Relation for the nonequilibrium population of the interface states: effects on the bias dependence of the ideality factors

By an analysis of the exchange of carriers through a semiconductor junction, a general relationship for the nonequilibrium population of the interface states in Schottky barrier diodes has been derived. Based on this relationship, an analytical expression for the ideality factor valid in the whole range of applied bias has been given. This quantity exhibits two different behaviours depending on the value of the applied bias with respect to a critical voltage. This voltage, which depends on the properties of the interfacial layer, constitutes a new parameter to complete the characterization of these junctions. A simple interpretation of the different behaviours of the ideality factor has been given in terms of the nonequilibrium charging properties of interface states, which in turn explains why apparently different approaches have given rise to similar results. Finally, the relevance of our results has been considered on the determination of the density of interface states from nonideal current-voltage characteristics and in the evaluation of the effects of the interfacial layer thickness in metal-insulator-semiconductor tunnelling diodes.

Plant species richness and environmental heterogeneity in a mountain landscape: effects of variability and spatial configuration

The loss of biodiversity has become a matter of urgent concern and a better understanding of local drivers is crucial for conservation. Although environmental heterogeneity is recognized as an important determinant of biodiversity, this has rarely been tested using field data at management scale. We propose and provide evidence for the simple hypothesis that local species diversity is related to spatial environmental heterogeneity. Species partition the environment into habitats. Biodiversity is therefore expected to be influenced by two aspects of spatial heterogeneity: 1) the variability of environmental conditions, which will affect the number of types of habitat, and 2) the spatial configuration of habitats, which will affect the rates of ecological processes, such as dispersal or competition. Earlier, simulation experiments predicted that both aspects of heterogeneity will influence plant species richness at a particular site. For the first time, these predictions were tested for plant communities using field data, which we collected in a wooded pasture in the Swiss Jura mountains using a four-level hierarchical sampling design. Richness generally increased with increasing environmental variability and "roughness" (i.e. decreasing spatial aggregation). Effects occurred at all scales, but the nature of the effect changed with scale, suggesting a change in the underlying mechanisms, which will need to be taken into account if scaling up to larger landscapes. Although we found significant effects of environmental heterogeneity, other factors such as history could also be important determinants. If a relationship between environmental heterogeneity and species richness can be shown to be general, recently available high-resolution environmental data can be used to complement the assessment of patterns of local richness and improve the prediction of the effects of land use change based on mean site conditions or land use history.

Triathlon event distance specialization: training and injury effects.

We conducted a preliminary, questionnaire-based, retrospective analysis of training and injury in British National Squad Olympic distance (OD) and Ironman distance (IR) triathletes. The main outcome measures were training duration and training frequency and injury frequency and severity. The number of overuse injuries sustained over a 5-year period did not differ between OD and IR. However, the proportions of OD and IR athletes who were affected by injury to particular anatomical sites differed (p < 0.05). Also, fewer OD athletes (16.7 vs. 36.8%, p < 0.05) reported that their injury recurred. Although OD sustained fewer running injuries than IR (1.6 +/- 0.5 vs. 1.9 +/- 0.3, p < 0.05), more subsequently stopped running (41.7 vs. 15.8%) and for longer (33.5 +/- 43.0 vs. 16.7 +/- 16.6 days, p < 0.01). In OD, the number of overuse injuries sustained inversely correlated with percentage training time, and number of sessions, doing bike hill repetitions (r = -0.44 and -0.39, respectively, both p < 0.05). The IR overuse injury number correlated with the amount of intensive sessions done (r = 0.67, p < 0.01 and r = 0.56, p < 0.05 for duration of "speed run" and "speed bike" sessions). Coaches should note that training differences between triathletes who specialize in OD or IR competition may lead to their exhibiting differential risk for injury to specific anatomical sites. It is also important to note that cycle and run training may have a "cumulative stress" influence on injury risk. Therefore, the tendency of some triathletes to modify rather than stop training when injured-usually by increasing load in another discipline from that in which the injury first occurred-may increase both their risk of injury recurrence and time to full rehabilitation.

Effects of new nonlinear couplings in relativistic effective field theory

We extend the relativistic mean field theory model of Sugahara and Toki by adding new couplings suggested by modern effective field theories. An improved set of parameters is developed with the goal to test the ability of the models based on effective field theory to describe the properties of finite nuclei and, at the same time, to be consistent with the trends of Dirac-Brueckner-Hartree-Fock calculations at densities away from the saturation region. We compare our calculations with other relativistic nuclear force parameters for various nuclear phenomena.

Behavioral avoidance tests to evaluate effects of cattle slurry and dairy sludge application to soil¹

The application of organic wastes to agricultural soils is not risk-free and can affect soil invertebrates. Ecotoxicological tests based on the behavioral avoidance of earthworms and springtails were performed to evaluate effects of different fertilization strategies on soil quality and habitat function for soil organisms. These tests were performed in soils treated with: i) slurry and chemical fertilizers, according to the conventional fertilization management of the region, ii) conventional fertilization + sludge and iii) unfertilized reference soil. Both fertilization strategies contributed to soil acidity mitigation and caused no increase in soil heavy metal content. Avoidance test results showed no negative effects of these strategies on soil organisms, compared with the reference soil. However, results of the two fertilization managements differed: Springtails did not avoid soils fertilized with dairy sludge in any of the tested combinations. Earthworms avoided soils treated with sludge as of May 2004 (DS1), when compared with conventional fertilization. Possibly, the behavioral avoidance of earthworms is more sensitive to soil properties (other than texture, organic matter and heavy metal content) than springtails

A Laboratory Investigation into the Effects of the Aggregated Related Facts of Critical VMA in Asphalt Paving Mixtures, June 2000

This report summarizes research conducted at Iowa State University on behalf of the Iowa Department of Transportation, focusing on the volumetric state of hot-mix asphalt (HMA) mixtures as they transition from stable to unstable configurations. This has raditionally been addressed during mix design by meeting a minimum voids in the mineral aggregate (VMA) requirement, based solely upon the nominal maximum aggregate size without regard to other significant aggregate-related properties. The goal was to expand the current specification to include additional aggregate properties, e.g., fineness modulus, percent crushed fine and coarse aggregate, and their interactions. The work was accomplished in three phases: a literature review, extensive laboratory testing, and statistical analysis of test results. The literature review focused on the history and development of the current specification, laboratory methods of identifying critical mixtures, and the effects of other aggregate-related factors on critical mixtures. The laboratory testing involved three maximum aggregate sizes (19.0, 12.5, and 9.5 millimeters), three gradations (coarse, fine, and dense), and combinations of natural and manufactured coarse and fine aggregates. Specimens were compacted using the Superpave Gyratory Compactor (SGC), conventionally tested for bulk and maximum theoretical specific gravities and physically tested using the Nottingham Asphalt Tester (NAT) under a repeated load confined configuration to identify the transition state from sound to unsound. The statistical analysis involved using ANOVA and linear regression to examine the effects of identified aggregate factors on critical state transitions in asphalt paving mixtures and to develop predictive equations. The results clearly demonstrate that the volumetric conditions of an HMA mixture at the stable unstable threshold are influenced by a composite measure of the maximum aggregate size and gradation and by aggregate shape and texture. The currently defined VMA criterion, while significant, is seen to be insufficient by itself to correctly differentiate sound from unsound mixtures. Under current specifications, many otherwise sound mixtures are subject to rejection solely on the basis of failing to meet the VMA requirement. Based on the laboratory data and statistical analysis, a new paradigm to volumetric mix design is proposed that explicitly accounts for aggregate factors (gradation, shape, and texture).

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

Effects of erosion and deposition on particle size distribution of deposited farmland soils on the chinese loess plateau

Particle size distribution (PSD) in the soil profile is strongly related to erosion, deposition, and physical and chemical processes. Water cycling and plant growth are also affected by PSD. Material sedimented upstream of the dam constructions formed large areas of deposited farmland (DF) soils on the Chinese Loess Plateau (CLP), which has been the site of the most severe soil erosion in the world. Two DFs without tillage on the CLP were chosen to study the combined effect of erosion and check dams on PSD. Eighty-eight layers (each 10 cm thick) of filled deposited farmland (FDF) soils and 22 layers of silting deposited farmland (SDF) soils of each studied soil profile were collected and 932 soil samples were investigated using laser granulometry. The particle sizes were stratified in both DFs based on soil properties and erosion resistance. The obtained results of clay and silt fractions showed similar horizontal distribution, indicating parallel characteristics of erosion and deposition processes. Fine sand represented the largest fraction, suggesting the preferential detachment of this fraction. The most erodible range of particle sizes was 0.25-0.5 mm, followed by 0.2-0.25 mm in the studied soil profiles. The correlation between particle size and soil water contents tended to increase with increasing water contents in FDF. Due to the abundant shallow groundwater, the relationship between particle size and soil water content in SDF was lost. Further studies on PSD in the DF area are needed to enhance the conservation management of soil and water resources in this region.

Effects of polymer-coated multi-wall carbon nanotubes on mouse RAW 264.7 macrophages

Surface characteristics (area, chemical reactivity) play an important role in cell response to nanomaterials. The aim of this study was to evaluate the oxidative and inflammatory effects of multi−wall carbon nanotubes (MWCNT) uncoated (P0) or coated with carboxylic polyacid or polystyrene polybutadiene polymetacrylate of methyl polymers (P1 and P2 respectively) on murine macrophages (RAW 264.7 cell line). Carbon black nanoparticles (CB, diameter 95 nm) and crocidolite fibers (diameter: 80 nm, length: < 10 μm) were used as controls. Surface functional groups present on MWCNTs were analyzed by Knudsen flow reactor. The amount of acidic sites was P1> P0> P2, for basic sites was P0> P1>> P2 and for oxidizable sites was P0> P2> P1. In contact with cells, P2 formed smaller aggregates than P0 and P1, which were of similar size. Optical microscopy showed the formation of vacuoles after exposure only to P0, P1 and crocidolite. Incubation of cells with P0, P1 and crocidolite fibers induced a significant and similar decrease in metabolic activity, whereas P2 and CB had no effect. Cell number and membrane permeability were unmodified by incubation with the different particles. Incubation of macrophages with P0, P1 and crocidolite induced a dose− and time−dependent increase in mRNA expression of oxidative stress marker (HO−1, GPX1) and inflammatory mediators (TNF−a, MIP−2). No such responses were observed with P2 and CB. In conclusion, MWCNT coated with a carboxylic polyacid polymer exerted similar oxidative and inflammatory effects to uncoated MWCNT. By contrast, no such effects were observed with MWCNT coated with a polystyrene−based polymer. This kind of coating could be useful to decrease MWCNT toxicity.

Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers.

Topical ocular drug delivery has always been a challenge for pharmaceutical technology scientists. In the last two decades, many nano-systems have been studied to find ways to overcome the typical problems of topical ocular therapy, such as difficult corneal penetration and poor drug availability. In this study, methoxy poly(ethylene glycol)-hexylsubstituted poly(lactides) (MPEG-hexPLA) micelle formulations, which are promising nanocarriers for poorly water soluble drugs, were investigated for the delivery of Cyclosporin A (CsA) to the eye. As a new possible pharmaceutical excipient, the ocular compatibility of MPEG-hexPLA micelle formulations was evaluated. An in vitro biocompatibility assessment on human corneal epithelial cells was carried out using different tests. Cytotoxicity was studied by using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), and clonogenic tests and revealed that the CsA formulations and copolymer solutions were not toxic. After incubation with MPEG-hexPLA micelle formulations, the activation of caspase-dependent and -independent apoptosis as well as autophagy was evaluated using immunohistochemistry by analyzing the localization of four antibodies: (1) anti-caspase 3; (2) anti-apoptotic inducing factor (AIF); (3) anti-IL-Dnase II and (4) anti-microtubule-associated protein 1 light chain 3 (LC3). No apoptosis was induced when the cells were treated with the micelle solutions that were either unloaded or loaded with CsA. The ocular tolerance was assessed in vivo on rabbit eyes by Confocal Laser Scanning Ophthalmoscopy (CLSO), and very good tolerability was seen. The observed corneal surface was comparable to a control surface that was treated with a 0.9% NaCl solution. In conclusion, these results demonstrate that MPEG-hexPLA micelles are promising drug carriers for ocular diseases involving the activation of cytokines, such as dry eye syndrome and autoimmune uveitis, or for the prevention of corneal graft rejection.

Ecotoxicological approaches to assess the long-term effects of four anticancer drugs and metabolites on Daphnia pulex

The aquatic environment is exposed continuously and increasingly to chemical substances such as pharmaceuticals. These medical compounds are released into the environment after having being consumed and body-excreted by patients. Pharmaceutical residues are synthetic molecules that are not always removed by traditional sewage treatment processes and thus escape degradation. Among pharmaceuticals that escape sewage treatment plants (STPs), the anticancer drugs were measured in STP effluents and natural waters. In the aquatic environment, their long-term effects at low concentrations are sparsely known on non-target species. Tamoxifen is an anticancer drug that is widely prescribed worldwide for the prevention and treatment of hormone receptor-positive breast cancers. Two of its metabolites, i.e., endoxifen and 4-hydroxy- tamoxifen (4OHTam), have high pharmacological potency in vivo and such as tamoxifen, they are excreted via faeces by patients. Tamoxifen was measured in STP effluents and natural waters but, to the best of our knowledge, its metabolites concentrations in waters have never been reported. Imatinib is another and recent anticancer compound that targets specific tumour cells. This pharmaceutical is also body excreted and because of its increasing use in cancer treatment, imatinib may reach the natural water. The effects of tamoxifen and imatinib are unknown upon more than one generation of aquatic species. And the effects of 4OHTam, endoxifen have never been studied in ecotoxicology so far. The aims of this thesis were threefold. First, the sensitivity of D. pulex exposed to tamoxifen, 4OHTam, endoxifen or imatinib was assessed using ecotoxicological experiments. Ecotoxicology is the science that considers the toxic effects of natural or synthetic substances, such as pharmaceuticals, on organisms, populations, community and ecosystem. Acute and multigenerational (2-4 generations) tests were performed on daphnids considering several studied endpoints, such as immobilisation, size, reproduction, viability and intrinsic rate of natural increase. Additional prospective assays were designed to evaluate whether 1) low concentrations of tamoxifen and 4OHTam were able to induce toxic effects when used in combination, and 2) daphnids were able to recover when offspring were withdrawn from solutions carrying the pharmaceutical. Second, the stability of tamoxifen, 4OHTam and endoxifen in incubation medium was evaluated in solution exempted from daphnids. Because the nominal concentrations of tamoxifen, 4OHTam and endoxifen did not correspond to the measured, we provide a predictive method to estimate the concentrations of these chemicals during long-term ecotoxicological tests. Finally, changes in protein expressions were analysed in D. pulex exposed 2 or 7 seven days to tamoxifen using ecotoxicoproteomic experiments with a shot-gun approach inducing a peptide fractionation step. Our results show that tamoxifen, 4OHTam and endoxifen induced adverse effects in D. pulex at environmentally relevant concentrations. At very low concentrations, these molecules displayed unusual and teratogenic effects because morphological abnormalities were observed in offspring, such as thick and short antennas, curved spines, premature neonates and aborted eggs. Tamoxifen was the most toxic compound among the test chemicals, followed by 4OHTam, endoxifen and imatinib. Tamoxifen no-observed effect concentrations (NOECs) that were calculated for size, reproduction and intrinsic rate were below or in the range of the concentrations measured in natural waters, i.e., between 0.12 µg/L and 0.67 µg/L. For instance, the tamoxifen NOECs that were calculated for reproduction were between 0.67 and 0.72 µg/L, whereas the NOEC was < 0.15 µg/L when based on morphological abnormalities. The NOECs of 4OHTam were higher but still in the same order of magnitude as tamoxifen environmental concentrations, with a value of 1.48 µg/L. Endoxifen NOEC for the intrinsic rate of natural increase (r) and the reproduction were 0.4 and 4.3 µg/L, respectively. Daphnids that were withdrawn from tamoxifen and 4OHTam were not able to recover. Also, the reproduction of D. pulex was reduced when the treated animals were exposed to the combination of tamoxifen and 4OHTam while no effects were observed when these chemicals were tested individually at the same concentration. Among the anticancer drugs that were tested during this thesis, imatinib was the less toxic molecule towards D. pulex. No effects on size and reproduction were observed within two generations, except for the first whose reproduction decreased at the highest test concentration, i.e., 626 µg/L. Our results also underline the need to use measured or predicted concentrations instead of the nominal during aquatic experiments, particularly when lipophilic molecules are tested. Indeed, notable differences between nominal (i.e., theoretical) and measured concentrations were found with tamoxifen, 4OHTam and endoxifen at all test concentrations. A cost and time sustainable method was proposed to predict the test exposure levels of these chemicals during long-term experiments. This predictive method was efficient particularly for low concentrations, which corresponded to the test concentrations in multigenerational tests. In the ecotoxicoproteomic experiments a total of 3940 proteins were identified and quantified in D. pulex exposed to tamoxifen. These results are currently the largest dataset from D. pulex that is published and the results of proteomic analyses are available for the scientific community. Among these 3940 proteins, 189 were significantly different from controls. After protein annotation, we assumed that treated daphnids with tamoxifen had shifted cost-energy functions, such as reproduction, to maintain their basic metabolism necessary to survive. This metabolic cost hypothesis was supported by the presence of proteins involved in oxidative stress. Biomarkers for early detection of tamoxifen harmful effects on D. pulex were not discovered but the proteins of the vitellogenin-2 family (E9H8K5) and the ryanodine receptor (E9FTU9) are promising potential biomarkers because their expression was already modified after 2 days of treatment. In this thesis, the effects of tamoxifen, 4OHTam and endoxifen on daphnids raise questions about the potential impact of tamoxifen and 4OHTam in other aquatic ecosystems, and therefore, about metabolites in ecotoxicology. Because the NOECs were environmentally relevant, these results suggest that tamoxifen and 4OHTam may be interesting pharmaceuticals to consider in risk assessment. Our findings also emphasize the importance of performing long-term experiments and of considering multi-endpoints instead of the standard reproductive endpoint. Finally, we open the discussion about the importance to measure test exposures or not, during ecotoxicological studies. -- Les milieux aquatiques sont exposés continuellement à un nombre croissant de substances chimiques, notamment les médicaments issus de la médecine vétérinaire et humaine. Chez les patients, les substances administrées sont utilisées par le corps avant d'être éliminées par l'intermédiaire des excrétas dans le système d'eaux usées de la ville. Ces eaux rejoignent ensuite une station de traitement afin d'y éliminer les déchets. Dans le cas des molécules chimiques, il arrive que les processus de traitement d'eaux usées ne soient pas suffisamment efficaces et que ces molécules ne soient pas dégradées. Elles sont alors libérées dans le milieu aquatique avec les effluents de la station d'épuration. Une fois dans l'environnement, ces résidus de médicaments sont susceptibles d'induire des effets sur la faune et la flore aquatique, dont les conséquences à long terme et à faibles concentrations sont peu connues. Les anticancéreux sont une famille de médicaments qui peuvent échapper aux traitements des stations d'épuration et qui sont retrouvées dans le milieu aquatique naturel. Parmi ces substances, le tamoxifen est une molécule utilisée dans le monde entier pour prévenir et traiter les cancers hormonaux dépendant du sein, notamment. Une fois ingéré, le tamoxifen est transformé par le foie en métabolites dont deux d'entre eux, le 4-hydroxy-tamoxifen (4OHTam) et l'endoxifen, possèdent un affinité pour les récepteurs aux estrogènes et une efficacité sur les cellules tumorales supérieure au tamoxifen lui- même. Tout comme la molécule mère, ces métabolites sont principalement éliminés par l'intermédiaire des fèces. Le tamoxifen a déjà été mesuré dans les effluents de stations d'épuration et dans les eaux naturelles, mais aucune valeur n'a été reportée pour ses métabolites jusqu'à présent. Un autre anticancéreux, également éliminé par voie biliaire et susceptible d'atteindre l'environnement, est l'imatinib. Cette récente molécule a révolutionné le traitement et la survie des patients souffrant de leucémie myéloïde chronique et de tumeur stromales gastrointestinales. Les effets du tamoxifen et de l'imatinib sur plusieurs générations d'organismes aquatiques, tels que les microcrustacés Daphnia, sont inconnus et le 4OHTam et l'endoxifen n'ont même jamais été testés en écotoxicologie. Cette thèse s'est articulée autour de trois objectifs principaux. Premièrement, la sensibilité des D. pulex exposés au tamoxifen, 4OHTam, endoxifen et imatinib a été évaluée par l'intermédiaire de tests aigus et de tests sur deux à quatre générations. La mobilité, la taille, la reproduction, la viabilité et la croissance potentielle de la population ont été relevées au cours de ces expériences. Des tests supplémentaires, à but prospectifs, ont également été réalisés afin d'évaluer 1) la capacité de récupération des daphnies, lorsque leurs descendants ont été placés dans un milieu exempté de tamoxifen ou de 4OHTam, 2) les effets chez les daphnies exposées à une solution contenant de faibles concentration de tamoxifen et de 4OHTam mélangés. Le deuxième objectif a été d'évaluer la stabilité du tamoxifen, 4OHTam et endoxifen dilué dans le milieu des daphnies. Après analyses, les concentrations mesurées ne correspondaient pas aux concentrations nominales (c.-à-d., théoriques) et il a été nécessaire de développer une méthode efficace de prédiction des niveaux d'exposition lors de tests de longue durée réalisés avec ces trois molécules. Finalement, des changements dans l'expression des protéines chez des daphnies exposées au tamoxifen ont été investigués par l'intermédiaire d'expériences écotoxicoprotéomiques avec une approche dite de shot-gun avec une étape de fractionnement des protéines. Les résultats obtenus dans cette thèse montrent que le tamoxifen, le 4OHTam et l'endoxifen induisent des effets indésirables chez les daphnies à des niveaux d'exposition proches ou identiques aux concentrations du tamoxifen mesurées dans l'environnement, c'est-à-dire 0.12 et 0.67 µg/L de tamoxifen. Ces molécules ont induit des effets inhabituels tels que la production de : nouveau-nés anormaux, avec des antennes et des queues déformées, des prématurés et des oeufs avortés. Le tamoxifen fut la molécule la plus toxique pour les D. pulex suivie du 4OHTam, de l'endoxifen et enfin de l'imatinib. Lors des expériences sur plusieurs générations, les concentrations n'ayant statistiquement pas d'effet (c.à.d. NOEC en anglais) sur la taille, la reproduction et la croissance intrinsèque de la population étaient du même ordre de grandeur que les concentrations environnementales du tamoxifen. Par exemple, les NOECs du tamoxifen calculées pour la reproduction étaient de 0.67 et 0.72 µg/L, tandis que celle calculée sur la base des anomalies chez les nouveau-nés était < 0.15 µg/L. Les NOECs du 4OHTam se situaient entre 0.16 et 1.48 µg/L et celles de l'endoxifen pour la croissance intrinsèque de la population, ainsi que pour la reproduction, étaient de 0.4 et 4.3 µg/L, respectivement. Dans l'expérience basée sur la récupération des daphnies, la taille et la reproduction ont diminué bien que la descendance fût placée dans un milieu sans substances chimiques. Les daphnies exposées au mélange de tamoxifen et de 4OHTam ont produit moins de nouveau-nés que les contrôles, alors que ces concentrations n'ont pas induit d'effets lorsque testées individuellement. Finalement, l'imatinib n'a pas montré d'effets sur les deux générations testées. Seule la première génération exposée à la plus haute concentration (626 µg/L) a montré une diminution de la reproduction. Les résultats obtenus lors de l'évaluation de la stabilité du tamoxifen, 4OHTam et endoxifen dans le milieu des daphnies ont souligné l'importance d'utiliser des concentrations mesurées ou prédites en écotoxicologie. En effet, des différences notables entre concentrations nominales et mesurées ont été observées à toutes les concentrations et l'hypothèse d'un phénomène d'adsorption sur le verre des récipients a été posée. De ce fait, il a été nécessaire d'élaborer une méthode prédictive efficace et acceptable, en terme de temps et de coûts. Une régression polynomiale basée sur des concentrations mesurées et nominales a permis de prédire avec efficacité les faibles niveaux d'exposition utilisés lors d'expériences écotoxicologiques à long terme, sur plusieurs générations. Suite aux expériences d'écotoxicoprotéomiques, un total de 3940 protéines ont été identifiées et quantifiées chez des daphnies exposées au tamoxifen. Ce nombre est actuellement la plus large série de données publiées et mises à disposition pour la communauté scientifique. Parmi ces protéines, 189 sont significatives et possiblement reliées à des processus de reproduction et de stress. Sur cette base, nous avons émis l'hypothèse que les individus subissant un stress, lié à l'exposition au tamoxifen, ont utilisé leur énergie de base pour favoriser leur survie plutôt que la reproduction. Enfin, la détermination de bio-marqueurs exprimant des dommages précoces des daphnies exposées au tamoxifen n'a pas abouti en tant que telle, mais des protéines prometteuses, telle que la famille de viellogenin-2 (E9H8K5) et le récepteur à la ryanodine (E9FTU9), ont été exprimées après deux jours d'exposition déjà. Ces protéines pourraient faire l'objet d'investigations écotoxicoprotéomiques futures. Les résultats de cette thèse posent certaines questions quant au risque du tamoxifen, du 4OHTam et de l'endoxifen sur la faune et la flore aquatique et plus particulièrement sur les anticancéreux présents dans l'environnement. Les effets toxiques de ces molécules ont été observés à des concentrations environnementales et sur plusieurs générations. La question de considérer les métabolites, et ainsi les pro-médicaments, en écotoxicologie est soulevée, notamment parce que ces molécules peuvent être plus actives et efficaces que la molécule mère. Les expériences chroniques, sur plusieurs générations sont également à favoriser car elles offrent un meilleur reflet de la réalité environnementale que des essais aigus ou d'une génération. L'utilisation de la protéomique permet d'agrandir les connaissances sur les effets des médicaments à un niveau inférieur de l'organisation biologique et ainsi, de mieux comprendre de potentiels mécanismes d'action ou de déterminer de potentiels biomarqueurs. Finalement, il semble important de discuter de l'opportunité de mesurer les concentrations qui sont testées en écotoxicologie afin de ne pas sous-estimer le risque pour la faune et la flore aquatique.

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence.

INTRODUCTION: Psychiatric disorders are among the leading causes of disability in Western societies. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs during pregnancy and the postpartum period. Over the last decade, conflicting findings regarding the safety of SSRI drugs during pregnancy and lactation have questioned whether such treatments should be used during this period. AREAS COVERED: We discuss the main criteria that should be considered in the risk/benefit assessment of SSRI treatment in pregnant and/or breastfeeding patients (i.e., risks associated with SSRI use and with untreated depression as well as therapeutic benefits of SSRI and some alternative treatment strategies). For each criterion, available evidence has been synthesized and stratified by methodological quality as well as discussed for clinical impact. EXPERT OPINION: Currently, it is impossible for most of the evaluated outcomes to distinguish between the effects related to the mother's underlying disease and those inherent to SSRI treatment. In women suffering from major depression and responding to a pharmacological treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal-infant bonding. The choice of the right drug depends above all on individual patient characteristics such as prior treatment response, diagnoses and comorbid conditions.

Finite-size effects in nonequilibrium correlation functions

We have shown that finite-size effects in the correlation functions away from equilibrium may be introduced through dimensionless numbers: the Nusselt numbers, accounting for both the nature of the boundaries and the size of the system. From an analysis based on fluctuating hydrodynamics, we conclude that the mean-square fluctuations satisfy scaling laws, since they depend only on the dimensionless numbers in addition to reduced variables. We focus on the case of diffusion modes and describe some physical situations in which finite-size effects may be relevant.

Relation for the nonequilibrium population of the interface states: effects on the bias dependence of the ideality factors

By an analysis of the exchange of carriers through a semiconductor junction, a general relationship for the nonequilibrium population of the interface states in Schottky barrier diodes has been derived. Based on this relationship, an analytical expression for the ideality factor valid in the whole range of applied bias has been given. This quantity exhibits two different behaviours depending on the value of the applied bias with respect to a critical voltage. This voltage, which depends on the properties of the interfacial layer, constitutes a new parameter to complete the characterization of these junctions. A simple interpretation of the different behaviours of the ideality factor has been given in terms of the nonequilibrium charging properties of interface states, which in turn explains why apparently different approaches have given rise to similar results. Finally, the relevance of our results has been considered on the determination of the density of interface states from nonideal current-voltage characteristics and in the evaluation of the effects of the interfacial layer thickness in metal-insulator-semiconductor tunnelling diodes.