Impact of family structure on long-term survivors of osteosarcoma

Rapport de synthèse : But du travail : le pronostic des patients atteints d'ostéosarcome s'est considérablement amélioré grâce à l'utilisation de thérapies combinées performantes. Cependant, ces traitements agressifs sont grevés de complications chroniques. Notre travail a consisté à l'évaluation du status fonctionnel, psychologique et familial chez des patients survivants au long cours d'ostéosarcome traités au centre pluridisciplinaire d'oncologie. Patients et méthodes: 15 survivants au long cours d'ostéosarcome ont été évalués à la recherche de séquelles physiques et psychologiques. Pour l'évaluation fonctionnelle, nous avons utilisé la méthode de Enneking. L'évaluation psychologique a été basée sur un test d'évaluation globale (GHQ-28), sur un test de cohésion familiale (FAST test) et sur une échelle d'évaluation de symptômes post-traumatiques. Résultats: sur le plan fonctionnel, seuls 5 patients présentaient des séquelles graves et 10 des handicaps modérés. 4 patients souffraient de symptômes dépressifs. 6 patients ont décrit uns structure familiale déséquilibrée dont 3 des 4 patients avec des symptômes dépressifs, les 4 patients avec symptômes post-traumatiques et 5 des 7 patients avec une mauvaise acceptation émotionnelle. Conclusions: la plupart des patients souffrant d'ostéosarcome présentent une bonne récupération fonctionnelle. Seule une minorité reste sévèrement handicapée. Un tiers des patients souffre de symptômes dépressifs et de stress post-traumatique. Une mauvaise acceptation émotionnelle est fortement liée à une structure familiale déséquilibrée. La situation psychologique et familiale des patients atteints d'ostéosarcome doit donc être rapidement prise en compte afin d'améliorer leur évolution au long cours.

Model structure of human APOBEC3G.

BACKGROUND: APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. APOBEC3G has two cytosine deaminase (CDA) domains; the catalytically inactive amino-terminal domain of APOBEC3G (N-CDA) carries the Vif interaction domain. There is no 3-D structure of APOBEC3G solved by X-ray or nuclear magnetic resonance. METHODOLOGY/PRINCIPAL FINDINGS: We predicted the structure of human APOBEC3G based on the crystal structure of APOBEC2. To assess the model structure, we evaluated 48 mutants of APOBEC3G N-CDA that identify novel variants altering DeltaVif HIV-1 infectivity and packaging of APOBEC3G. Results indicated that the key residue D128 is exposed at the surface of the model, with a negative local electrostatic potential. Mutation D128K changes the sign of that local potential. In addition, two novel functionally relevant residues that result in defective APOBEC3G encapsidation, R122 and W127, cluster at the surface. CONCLUSIONS/SIGNIFICANCE: The structure model identifies a cluster of residues important for packaging of APOBEC3G into virions, and may serve to guide functional analysis of APOBEC3G.

Dense granular bodies: a novel nucleoplasmic structure in hibernating dormice.

Dense granular bodies (DGB) are particular structural constituents observed in cell nuclei of different tissues-liver, pancreas, brown adipose tissue, adrenal cortex-of hibernating dormice. They appear as strongly electron-dense clusters of closely packed granules, with thin fibrils spreading out at their periphery. DGB always occur in the nucleoplasm, sometimes making contact with other nuclear structural constituents typical of the hibernating state, such as coiled bodies, amorphous bodies and nucleoplasmic fibrils. DGB are present only during deep hibernation and rapidly disappear upon arousal from hibernation. Cytochemical and immunocytochemical analyses showed that DGB contain ribonucleoproteins and several nucleoplasmic RNA processing factors, suggesting that DGB can represent accumulation sites of splicing factors which are provided to splicing sites when normal metabolic activity is rapidly restored during arousal.

Coordination et décentralisation des règles budgétaires dans une structure fédéraliste : le cas des cantons suisses

La coordination des politiques budgétaires entre collectivités publiques se heurte à leur souveraineté individuelle. Les règles budgétaires indépendamment adoptées peuvent potentiellement aller à l'encontre des besoins généraux de stabilisation macroéconomique. En utilisant l'exemple des cantons suisses, cette contribution analyse la possibilité de dégager une politique anti-cyclique lorsque les collectivités locales se dotent de règles les contraignant à un équilibre budgétaire ou à un quasi-équilibre. On montre que, dotées ou non de règles, les collectivités adoptent généralement un comportement pro-cyclique. Toutefois, ce comportement peut être contrecarré si le gouvernement central instrumentalise la péréquation financière verticale au profit de la stabilisation.

Structure et évolution thermique de la croûte supérieure des chaînes de subduction : approches thermologique et modélisation numérique, dans les North Cascades (U.S.A) et de la zone de faille Motagua (Guatemala)

Cette thèse cible l'étude de la structure thermique de la croûte supérieure (<10km) dans les arcs magmatiques continentaux, et son influence sur l'enregistrement thermochronologique de leur exhumation et de leur évolution topographique. Nous portons notre regard sur deux chaînes de montagne appartenant aux Cordillères Américaines : Les Cascades Nord (USA) et la zone de faille Motagua (Guatemala). L'approche utilisée est axée sur la thermochronologie (U-Th-Sm)/He sur apatite et zircon, couplée avec la modélisation numérique de la structure thermique de la croûte. Nous mettons en évidence la variabilité à la fois spatiale et temporelle du gradient géothermique, et attirons l'attention du lecteur sur l'importance de prendre en compte la multitude des processus géologiques perturbant la structure thermique dans les chaînes de type cordillère, c'est à dire formées lors de la subduction océanique sous un continent.Une nouvelle approche est ainsi développée pour étudier et contraindre la perturbation thermique autour des chambres magmatiques. Deux profiles âge-elevation (U-Th-Sm)/He sur apatite et zircon, ont été collectées 7 km au sud du batholithe de Chilliwack, Cascades Nord. Les résultats montrent une variabilité spatiale et temporelle du gradient géothermique lors de l'emplacement magmatique qui peut être contrainte et séparé de l'exhumation. Durant l'emplacement de l'intrusion, la perturbation thermique y atteint un état d'équilibre (-80-100 °C/km) qui est fonction du flux de magma et de ia distance à la source du magma, puis rejoint 40 °C/km à la fin du processus d'emplacement magmatique.Quelques nouvelles données (U-Th)/He, replacées dans une compilation des données existantes dans les Cascades Nord, indiquent une vitesse d'exhumation constante (-100 m/Ma) dans le temps et l'espace entre 35 Ma et 2 Ma, associée à un soulèvement uniforme de la chaîne contrôlé par l'emplacement de magma dans la croûte durant toute l'activité de l'arc. Par contre, après ~2 Ma, le versant humide de la chaîne est affecté par une accélération des taux d'exhumation, jusqu'à 3 km de croûte y sont érodés. Les glaciations ont un triple effet sur l'érosion de cette chaîne: (1) augmentation des vitesses d'érosion, d'exhumation et de soulèvement la où les précipitations sont suffisantes, (2) limitation de l'altitude contrôlé par la position de Γ Ε LA, (3) élargissement du versant humide et contraction du versant aride de la chaîne.Les modifications des réseaux de drainage sont des processus de surface souvent sous-estimés au profil d'événements climatiques ou tectoniques. Nous proposons une nouvelle approche couplant une analyse géomorphologique, des données thermochronologiques de basse température ((U-Th-Sm)/He sur apatite et zircon), et l'utilisation de modélisation numérique thermo-cinématique pour les mettre en évidence et les dater; nous testons cette approche sur la gorge de la Skagit river dans les North Cascades.De nouvelles données (U-Th)/He sur zircons, complétant les données existantes, montrent que le déplacement horizontal le long de la faille transformante continentale Motagua, la limite des plaques Caraïbe/Amérique du Nord, a juxtaposé un bloc froid, le bloc Maya (s.s.), contre un bloque chaud, le bloc Chortis (s.s.) originellement en position d'arc. En plus de donner des gammes d'âges thermochronologiques très différents des deux côtés de la faille, le déplacement horizontal rapide (~2 cm/a) a produit un fort échange thermique latéral, résultant en un réchauffement du côté froid et un refroidissement du côté chaud de la zone de faille de Motagua.Enfin des données (U-Th-Sm)/He sur apatite témoignent d'un refroidissement Oligocène enregistré uniquement dans la croûte supérieure de la bordure nord de la zone de faille Motagua. Nous tenterons ultérieurement de reproduire ce découplage vertical de la structure thermique par la modélisation de la formation d'un bassin transtensif et de circulation de fluides le long de la faille de Motagua. - This thesis focuses on the influence of the dynamic thermal structure of the upper crust (<10km) on the thermochronologic record of the exhumational and topographic history of magmatic continental arcs. Two mountain belts from the American Cordillera are studied: the North Cascades (USA) and the Motagua fault zone (Guatemala). I use a combined approach coupling apatite and zircon (U-Th-Sm}/He thermochronology and thermo- kinematic numerical modelling. This study highlights the temporal and spatial variability of the geothermal gradient and the importance to take into account the different geological processes that perturb the thermal structure of Cordilleran-type mountain belts (i.e. mountain belts related to oceanic subduction underneath a continent}.We integrate apatite and zircon (U-Th)/He data with numerical thermo-kinematic models to study the relative effects of magmatic and surface processes on the thermal evolution of the crust and cooling patterns in the Cenozoic North Cascades arc (Washington State, USA). Two age-elevation profiles that are located 7 km south of the well-studied Chiliiwack intrusions shows that spatial and temporal variability in geothermal gradients linked to magma emplacement can be contrained and separated from exhumation processes. During Chiliiwack batholith emplacement at -35-20 Ma, the geothermal gradient of the country rocks increased to a very high steady-state value (80-100°C/km), which is likely a function of magma flux and the distance from the magma source area. Including temporally varying geothermal gradients in the analysis allows quantifying the thermal perturbation around magmatic intrusions and retrieving a relatively simple denudation history from the data.The synthesis of new and previously published (U-Th)/He data reveals that denudation of the Northern Cascades is spatially and temporally constant at -100 m/Ma between ~32 and ~2 Ma, which likely reflects uplift due to magmatic crustal thickening since the initiation of the Cenozoic stage of the continental magmatic arc. In contrast, the humid flank of the North Cascades is affected by a ten-fold acceleration in exhumation rate at ~2 Ma, which we interpret as forced by the initiation of glaciations; around 3 km of crust have been eroded since that time. Glaciations have three distinct effects on the dynamics of this mountain range: (1) they increase erosion, exhumation and uplift rates where precipitation rates are sufficient to drive efficient glacial erosion; (2) they efficiently limit the elevation of the range; (3) they lead to widening of the humid flank and contraction of the arid flank of the belt.Drainage reorganizations constitute an important agent of landscape evolution that is often underestimated to the benefit of tectonic or climatic events. We propose a new method that integrates geomorphology, low-temperature thermochronometry (apatite and zircon {U-Th-Sm)/He), and 3D numerical thermal-kinematic modelling to detect and date drainage instability producing recent gorge incision, and apply this approach to the Skagit River Gorge, North Cascades.Two zircon (U-Th)/He age-elevation profiles sampled on both sides of the Motagua Fault Zone (MFZ), the boundary between the North American and the Caribbean plates, combined with published thermochronological data show that strike-slip displacement has juxtaposed the cold Maya block (s.s.) against the hot, arc derived, Chortis block (s.s ), producing different age patterns on both sides of the fault and short-wavelength lateral thermal exchange, resulting in recent heating of the cool side and cooling of the hot side of the MFZ.Finally, an apatite (U-Th-Sm)/He age-elevation profile records rapid cooling at -35 Ma localized only in the upper crust along the northern side of the Motagua fault zone. We will try to reproduce these data by modeling the thermal perturbation resulting from the formation of a transtensional basin and of fluid flow activity along a crustal- scale strike-slip fault.

GLUTAMATE RECEPTOR-LIKE genes mediate leaf-to-leaf wound signalling.

Wounded leaves communicate their damage status to one another through a poorly understood process of long-distance signalling. This stimulates the distal production of jasmonates, potent regulators of defence responses. Using non-invasive electrodes we mapped surface potential changes in Arabidopsis thaliana after wounding leaf eight and found that membrane depolarizations correlated with jasmonate signalling domains in undamaged leaves. Furthermore, current injection elicited jasmonoyl-isoleucine accumulation, resulting in a transcriptome enriched in RNAs encoding key jasmonate signalling regulators. From among 34 screened membrane protein mutant lines, mutations in several clade 3 GLUTAMATE RECEPTOR-LIKE genes (GLRs 3.2, 3.3 and 3.6) attenuated wound-induced surface potential changes. Jasmonate-response gene expression in leaves distal to wounds was reduced in a glr3.3 glr3.6 double mutant. This work provides a genetic basis for investigating mechanisms of long-distance wound signalling in plants and indicates that plant genes related to those important for synaptic activity in animals function in organ-to-organ wound signalling.

Dispersal strategies, few dominating or many coexisting: the effect of environmental spatial structure and multiple sources of mortality.

Interspecific competition, life history traits, environmental heterogeneity and spatial structure as well as disturbance are known to impact the successful dispersal strategies in metacommunities. However, studies on the direction of impact of those factors on dispersal have yielded contradictory results and often considered only few competing dispersal strategies at the same time. We used a unifying modeling approach to contrast the combined effects of species traits (adult survival, specialization), environmental heterogeneity and structure (spatial autocorrelation, habitat availability) and disturbance on the selected, maintained and coexisting dispersal strategies in heterogeneous metacommunities. Using a negative exponential dispersal kernel, we allowed for variation of both species dispersal distance and dispersal rate. We showed that strong disturbance promotes species with high dispersal abilities, while low local adult survival and habitat availability select against them. Spatial autocorrelation favors species with higher dispersal ability when adult survival and disturbance rate are low, and selects against them in the opposite situation. Interestingly, several dispersal strategies coexist when disturbance and adult survival act in opposition, as for example when strong disturbance regime favors species with high dispersal abilities while low adult survival selects species with low dispersal. Our results unify apparently contradictory previous results and demonstrate that spatial structure, disturbance and adult survival determine the success and diversity of coexisting dispersal strategies in competing metacommunities.

Phylogeographical structure, postglacial recolonization and barriers to gene flow in the distinctive Valais chromosome race of the common shrew (Sorex araneus).

Using one male-inherited and eight biparentally inherited microsatellite markers, we investigate the population genetic structure of the Valais chromosome race of the common shrew (Sorex araneus) in the Central Alps of Europe. Unexpectedly, the Y-chromosome microsatellite suggests nearly complete absence of male gene flow among populations from the St-Bernard and Simplon regions (Switzerland). Autosomal markers also show significant genetic structuring among these two geographical areas. Isolation by distance is significant and possible barriers to gene flow exist in the study area. Two different approaches are used to better understand the geographical patterns and the causes of this structuring. Using a principal component analysis for which testing procedure exists, and partial Mantel tests, we show that the St-Bernard pass does not represent a significant barrier to gene flow although it culminates at 2469 m, close to the highest altitudinal record for this species. Similar results are found for the Simplon pass, indicating that both passes represented potential postglacial recolonization routes into Switzerland from Italian refugia after the last Pleistocene glaciations. In contrast with the weak effect of these mountain passes, the Rhône valley lowlands significantly reduce gene flow in this species. Natural obstacles (the large Rhône river) and unsuitable habitats (dry slopes) are both present in the valley. Moreover, anthropogenic changes to landscape structures are likely to have strongly reduced available habitats for this shrew in the lowlands, thereby promoting genetic differentiation of populations found on opposite sides of the Rhône valley.

Neutralization of Macrophage Migration Inhibitory Factor (MIF) by Fully Human Antibodies Correlates with Their Specificity for the β-Sheet Structure of MIF.

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.

Further insights on the French WISC-IV factor structure through Bayesian structural equation modeling

The interpretation of the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) is based on a 4-factor model, which is only partially compatible with the mainstream Cattell-Horn-Carroll (CHC) model of intelligence measurement. The structure of cognitive batteries is frequently analyzed via exploratory factor analysis and/or confirmatory factor analysis. With classical confirmatory factor analysis, almost all crossloadings between latent variables and measures are fixed to zero in order to allow the model to be identified. However, inappropriate zero cross-loadings can contribute to poor model fit, distorted factors, and biased factor correlations; most important, they do not necessarily faithfully reflect theory. To deal with these methodological and theoretical limitations, we used a new statistical approach, Bayesian structural equation modeling (BSEM), among a sample of 249 French-speaking Swiss children (8-12 years). With BSEM, zero-fixed cross-loadings between latent variables and measures are replaced by approximate zeros, based on informative, small-variance priors. Results indicated that a direct hierarchical CHC-based model with 5 factors plus a general intelligence factor better represented the structure of the WISC-IV than did the 4-factor structure and the higher order models. Because a direct hierarchical CHC model was more adequate, it was concluded that the general factor should be considered as a breadth rather than a superordinate factor. Because it was possible for us to estimate the influence of each of the latent variables on the 15 subtest scores, BSEM allowed improvement of the understanding of the structure of intelligence tests and the clinical interpretation of the subtest scores.

Heritability of left ventricular structure and function in Caucasian families.

AIMS: The aim of this study was to investigate the heritability as well as genetic and environmental correlations of left ventricular (LV) structural and functional traits in complex pedigrees of a Caucasian population. METHODS AND RESULTS: We randomly recruited 459 white European subjects from 52 families (50% women; mean age 45 years). LV structure was measured by M-mode and 2D echocardiography and LV function was measured by conventional Doppler and tissue Doppler imaging (TDI). Other measurements included blood pressure, anthropometric, and biochemical measurements. We estimated the heritability of LV traits while adjusting for covariables, including sex, age, body height and weight, systolic and diastolic blood pressures, and heart rate. With full adjustment, heritability of LV mass was 0.23 (P= 0.025). The TDI-derived mitral annular velocities Ea and Aa showed moderate heritability (h(2)= 0.36 and 0.53, respectively), whereas the mitral inflow A peak had weak heritability (h(2) = 0.25) and the E peak was not heritable (h(2) = 0.11). We partitioned the total phenotypic correlation when it reached significance, into a genetic and an environmental component. The genetic correlations were 0.61 between the E and Ea peaks and 0.90 between the A and Aa peaks. CONCLUSION: Our study demonstrated moderate heritability for LV mass as well as the mitral annular Ea and Aa peaks. We also found significant genetic correlations between the E and Ea peaks and between the A and Aa peaks. Our current findings support the ongoing research to map and detect genetic variants that contribute to the variation in LV mass and other LV structural and functional phenotypes.