de désastres.¦La méthode est basée sur les systèmes d'information géographique, la télédétection, les bases de données et l'analyse statistique. Une importante quantité de données (1,7 Tb) et plusieurs milliers d'heures de calculs ont été nécessaires. Un modèle de risque global a été élaboré pour révéler la distribution des aléas, de l'exposition et des risques, ainsi que pour l'identification des facteurs de risque sous- jacent de plusieurs aléas (inondations, cyclones tropicaux, séismes et glissements de terrain). Deux indexes de risque multiples ont été générés pour comparer les pays. Les résultats incluent une évaluation du rôle de l'intensité de l'aléa, de l'exposition, de la pauvreté, de la gouvernance dans la configuration et les tendances du risque. Il apparaît que les facteurs de vulnérabilité changent en fonction du type d'aléa, et contrairement à l'exposition, leur poids décroît quand l'intensité augmente.¦Au niveau local, la méthode a été testée pour mettre en évidence l'influence du changement climatique et du déclin des écosystèmes sur l'aléa. Dans le nord du Pakistan, la déforestation induit une augmentation de la susceptibilité des glissements de terrain. Les recherches menées au Pérou (à base d'imagerie satellitaire et de collecte de données au sol) révèlent un retrait glaciaire rapide et donnent une évaluation du volume de glace restante ainsi que des scénarios sur l'évolution possible.¦Ces résultats ont été présentés à des publics différents, notamment en face de 160 gouvernements. Les résultats et les données générées sont accessibles en ligne (http://preview.grid.unep.ch). La méthode est flexible et facilement transposable à des échelles et problématiques différentes, offrant de bonnes perspectives pour l'adaptation à d'autres domaines de recherche.¦La caractérisation du risque au niveau global et l'identification du rôle des écosystèmes dans le risque de catastrophe est en plein développement. Ces recherches ont révélés de nombreux défis, certains ont été résolus, d'autres sont restés des limitations. Cependant, il apparaît clairement que le niveau de développement configure line grande partie des risques de catastrophes. La dynamique du risque est gouvernée principalement par le changement global.¦Disasters are often perceived as fast and random events. If the triggers may be sudden, disasters are the result of an accumulation of actions, consequences from inappropriate decisions and from global change. To modify this perception of risk, advocacy tools are needed. Quantitative methods have been developed to identify the distribution and the underlying factors of risk.¦Disaster risk is resulting from the intersection of hazards, exposure and vulnerability. The frequency and intensity of hazards can be influenced by climate change or by the decline of ecosystems. Population growth increases the exposure, while changes in the level of development affect the vulnerability. Given that each of its components may change, the risk is dynamic and should be reviewed periodically by governments, insurance companies or development agencies. At the global level, these analyses are often performed using databases on reported losses. Our results show that these are likely to be biased in particular by improvements in access to information. International losses databases are not exhaustive and do not give information on exposure, the intensity or vulnerability. A new approach, independent of reported losses, is necessary.¦The researches presented here have been mandated by the United Nations and agencies working in the development and the environment (UNDP, UNISDR, GTZ, UNEP and IUCN). These organizations needed a quantitative assessment of the underlying factors of risk, to raise awareness amongst policymakers and to prioritize disaster risk reduction projects.¦The method is based on geographic information systems, remote sensing, databases and statistical analysis. It required a large amount of data (1.7 Tb of data on both the physical environment and socio-economic parameters) and several thousand hours of processing were necessary. A comprehensive risk model was developed to reveal the distribution of hazards, exposure and risk, and to identify underlying risk factors. These were performed for several hazards (e.g. floods, tropical cyclones, earthquakes and landslides). Two different multiple risk indexes were generated to compare countries. The results include an evaluation of the role of the intensity of the hazard, exposure, poverty, governance in the pattern and trends of risk. It appears that the vulnerability factors change depending on the type of hazard, and contrary to the exposure, their weight decreases as the intensity increases.¦Locally, the method was tested to highlight the influence of climate change and the ecosystems decline on the hazard. In northern Pakistan, deforestation exacerbates the susceptibility of landslides. Researches in Peru (based on satellite imagery and ground data collection) revealed a rapid glacier retreat and give an assessment of the remaining ice volume as well as scenarios of possible evolution.¦These results were presented to different audiences, including in front of 160 governments. The results and data generated are made available online through an open source SDI (http://preview.grid.unep.ch). The method is flexible and easily transferable to different scales and issues, with good prospects for adaptation to other research areas. The risk characterization at a global level and identifying the role of ecosystems in disaster risk is booming. These researches have revealed many challenges, some were resolved, while others remained limitations. However, it is clear that the level of development, and more over, unsustainable development, configures a large part of disaster risk and that the dynamics of risk is primarily governed by global change.

Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy.

Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycemic control still remains a major challenge in the management of diabetic patients. Hyperglycemia triggers formation of advanced glycosylation end products (AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.