Geochemical compositions of Neogene phosphatic brachiopods: Implications for ancient environmental and marine conditions

Isotopic and trace element compositions of Miocene and Pliocene phosphatic brachiopods (Lingulidae and Discinidae) from southern North Sea, the Central Paratethys and the Atlantic coast of Europe were investigated in order to trace past environmental conditions and marine connections between the northern boreal and the southern subtropical-tropical marine basins. The North Sea genus Glottidia yielded low epsilon(Nd) and high delta O-18(PO4) values through the Mio-Pliocene indicating cold habitat temperature where the local seawater was dominated by the Atlantic Ocean. In contrast, the Middle Miocene Lingulidae and Discinidae of the Paratethys inhabited warm subtropical seawater with the possible influence of the Indian Ocean via the Mediterranean, as supported by their average epsilon(Nd) value of -8.3. The combined geochemical data support a thermal and marine separation of the Paratethys from the North Sea with no direct connection or major exchange of water from the Miocene onwards. The temperature in the Paratethys was very similar to that inferred from brachiopods from the Middle Miocene of western France, but the seawater epsilon(Nd) value here is identical to that of contemporaneous Atlantic Ocean. A Late Miocene lingulid brachiopod from southern Portugal has a high delta O-18(PO4), similar to the specimens investigated from the North Sea, reflecting either a deep water habitat or formation after the onset of major global cooling that resulted in an increased delta O-18 value of seawater. The epsilon(Nd) value of -8.4 for this site is compatible with an influence of Mediterranean outflow. (C) 2012 Elsevier B.V. All rights reserved.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Environmental data mining and modeling based on machine learning algorithms and geostatistics

The paper presents some contemporary approaches to spatial environmental data analysis. The main topics are concentrated on the decision-oriented problems of environmental spatial data mining and modeling: valorization and representativity of data with the help of exploratory data analysis, spatial predictions, probabilistic and risk mapping, development and application of conditional stochastic simulation models. The innovative part of the paper presents integrated/hybrid model-machine learning (ML) residuals sequential simulations-MLRSS. The models are based on multilayer perceptron and support vector regression ML algorithms used for modeling long-range spatial trends and sequential simulations of the residuals. NIL algorithms deliver non-linear solution for the spatial non-stationary problems, which are difficult for geostatistical approach. Geostatistical tools (variography) are used to characterize performance of ML algorithms, by analyzing quality and quantity of the spatially structured information extracted from data with ML algorithms. Sequential simulations provide efficient assessment of uncertainty and spatial variability. Case study from the Chernobyl fallouts illustrates the performance of the proposed model. It is shown that probability mapping, provided by the combination of ML data driven and geostatistical model based approaches, can be efficiently used in decision-making process. (C) 2003 Elsevier Ltd. All rights reserved.

Effect of spatial processes on the evolution of ecological niches and dispersal in metacommunity systems

RésuméLa coexistence de nombreuses espèces différentes a de tout temps intrigué les biologistes. La diversité et la composition des communautés sont influencées par les perturbations et l'hétérogénéité des conditions environnementales. Bien que dans la nature la distribution spatiale des conditions environnementales soit généralement autocorrélée, cet aspect est rarement pris en compte dans les modèles étudiant la coexistence des espèces. Dans ce travail, nous avons donc abordé, à l'aide de simulations numériques, la coexistence des espèces ainsi que leurs caractéristiques au sein d'un environnement autocorrélé.Afin de prendre en compte cet élément spatial, nous avons développé un modèle de métacommunauté (un ensemble de communautés reliées par la dispersion des espèces) spatialement explicite. Dans ce modèle, les espèces sont en compétition les unes avec les autres pour s'établir dans un nombre de places limité, dans un environnement hétérogène. Les espèces sont caractérisées par six traits: optimum de niche, largeur de niche, capacité de dispersion, compétitivité, investissement dans la reproduction et taux de survie. Nous nous sommes particulièrement intéressés à l'influence de l'autocorrélation spatiale et des perturbations sur la diversité des espèces et sur les traits favorisés dans la métacommunauté. Nous avons montré que l'autocorrélation spatiale peut avoir des effets antagonistes sur la diversité, en fonction du taux de perturbations considéré. L'influence de l'autocorrélation spatiale sur la capacité de dispersion moyenne dans la métacommunauté dépend également des taux de perturbations et survie. Nos résultats ont aussi révélé que de nombreuses espèces avec différents degrés de spécialisation (i.e. différentes largeurs de niche) peuvent coexister. Toutefois, les espèces spécialistes sont favorisées en absence de perturbations et quand la dispersion est illimitée. A l'opposé, un taux élevé de perturbations sélectionne des espèces plus généralistes, associées avec une faible compétitivité.L'autocorrélation spatiale de l'environnement, en interaction avec l'intensité des perturbations, influence donc de manière considérable la coexistence ainsi que les caractéristiques des espèces. Ces caractéristiques sont à leur tour souvent impliquées dans d'importants processus, comme le fonctionnement des écosystèmes, la capacité des espèces à réagir aux invasions, à la fragmentation de l'habitat ou aux changements climatiques. Ce travail a permis une meilleure compréhension des mécanismes responsables de la coexistence et des caractéristiques des espèces, ce qui est crucial afin de prédire le devenir des communautés naturelles dans un environnement changeant.AbstractUnderstanding how so many different species can coexist in nature is a fundamental and long-standing question in ecology. Community diversity and composition are known to be influenced by heterogeneity in environmental conditions and disturbance. Though in nature the spatial distribution of environmental conditions is frequently autocorrelated, this aspect is seldom considered in models investigating species coexistence. In this work, we thus addressed several questions pertaining to species coexistence and composition in spatially autocorrelated environments, with a numerical simulations approach.To take into account this spatial aspect, we developed a spatially explicit model of metacommunity (a set of communities linked by dispersal of species). In this model, species are trophically equivalent, and compete for space in a heterogeneous environment. Species are characterized by six life-history traits: niche optimum, niche breadth, dispersal, competitiveness, reproductive investment and survival rate. We were particularly interested in the influence of environmental spatial autocorrelation and disturbance on species diversity and on the traits of the species favoured in the metacommunity. We showed that spatial autocorrelation can have antagonistic effects on diversity depending on disturbance rate. Similarly, spatial autocorrelation interacted with disturbance rate and survival rate to shape the mean dispersal ability observed in the metacommunity. Our results also revealed that many species with various degrees of specialization (i.e. different niche breadths) can coexist together. However specialist species were favoured in the absence of disturbance, and when dispersal was unlimited. In contrast, high disturbance rate selected for more generalist species, associated with low competitive ability.The spatial structure of the environment, together with disturbance and species traits, thus strongly impacts species diversity and, more importantly, species composition. Species composition is known to affect several important metacommunity properties such as ecosystem functioning, resistance and reaction to invasion, to habitat fragmentation and to climate changes. This work allowed a better understanding of the mechanisms responsible for species composition, which is of crucial importance to predict the fate of natural metacommunities in changing environments

Identification of in vitro HSC fate regulators by differential lipid raft clustering.

Most hematopoietic stem cells (HSC) in the bone marrow reside in a quiescent state and occasionally enter the cell cycle upon cytokine-induced activation. Although the mechanisms regulating HSC quiescence and activation remain poorly defined, recent studies have revealed a role of lipid raft clustering (LRC) in HSC activation. Here, we tested the hypothesis that changes in lipid raft distribution could serve as an indicator of the quiescent and activated state of HSCs in response to putative niche signals. A semi-automated image analysis tool was developed to map the presence or absence of lipid raft clusters in live HSCs cultured for just one hour in serum-free medium supplemented with stem cell factor (SCF). By screening the ability of 19 protein candidates to alter lipid raft dynamics, we identified six factors that induced either a marked decrease (Wnt5a, Wnt3a and Osteopontin) or increase (IL3, IL6 and VEGF) in LRC. Cell cycle kinetics of single HSCs exposed to these factors revealed a correlation of LRC dynamics and proliferation kinetics: factors that decreased LRC slowed down cell cycle kinetics, while factors that increased LRC led to faster and more synchronous cycling. The possibility of identifying, by LRC analysis at very early time points, whether a stem cell is activated and possibly committed upon exposure to a signaling cue of interest could open up new avenues for large-scale screening efforts.

Environmental and T cell-intrinsic factors limit the expansion of neonatal follicular T helper cells but may be circumvented by specific adjuvants.

Follicular Th (T(FH)) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5(high)PD-1(high) CD4(+) T(FH) cells that exhibit T(FH) features (including Batf, Bcl6, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal T(FH) cells fail to expand and to acquire a full-blown GC T(FH) phenotype, as reflected by a higher ratio of GC T(FH)/non-GC CD4(+) T cells in immunized adults than neonates (3.8 × 10(-3) versus 2.2 × 10(-3), p = 0.01). Following the adoptive transfer of naive adult OT-II CD4(+) T cells, OT-II T(FH) cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4(+) OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell-intrinsic factors. Postponing immunization to later in life increases the number of T(FH) cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC T(FH) and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the T(FH) cell development limits early life GC responses and that adjuvants/delivery systems supporting T(FH) differentiation may restore adultlike early life GC B cell responses.

Micronucleus test on Triturus carnifex as a tool for environmental biomonitoring.

The amphibian micronucleus test has been widely used during the last 30 years to test the genotoxic properties of several chemicals and as a tool for ecogenotoxic monitoring. The vast majority of these studies were performed on peripheral blood of urodelan larvae and anuran tadpoles and to a lesser extent adults were also used. In this study, we developed protocols for measuring micronuclei in adult shed skin cells and larval gill cells of the Italian crested newt (Triturus carnifex). Amphibians were collected from ponds in two protected areas in Italy that differed in their radon content. Twenty-three adult newts and 31 larvae were captured from the radon-rich pond, while 20 adults and 27 larvae were taken from the radon-free site. The animals were brought to the laboratory and the micronucleus test was performed on peripheral blood and shed skins taken from the adults and on larval gills. Samples from the radon-rich site showed micronucleus frequencies higher than those from the radon-free site and the difference was statistically significant in gill cells (P < 0.00001). Moreover, the larval gills seem to be more sensitive than the adult tissues. This method represents an easy (and noninvasive in the case of the shed skin) application of the micronucleus assay that can be useful for environmental studies in situ. Environ. Mol. Mutagen. 56:412-417, 2015. © 2014 Wiley Periodicals, Inc.

Sphingomonas wittichii RW1 gene reporters interrogating the dibenzofuran metabolic network highlight conditions for early successful development in contaminated microcosms.

In order to better understand the fate and activity of bacteria introduced into contaminated material for the purpose of enhancing biodegradation rates, we constructed Sphingomonas wittichii RW1 variants with gene reporters interrogating dibenzofuran metabolic activity. Three potential promoters from the dibenzofuran metabolic network were selected and fused to the gene for enhanced green fluorescent protein (EGFP). The stability of the resulting genetic constructions in RW1 was examined, with plasmids based on the broad-host range vector pME6012 being the most reliable. One of the selected promoters, upstream of the gene Swit_4925 for a putative 2-hydroxy-2,4-pentadienoate hydratase, was inducible by growth on dibenzofuran. Sphingomonas wittichii RW1 equipped with the Swit_4925 promoter egfp fusion grew in a variety of non-sterile sandy microcosms contaminated with dibenzofuran and material from a former gasification site. The strain also grew in microcosms without added dibenzofuran but to a very limited extent, and EGFP expression indicated the formation of consistent small subpopulations of cells with an active inferred dibenzofuran metabolic network. Evidence was obtained for competition for dibenzofuran metabolites scavenged by resident bacteria in the gasification site material, which resulted in a more rapid decline of the RW1 population. Our results show the importance of low inoculation densities in order to observe the population development of the introduced bacteria and further illustrate that the limited availability of unique carbon substrate may be the most important factor impinging growth.

Morph-specific genetic and environmental variation in innate and acquired immune response in a color polymorphic raptor.

Genetic color polymorphism is widespread in nature. There is an increasing interest in understanding the adaptive value of heritable color variation and trade-off resolution by differently colored individuals. Melanin-based pigmentation is often associated with variation in many different life history traits. These associations have recently been suggested to be the outcome of pleiotropic effects of the melanocortin system. Although pharmacological research supports that MC1R, a gene with a major role in vertebrate pigmentation, has important immunomodulatory effects, evidence regarding pleiotropy at MC1R in natural populations is still under debate. We experimentally assessed whether MC1R-based pigmentation covaries with both inflammatory and humoral immune responses in the color polymorphic Eleonora's falcon. By means of a cross-fostering experiment, we disentangled potential genetic effects from environmental effects on the covariation between coloration and immunity. Variation in both immune responses was primarily due to genetic factors via the nestlings' MC1R-related color genotype/phenotype, although environmental effects via the color morph of the foster father also had an influence. Overall, dark nestlings had lower immune responses than pale ones. The effect of the color morph of the foster father was also high, but in the opposite direction, and nestlings raised by dark eumelanic foster fathers had higher immune responses than those raised by pale foster fathers. Although we cannot completely discard alternative explanations, our results suggest that MC1R might influence immunity in this species. Morph-specific variation in immunity as well as pathogen pressure may therefore contribute to the long-term maintenance of genetic color polymorphism in natural populations.

How environmental sounds become meaningful

The term "sound object" describes an auditory experience that is associated with an acoustic event produced by a sound source. In natural settings, a sound produced by a living being or an object provides information about the identity and the location of the sound source. Sound's identity is orocessed alono the ventral "What" pathway which consists of regions within the superior and middle temporal cortices as well as the inferior frontal gyrus. This work concerns the creation of individual auditory object representations in narrow semantic categories and their plasticity using electrical imaging. Discrimination of sounds from broad category has been shown to occur along a temporal hierarchy and in different brain regions along the ventral "What" pathway. However, sounds belonging to the same semantic category, such as faces or voices, were shown to be discriminated in specific brain areas and are thought to represent a special class of stimuli. I have investigated how cortical representations of a narrow category, here birdsongs, is modulated by training novices to recognized songs of individual bird species. Dynamic analysis of distributed source estimations revealed differential sound object representations within the auditory ventral "What" pathway as a function of the level of expertise newly acquired. Correct recognition of trained items induces a sharpening within a left-lateralized semantic network starting around 200ms, whereas untrained items' processing occurs later in lower-level and memory-related regions. With another category of sounds belonging to the same category, here heartbeats, I investigated the cortical representations of correct and incorrect recognition of sounds. Source estimations revealed differential representations partially overlapping with regions involved in the semantic network that is activated when participants became experts in the task. Incorrect recognition also induces a higher activation when compared to correct recognition in regions processing lower-level features. The discrimination of heartbeat sounds is a difficult task and requires a continuous listening. I investigated whether the repetition effects are modulated by participants' behavioral performance. Dynamic source estimations revealed repetition suppression in areas located outside of the semantic network. Therefore, individual environmental sounds become meaningful with training. Their representations mainly involve a left-lateralized network of brain regions that are tuned with expertise, as well as other brain areas, not related to semantic processing, and occurring in early stages of semantic processing. -- Le terme objet sonore" décrit une expérience auditive associée à un événement acoustique produit par une source sonore. Dans l'environnement, un son produit par un être vivant ou un objet fournit des informations concernant l'identité et la localisation de la source sonore. Les informations concernant l'identité d'un son sont traitée le long de la voie ventrale di "Quoi". Cette voie est composée de regions situées dans le cortex temporal et frontal. L'objet de ce travail est d'étudier quels sont les neuro-mecanismes impliqués dans la représentation de nouveaux objets sonores appartenant à une meme catégorie sémantique ainsi que les phénomènes de plasticité à l'aide de l'imagerie électrique. Il a été montré que la discrimination de sons appartenant à différentes catégories sémantiques survient dans différentes aires situées le long la voie «Quoi» et suit une hiérarchie temporelle II a également été montré que la discrimination de sons appartenant à la même catégorie sémantique tels que les visages ou les voix, survient dans des aires spécifiques et représenteraient des stimuli particuliers. J'ai étudié comment les représentations corticales de sons appartenant à une même catégorie sémantique, dans ce cas des chants d'oiseaux, sont modifiées suite à un entraînement Pour ce faire, des sujets novices ont été entraînés à reconnaître des chants d'oiseaux spécifiques L'analyse des estimations des sources neuronales au cours du temps a montré que les representations des objets sonores activent de manière différente des régions situées le long de la vo,e ventrale en fonction du niveau d'expertise acquis grâce à l'entraînement. La reconnaissance des chants pour lesquels les sujets ont été entraînés implique un réseau sémantique principalement situé dans l'hémisphère gauche activé autour de 200ms. Au contraire, la reconnaissance des chants pour lesquels les sujets n'ont pas été entraînés survient plus tardivement dans des régions de plus bas niveau. J'ai ensuite étudié les mécanismes impliqués dans la reconnaissance et non reconnaissance de sons appartenant à une autre catégorie, .es battements de coeur. L'analyse des sources neuronales a montre que certaines régions du réseau sémantique lié à l'expertise acquise sont recrutées de maniere différente en fonction de la reconnaissance ou non reconnaissance du son La non reconnaissance des sons recrute des régions de plus bas niveau. La discrimination des bruits cardiaques est une tâche difficile et nécessite une écoute continue du son. J'ai étudié l'influence des réponses comportementales sur les effets de répétitions. L'analyse des sources neuronales a montré que la reconnaissance ou non reconnaissance des sons induisent des effets de repétition différents dans des régions situées en dehors des aires du réseau sémantique. Ainsi, les sons acquièrent un sens grâce à l'entraînement. Leur représentation corticale implique principalement un réseau d'aires cérébrales situé dans l'hémisphère gauche, dont l'activité est optimisée avec l'acquisition d'un certain niveau d'expertise, ainsi que d'autres régions qui ne sont pas liée au traitement de l'information sémantique. L'activité de ce réseau sémantique survient plus rapidemement que la prédiction par le modèle de la hiérarchie temporelle.